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Fertility/Reproductive Health Online Abstracts Library
The CHE-Fertility Online Abstracts Library is a representative sample of the peer-reviewed scientific literature related to fertility, reproductive health and the environment. Articles and study synopses/nontechnical summaries continue to be added. Read about what the library includes »
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Author(s). Title. Journal. Year Month;Volume(Issue):Pages.
Study Synopsis: Thyroid hormone is essential to human growth and brain development and plays an important role in reproductive system function. This paper reviews the evidence for thyroid hormone disruption by environmental chemicals. It concludes that despite the complications due to human exposure to a vast mixture of chemicals and the important intra-individual variation in thyroid hormone levels, there is reasonable evidence that polychlorinated biphenyls (PCBs) have thyroid-disrupting effects and that there is emerging evidence that phthalates, bisphenol A, brominated flame retardants and perfluorinated chemicals may also impact thyroid hormone levels and function.
Scientific abstract:
In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert thyroid effects through a variety of mechanisms of action, and some animal experiments and in vitro studies have focused on elucidating the mode of action of specific chemical compounds. Long-term human studies on effects of environmental chemicals on thyroid related outcomes such as growth and development are still lacking. The human exposure scenario with life long exposure to a vast mixture of chemicals in low doses and the large physiological variation in thyroid hormone levels between individuals render human studies very difficult. However, there is now reasonably firm evidence that PCBs have thyroid-disrupting effects, and there is emerging evidence that also phthalates, bisphenol A, brominated flame retardants and perfluorinated chemicals may have thyroid disrupting properties.
The study objective was to determine the relation of prenatal smoking exposure to the use of psychotropic medication up to young adulthood by using population-based longitudinal register data consisting of all singletons born in Finland from 1987 to 1989 (n = 175,869). Information on maternal smoking was assessed during antenatal care and received from the Finnish Medical Birth Register. Information on the children's psychotropic medication (19942007) was received from the Drug Prescription Register, and the children's psychiatric diagnoses related to outpatient (19982007) and inpatient (19872007) care were derived from the Finnish Hospital Discharge Register. A total of 15.3% (n = 26,083) of the children were exposed to prenatal smoking. The incidence of psychotropic medication use was 8.3% in unexposed children, 11.3% in children exposed to <10 cigarettes per day (adjusted odds ratio = 1.36, 95% confidence interval: 1.29, 1.43), and 13.6% in children exposed to >10 cigarettes per day (odds ratio = 1.63, 95% confidence interval: 1.53, 1.74). The exposure was significantly associated with the risk for all medication use and for both single- and multiple-drug consumption even after adjustment (e.g., mothers severe psychiatric illnesses). These findings show that exposure to smoking during pregnancy is linked to both mild and severe psychiatric morbidity.
Objectives: Exposure to high concentrations of persistent organochlorines may cause fetal toxicity, but the evidence at low exposure levels is limited. Large studies with substantial exposure contrasts and appropriate exposure assessment are warranted. Within the framework of the EU ENRIECO and EU OBELIX projects, we examined the hypothesis that polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) adversely affects birth weight. Methods: We used maternal and cord blood and breast milk samples in 7,990 women enrolled in 15 study populations from 12 European birth cohorts from 1990-2008. Using identical variable definitions, we performed for each cohort linear regression of birth weight on estimates of cord serum concentration of PCB 153 and p,p'-DDE adjusted for gestational age and a priori selected covariates. We obtained summary estimates by meta-analysis and performed analyses of interactions. (range of cohort medians 20-484) and that of p,p'-DDE was 528 ng/L (range of cohort medians 50-1208). Birth weight decreased with increasing cord serum concentration of PCB 153 after adjustment for potential confounders in 12 of 15 study populations. The meta-analysis including all cohorts indicated a birth weight decline of 150 g (95% CI -250, -50) per 1-microg/L increase in PCB 153, an exposure contrast that is close to the range of exposuress across the cohorts. A 1-microg/L increase in p,p'-DDE was associated with a 7 g decrease in birth weight (95% CI -18, 4 g). Conclusions: The findings suggest that low-level exposure to PCB (or correlated exposures) impairs fetal growth, while p,p'-DDE exposure does not. The study adds to mounting evidence that low-level exposure to PCBs is inversely associated with fetal growth.
Abdallah MA, Harrad S. Tetrabromobisphenol-A, hexabromocyclododecane and its degradation products in UK human milk: relationship to external exposure. Environ Int. 2011 Feb;37(2):443-8.
Tetrabromobisphenol-A (TBBP-A), hexabromocyclododecane (HBCD) and its degradation products were determined in 34 human milk samples from Birmingham, UK. TBBP-A was detected in 36% of samples (average=0.06 ng g(-1) lw), with HBCDs detected in all samples (average SigmaHBCDs=5.95 ng g(-1) lw). alpha-HBCD comprised 62-95% SigmaHBCDs while beta- and gamma-HBCD constituted 2-18% and 3-33% respectively. Enantioselective enrichment of (-)-alpha-HBCD (average enantiomer fraction=0.29) was observed indicating potential enantioselectivity associated with HBCD absorption, metabolism and/or excretion. The degradation products pentabromocyclododecenes (average=0.04 ng g(-1) lw; n=9) and tetrabromocyclododecadienes (average=0.15 ng g(-1) lw; n=25) were detected for the first time in human tissues. Average exposures of a nursing infant to SigmaHBCDs and TBBP-A (35 and 1 ng kg(-1) bw day(-1) respectively) via breast milk exceeded upper-bound dietary intakes of both UK adults and toddlers. Using a simple pharmacokinetic model, intakes of UK adults via inhalation, diet and dust ingestion were converted to predicted body burdens. Predictions compared well with those observed for HBCDs but observed body burdens of TBBP-A exceeded predictions. This may indicate the human half-life of TBBP-A is greater than observed previously, that intakes may be underestimated, or that concentrations reported here reflect recent elevated episodic exposure.
Abdelouahab N, Ainmelk Y, Takser L. Polybrominated diphenyl ethers and sperm quality. Reprod Toxicol. 2011 May;31(4):546-50.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. The objective of this study was to evaluate whether exposure to PBDEs, structurally similar polybrominated biphenyls (PCBs) and dichlorodiphenyl dichloroethylene (DDE, the breakdown product of the insecticide DDT), was related with semen quality and thyroid hormone levels in humans. Researchers measured the levels of PBDEs, PCBs and DDE in the blood of 52 men recruited in a fertility clinic. Men with higher blood levels of the PBDE congeners BDE-47 and BDE-100 had reduced sperm mobility and those with higher levels of BDE-47, BDE-99 and DDE had lower levels of the thyroid hormone thyroxine (T4). Those with higher blood concentrations of total PCBs had higher T4 levels. These results suggest that blood PBDE levels may be related to reduced semen qualilty and that PBDEs, DDE and PCBs may be related with alteration in thyroid hormone blood concentrations.
Scientific abstract:
BACKGROUND: Polybrominated diphenyl ethers are known to be endocrine disruptors and may affect male reproduction. This exploratory study investigated semen parameters and serum thyroid hormones in relation to serum PBDE, PCBs and p-p' DDE in adult men. METHODS: Fifty-two men were recruited in a fertility clinic. Semen counts were done for each participant. Serum thyroid hormone and PBDE, PCB and p-p' DDE levels were measured. Sociodemographic questionnaire were administered to each participant and all medical data were obtained from medical record. RESULTS: Semen mobility was negatively related to BDE-47, BDE-100 and SigmaBDE. No relations were observed with other semen parameters. Thyroxin levels were negatively associated to serum BDE-47, BDE-99, SigmaBDE and p-p' DDE and positively related to SigmaPCB. No relations were observed between T3, TSH and any of the chemicals measured. CONCLUSION: These findings increased the evidence that PBDE may interfere with semen quality and thyroid status in general population.
Alonso-Magdalena P, Quesada I, Nadal A. Endocrine disruptors in the etiology of type 2 diabetes mellitus. Nat Rev Endocrinol. 2011 Jun;7(6):346-53.
Study Synopsis: This paper reviews the evidence for the role of endocrine-disrupting chemicals (EDCs) such as dioxins, pesticides and bisphenol A (BPA) in type 2 diabetes. Authors report that many EDCs act as estrogens in insulin-sensitive tissues and in beta cells, generating a pregnancy-like metabolic state characterized by insulin resistance and hyperinsulinemia. Exposure to EDCs has been shown to produce insulin resistance and other metabolic alterations in adult mice, to alter glucose metabolism in pregnant mice, and to interfere with glucose homeostasis and endocrine pancreatic function in offspring. Although authors believe that more experimental work is necessary, they indicate that current evidence suggest that exposure to EDCs should be considered a risk factor in the etiology of type 2 diabetes mellitus and other diseases related to insulin resistance.
Scientific abstract:
The etiology of type 2 diabetes mellitus involves the induction of insulin resistance along with the disruption of pancreatic beta-cell function and the loss of beta-cell mass. In addition to a genetic predisposition, lifestyle factors seem to have an important role. Epidemiological studies indicate that the increased presence of endocrine disrupting chemicals (EDCs) in the environment may also play an important part in the incidence of metabolic diseases. Widespread EDCs, such as dioxins, pesticides and bisphenol A, cause insulin resistance and alter beta-cell function in animal models. These EDCs are present in human blood and can accumulate in and be released from adipocytes. After binding to cellular receptors and other targets, EDCs either imitate or block hormonal responses. Many of them act as estrogens in insulin-sensitive tissues and in beta cells, generating a pregnancy-like metabolic state characterized by insulin resistance and hyperinsulinemia. Adult exposure in mice produces insulin resistance and other metabolic alterations; in addition, during pregnancy, EDCs alter glucose metabolism in female mice, as well as glucose homeostasis and endocrine pancreatic function in offspring. Although more experimental work is necessary, evidence already exists to consider exposure to EDCs as a risk factor in the etiology of type 2 diabetes mellitus and other diseases related to insulin resistance.
Love Canal, located in Niagara Falls, NY, and among the earliest and most significant hazardous waste sites in the United States, first came to public attention in 1978. In this study, researchers evaluated 1,799 live births from 1960 through 1996 to 980 women who formerly lived in the Love Canal Emergency Declaration Area and were of reproductive age sometime during that time period. Using Upstate New York and Niagara County as external comparison populations, standardized incidence ratios with 95% confidence intervals were calculated for low birth weight, preterm birth, small for gestational age, and congenital malformations, and unadjusted proportions of male to female births were calculated. Internal comparisons among the infants were also performed according to several measures of potential exposure using generalized estimating equations. The results indicated a statistically significant elevated risk of preterm birth among children born on the Love Canal prior to the time of evacuation and relocation of residents from the Emergency Declaration Area, using Upstate New York as the standard population (standardized incidence ratio=1.40; 95% confidence interval: 1.01, 1.90). Additionally, the ratio of male to female births was lower for children conceived in the Emergency Declaration Area (sex ratio=0.94 versus sex ratio=1.05 in the standard population) and the frequency of congenital malformations was greater than expected among Love Canal boys born from 1983 to 1996 (standardized incidence ratio=1.50 when compared to Upstate New York), although in both cases the 95% confidence interval included the null value. Finally, increased risk for low birth weight infants among mothers who lived closest to the Canal as children was found (odds ratio=4.68; 95% confidence interval: 1.24, 17.66), but this estimate was limited due to small numbers (n=4). The study adds to the knowledge of the possible reproductive effects from exposure to chemicals arising from hazardous waste; however, given the small number of some events, the qualitative nature of the exposure assessment, and possibility of spurious associations due to multiple comparisons, the findings should be interpreted cautiously.
Key Words: Adult, Birth Weight/drug effects, Congenital Abnormalities/*epidemiology, Female, Hazardous Waste/*statistics & numerical data, Humans, Infant, Newborn, Male, Maternal Exposure/*statistics & numerical data, New York, Pregnancy, Pregnancy Outcome/*epidemiology, Premature Birth/epidemiology, Reproduction/drug effects, Water Pollutants, Chemical/*toxicity, Young Adult
Balabanic D, Rupnik M, Klemencic AK. Negative impact of endocrine-disrupting compounds on human reproductive health. Reprod Fertil Dev. 2011 Apr;23(3):403-16.
Study Synopsis: This paper critically reviews evidence on the relation between exposure to endocrine-disrupting compounds (EDCs) and reproductive outcomes. Chemicals investigated include polychlorinated biphenyls, dioxins, polycyclic aromatic hydrocarbons, phthalates, bisphenol A, pesticides, alkylphenols and heavy metals (arsenic, cadmium, lead, mercury). Authors investigate their potential effects on sperm count and quality, testicular germ cells, male breast cancer, cryptorchidism, hypospadias, miscarriage, endometriosis, impaired fertility, irregularities of the menstrual cycle, and infertility.
Scientific abstract:
There is increasing concern about chemical pollutants that are able to mimic hormones, the so-called endocrine-disrupting compounds (EDCs), because of their structural similarity to endogenous hormones, their ability to interact with hormone transport proteins or because of their potential to disrupt hormone metabolic pathways. Thus, the effects of endogenous hormones can be mimicked or, in some cases, completely blocked. A substantial number of environmental pollutants, such as polychlorinated biphenyls, dioxins, polycyclic aromatic hydrocarbons, phthalates, bisphenol A, pesticides, alkylphenols and heavy metals (arsenic, cadmium, lead, mercury), have been shown to disrupt endocrine function. These compounds can cause reproductive problems by decreasing sperm count and quality, increasing the number of testicular germ cells and causing male breast cancer, cryptorchidism, hypospadias, miscarriages, endometriosis, impaired fertility, irregularities of the menstrual cycle, and infertility. Although EDCs may be released into the environment in different ways, the main sources is industrial waste water. The present paper critically reviews the current knowledge of the impact of EDCs on reproductive disorders in humans.
Study Synopsis: Endometriosis, the growth of tissue normally lining the inside of the uterus (the endometrium) outside of the uterine cavity, is a common gynecological condition. This paper reviews the influence of environmental and dietary factors on the risk of endometriosis. Authors conclude that toxicological mechanisms of action of environemental exposures such as dioxin and other similar compounds remain uncertain due to the difficulty in assessing exposure. A call to ramp up research to understand mechanisms throught which pollutants may affect endometriosis and other adverse health effects is made.
Scientific abstract:
Endometriosis represents a common gynecological condition affecting 5%-15% of childbearing age women and up to 3% 5% of post-menopausal women. This disease is defined by the presence of stromal and/or endometrial glandular epithelium implants in extra-uterine locations possibly compromising several sites. Humans and animals are daily exposed to chemical pollutants that could adversely influence physiological processes and potentially cause diseases, including endometriosis. In this review, the authors aimed at settling the influence of environmental and dietary factors on endometriosis pathogenesis. The mechanism by which dioxin and its similes (TCDD/PCBs) act changing the endometrial physiology remains uncertain and is speculative due to the difficulty in assessing the exposure over intrauterine life, childhood and adulthood and its actual consequences, in addition to the limitations to its in vitro reproducibility. We need to better understand the mechanism of action of these environmental pollutants, not only on reproductive health, but also on overall health of individuals and so prevention strategies, including not only population education, but setting exposure limits, less polluting techniques and a better use of our natural resources, could be promoted.
Blake CA, Mccoy GL, Hui YY, Lavoie HA. Perinatal exposure to low-dose DE-71 increases serum thyroid hormones and gonadal osteopontin gene expression. Exp Biol Med (Maywood). 2011 Apr;236(4):445-55.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. While a large body of evidence suggests that exposure to high doses of PBDEs results in reduced circulating T3 and/or T4 levels in rodents, human studies have reported increased T3 and/or T4 with elevated PBDE blood levels. In this study, researchers exposed rats daily to low doses of the commercial PBDE mixture DE-71 during pregnancy and through lactation. Lower body weight and elevated blood T3 and T4 levels were observed in treated animals relative to controls. These results suggest that exposure to low doses of PBDEs is related to increased T3 and T4 in rats, consistent with findings from human studies.
Scientific abstract:
Polybrominated diphenyl ethers (PBDEs) are flame retardants that have been widely used in manufacturing. They are major household and environmental contaminants that bioaccumulate. Humans are exposed primarily through dust inhalation and dietary ingestion of animal products. In animal studies, high doses of penta-brominated diphenyl ethers (penta-BDEs) in the mg/kg body weight (BW) range negatively impact brain development, behavior, memory, circulating thyroid hormone concentrations, the reproductive system and bone development. We investigated the effects of ingestion of a relatively low dose of the penta-BDE mixture DE-71 by pregnant and lactating rats on reproductive and thyroid parameters of the F1 offspring. F0 mothers received 60 mug/kg BW of DE-71 or vehicle daily by gavage from Day 1.5 of pregnancy through lactation (except the day of parturition). F1 pups were sacrificed at 21 d of age or outbred at approximately 80 d of age. Bred F1 females were sacrificed at Day 14.5 of pregnancy or at five months of age. Bred F1 males were sacrificed at five months of age. DE-71 treatment of the mothers affected the F1 females as evidenced by lower body weights at 80 d and five months of age, elevated serum T3 and T4 concentrations at Day 14.5 of pregnancy and increased thyroid gland weight and ovarian osteopontin mRNA at five months of age. Perinatal DE-71 exposure also increased testicular osteopontin mRNA in 21-day-old F1 males. Utilizing a granulosa cell in vitro model, we demonstrated that DE-71 activated the rat osteopontin gene promoter. Our results are the first to demonstrate that PBDEs increase rodent circulating T3 and T4 concentrations and gonadal osteopontin mRNA, and activate the osteopontin gene promoter. These changes may have clinical implications as others have shown associations between human exposure to PBDEs and subclinical hyperthyroidism, and overexpression of ovarian osteopontin has been associated with ovarian cancer.
Diisononyl phthalate (DINP) is a plasticizer abundantly used in consumer products as a substitute for other plasticizers prohibited in certain products due to reproductive toxicity. As anti-androgenic effects of DINP are suspected, DINP effects on reproduction and sexually dimorphic behavior were studied. Pregnant Wistar rats were gavaged from gestation day 7 to postnatal day (PND) 17 with vehicle, 300, 600, 750 or 900 mg DINP/kg bw/day. In fetal testes histopathological effects typical of phthalates were observed. In male offspring, DINP caused increased nipple retention, reduced anogenital distance, reduced sperm motility and increased sperm count. DINP affected spatial learning as female offspring performed better than controls and similarly to control males in the Morris Water Maze, indicating masculinization of behavior in DINP exposed females. These results show that DINP causes anti-androgenic effects on reproductive development, though less potent than DEHP, DBP and BBP, and further safety evaluation of DINP appears warranted.
Study Synopsis: Perfluorinated compounds (PFCs) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Persistent Organic Pollutants (POPs) are ubiquitous synthetic chemicals that persist in the environment and in humans, accumulate in fat and are generally found at higher concentration in animals situated higher in the food chain. Studies report that virtually all U.S. residents have detectable blood levels of PFCs and most have detectable levels of POPs. In this study, researchers measured the blood concentrations of POPs, PFCs and of some metals in 31 Greenlandic Inuit women with breast cancer and 115 controls. Significantly increased odds of breast cancer were observed among women with higher blood levels of PFCs and polychlorinated biphenyls (PCBs). The total testosterone-like and estrogen-like effect of measured chemicals was also related to an increase in the odds of breast cancer. Results suggest that PFCs as well as POPs may contribute to the risk of breast cancer in Inuit women.
Scientific abstract:
BACKGROUND: Breast cancer (BC) is the most common cancer for women in the western world. From very few cases an extraordinary increase in BC was observed in the Inuit population of Greenland and Canada although still lower than in western populations. Previous data suggest that exposure to persistent organic pollutants (POPs) might contribute to the risk of BC. Rat studies showed that perfluorinated compounds (PFCs) cause significantly increase in mammary fibroadenomas. This study aimed at evaluating the association between serum levels of POPs/PFCs in Greenlandic Inuit BC cases and their controls, and whether the combined POP related effect on nuclear hormone receptors affect BC risk. METHODS: Thirty-one BC cases and 115 controls were sampled during 2000-2003 from various Greenlandic districts. The serum levels of POPs, PFCs, some metals and the combined serum POP related effect on estrogen- (ER), androgen- (AR) and Ah-receptor (AhR) transactivity were determined. Independent student t-test was used to compare the differences and the odds ratios were estimated by unconditional logistic regression models. RESULTS: We observed for the very first time a significant association between serum PFC levels and the risk of BC. The BC cases also showed a significantly higher concentration of polychlorinated biphenyls at the highest quartile. Also for the combined serum POP induced agonistic AR transactivity significant association to BC risk was found, and cases elicited a higher frequency of samples with significant POP related hormone-like agonistic ER transactivity. The AhR toxic equivalent was lowest in cases. CONCLUSIONS: The level of serum POPs, particularly PFCs, might be risk factors in the development of BC in Inuit. Hormone disruption by the combined serum POP related xenoestrogenic and xenoandrogenic activities may contribute to the risk of developing breast cancer in Inuit. Further investigations are needed to document these study conclusions.
OBJECTIVES: To estimate the impact of gestational and childhood bisphenol A (BPA) exposures on behavior and executive function at 3 years of age and to determine whether child gender modified those associations. METHODS: We used a prospective birth cohort of 244 mothers and their 3-year-old children from the greater Cincinnati, Ohio, area. We characterized gestational and childhood BPA exposures by using the mean BPA concentrations in maternal (16 and 26 weeks of gestation and birth) and child (1, 2, and 3 years of age) urine samples, respectively. Behavior and executive function were measured by using the Behavior Assessment System for Children 2 (BASC-2) and the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P). RESULTS: BPA was detected in >97% of the gestational (median: 2.0 mug/L) and childhood (median: 4.1 mug/L) urine samples. With adjustment for confounders, each 10-fold increase in gestational BPA concentrations was associated with more anxious and depressed behavior on the BASC-2 and poorer emotional control and inhibition on the BRIEF-P. The magnitude of the gestational BPA associations differed according to child gender; BASC-2 and BRIEF-P scores increased 9 to 12 points among girls, but changes were null or negative among boys. Associations between childhood BPA exposure and neurobehavior were largely null and not modified by child gender. CONCLUSIONS: In this study, gestational BPA exposure affected behavioral and emotional regulation domains at 3 years of age, especially among girls. Clinicians may advise concerned patients to reduce their exposure to certain consumer products, but the benefits of such reductions are unclear.
Brucker-Davis F, Ferrari P, Boda-Buccino M, Wagner-Mahler K, Pacini P, Gal J, Azuar P, Fenichel P. Cord blood thyroid tests in boys born with and without cryptorchidism: correlations with birth parameters and in utero xenobiotics exposure. Thyroid. 2011 Oct;21(10):1133-41.
Study Synopsis: In this study, researchers examined the relation between thyroid hormone levels in cord blood and exposure to environmental chemicals during pregnancy based on their concentrations in breast milk. Measured contaminants included polychlorinated biphenyls (PCBs), dibutylphthalate, hexachlorobenzene and bishenol A. They did so among 76 healthy controls selected as part of a study examining whether boys affected by cryptorchidism (undescended testes) had different levels of thyroid hormones (they did not). Women with higher levels of two types of PCBs (numbers 118 and 180) and DDE (DDT's breakdown product) in breast milk had lower levels of the thyroid hormone free thyroxine (T4) in cord blood. Increased levels of free triiodothyronine (T3), the biologically active form of thyroid hormones, were found among women with higher levels of two other types of PCBs (numbers 138 and 153) and dibutylphthalate. Bisphenol A and hexachlorobenzene were not related to cord thyroid hormone levels in this study. Results suggest that some PCBs and dibutylphthalate may be related with lower free T4 and higher free T3 in cord blood.
Scientific abstract:
BACKGROUND: In utero exposure to environmental chemicals can result in reproductive toxicity via endocrine disruption mechanisms. Whether some of those contaminants also have an impact on fetal thyroid function or pathways, and, thus, potentially on neuropsychological development, is still debated. METHODS: We used samples from a cord blood (CB) and milk bank, established for a research on cryptorchidism and xenobiotic exposure to compounds known for their anti-androgenic and/or estrogenic activity, to study CB thyroid tests and their correlation with CB and milk xenobiotics concentrations in boys born in Nice area. RESULTS: No difference was found in thyroid tests between 60 cryptorchid boys and 76 matched controls (median thyroid stimulating hormone 5.97 vs. 6.55 mUI/L, free thyroxine [fT4] 13.1 vs. 12.9 pmol/L, free triiodothyronine [fT3] 1.9 vs. 2.1 pmol/L), with no influence of season of birth, gestational age, maternal smoking, or mode of delivery (except for higher fT4 in control boys born vaginally). FT4 was correlated with fetal growth only in cryptorchid boys. Since we had previously shown differences between cryptorchid and controls exposure, we studied correlations of thyroid tests with xenobiotics in control boys only. All tested CB or maternal milk was contaminated by one or more selected xenobiotics, mainly polychlorinated biphenyls (PCBs), dichloro diphenyl dichloroethylene (DDE), dibutylphthalate, hexachlorobenzene, and bisphenol A. We found a significant negative correlation between fT4 and concentrations of PCB118, PC180, and DDE in milk (respectively r = -0.342, p < 0.03, r = -0.296, p = 0.031, r = -0.315, p = 0.016), persisting after adjustment for mode of delivery. There was a significant positive correlation of fT3 with milk concentrations of PCB138, PCB153, SigmaPCB, and dibutylphthalate (respectively r = 0.31, p = 0.016, r = 0.28, p = 0.029; r = 0.34, p = 0.0079 and r = 0.272, p = 0.0295), with a trend for PCB180 (r = 0.259, p = 0.061). There was no correlation of thyroid stimulating hormone with any of the measured xenobiotics, except for a weak negative trend with CB bisphenol A (r = -0.25, p = 0.077). CONCLUSIONS: CB thyroid tests are within normal range in cryptorchid boys, similar to controls. Our data in controls suggest a possible weak correlation between in utero exposure to some xenobiotics (PCBs, DDE) and fT3 and fT4 CB concentrations, with usually negative correlations with fT4 and positive with fT3 concentrations, which we speculate could suggest an impact on deiodinases.
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is a ubiquitous environmental contaminant and known endocrine disruptor. Since humans and animals are most sensitive to toxicant exposure during development, we previously developed a mouse model of in utero TCDD exposure in order to examine the impact of this toxicant on adult reproductive function. Our initial in utero toxicant-exposure study revealed a dose-dependent reduction in uterine sensitivity to progesterone; however, we did not previously explore establishment or maintenance of pregnancy. Thus, in the current study, we examined pregnancy outcomes in adult C57BL/6 mice with a history of developmental TCDD exposure. Herein we demonstrate reduced fertility and an increased incidence of premature birth (PTB) in F1 mice exposed in utero to TCDD as well as in three subsequent generations. Finally, our studies revealed that mice with a history of developmental TCDD exposure exhibit an increased sensitivity to inflammation which further negatively impacted gestation length in all generations examined.
Brunnberg S, Andersson P, Poellinger L, Hanberg A. The constitutively active Ah receptor (CA-AhR) mouse as a model for dioxin exposure—Effects in reproductive organs. Chemosphere. 2011 Dec;85(11):1701-6.
Study Synopsis: Dioxins are highly toxic chemicals that persist in the environment, accumulate in human fatty tissue and concentrate up the food chain. Most toxic effects of dioxins are beleived to be mediated through binding to an orphan (no known natural ligand) receptor called the aryl hydrocarbon receptor (AhR). In this study, researchers examined health impairments in genetically modified mice whose AhR was constantly activated. They found that female mice had increased uterine weight before being sexually mature but reduced uterine weight after becoming mature. Sexually mature males had reduced testis and ventral prostate weights and decreased sperm reserves relative to normal mice. Similar results have been reported among rodents exposed to dioxins. These results support the hypothesis that dioxins exert their effects throught binding to the AhR resulting in antiestrogenic effects in the presence of estrogen (such as in sexually mature mice) but to estrogenic effects in the absence of estrogen (such as in males and sexually immature females).
Scientific abstract:
The dioxin/aryl hydrocarbon receptor (AhR) mediates most toxic effects of dioxins. In utero/lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impairs fetal/neonatal development and the developing male reproductive tract are among the most sensitive tissues. TCDD causes antiestrogenic responses in rodent mammary gland and uterus and in human breast cancer cell lines in the presence of estrogen. Also, more recently an estrogen-like effect of TCDD/AhR has been suggested in the absence of estrogen. A transgenic mouse expressing a constitutively active AhR (CA-AhR) was developed as a model mimicking a situation of constant exposure to AhR agonists. Male and female reproductive tissues of CA-AhR mice were characterized for some of the effects commonly seen after dioxin exposure. Sexually mature CA-AhR female mice showed decreased uterus weight, while an uterotrophic assay in immature CA-AhR mice resulted in increased uterus weight. In immature mice, both TCDD-exposure and CA-AhR increased the expression of the estrogen receptor target gene Cathepsin D. When co-treated with 17beta-estradiol no increase in Cathepsin D levels occurred in either TCDD-exposed or CA-AhR mice. In sexually mature male CA-AhR mice the weights of testis and ventral prostate were decreased and the epididymal sperm reserve was reduced. The results of the present study are in accordance with previous studies on dioxin-exposed rodents in that an activated AhR (here CA-AhR) leads to antiestrogenic effects in the presence of estrogen, but to estrogenic effects in the absence of estrogen. These results suggest the CA-AhR mouse model as a useful tool for studies of continuous low activity of the AhR from early development, resembling the human exposure situation.
Burdorf A, Brand T, Jaddoe VW, Hofman A, Mackenbach JP, Steegers EA. The effects of work-related maternal risk factors on time to pregnancy, preterm birth and birth weight: the Generation R Study. Occup Environ Med. 2011 Mar;68(3):197-204.
Study Synopsis: A number of environmental exposures and conditions may affect fertility and pregnancy outcomes. In this study, researchers collected information on job-related physical exercise and exposure to chemicals based on questionnaires and expert judgment. Exposure to phthalates was associated with a doubling of the odds of prolonged time to pregnancy (> 6 months) and exposure to pesticides was related to a 2.4-fold increased in the odds of decreased birth weight (< 3,000 g). Women handling loads of 5 kg or more was associated with lower odds of preterm birth (< 37 weeks) and reduced birth weight. These results suggest that exposure to phthalates and pesticides may be associated with reduced fecundability and birth weight, and that job-related load handling is related to better birth outcomes.
Scientific abstract:
OBJECTIVE: To investigate the influence of maternal working conditions on fertility and pregnancy outcomes. METHODS: 8880 women were enrolled in a large prospective birth cohort during early (76%), mid (21%) or late pregnancy (3%) (61% participation). Complete questionnaire information was available for 6302 women (71% response). Outcomes were prolonged time to pregnancy (TTP) (> 6 months), preterm birth (< 37 weeks) and decreased birth weight (< 3000 g). Self-reported exposure to chemical agents was based on a limited list of chemicals. Physical load questions concerned manual materials handling, prolonged sitting and long periods of standing. A job-exposure matrix (JEM) linked reported job title to workplace chemical exposure within jobs according to expert judgement. Associations between maternal occupational exposure and fertility and pregnancy outcomes, adjusted for age, education, minority, parity, smoking and alcohol use, were studied using logistic regression analysis. RESULTS: Women in jobs with regular handling of loads >/= 5 kg had better fertility and pregnancy outcomes. No self-reported exposure to chemicals was associated with any outcomes and self-assessments had very low reliability compared with JEM-based assessments. JEM-based maternal occupational exposure to phthalates was associated with prolonged TTP (OR 2.16, 95% CI 1.02 to 4.57) and exposure to pesticides was associated with decreased birth weight (OR 2.42, 95% CI 1.10 to 5.34). The population attributable fractions were small at 0.7% for phthalates and 0.7% for pesticides. CONCLUSION: This birth cohort study presents evidence of health-based selection into the workforce and adverse effects of maternal occupational exposure to phthalates and pesticides on fertility and pregnancy outcomes.
Caserta D, Mantovani A, Marci R, Fazi A, Ciardo F, La Rocca C, Maranghi F, Moscarini M. Environment and women's reproductive health. Hum Reprod Update. 2011 May-Jun;17(3):418-33.
Study Synopsis: This paper reviews the evidence for altered fertility and fecundity in women in relation with exposure to endocrine-disrupting chemicals (EDCs). Results regarding pregnancy outcomes, transgenerational exposure and effects are also summarized. Authors report that epidemiological studies on EDCs are not always consistent, in part due to limitations imposed by practical constraints. They recommend that further studies be undertaken regarding exposure to emergent EDCs such as bisphenol A, phthalates and polybrominated flame retardants. They conclude that the current evidence is sufficient to prompt precautionary actions to protect women's reproductive health.
Scientific abstract:
BACKGROUND There is significant evidence that continuous and prolonged exposure to several endocrine disrupting chemicals (EDC) is a risk factor for reduced fertility and fecundity in women. There is also evidence that ED exposure has trans-generational effects. In this systematic review, we evaluate the evidence for an association between EDC exposure and women's reproductive health. METHODS Studies were found by searching the PubMed database for articles published up to 2010. Associations between ED exposure and women's reproductive health reported in the PubMed database are summarized and classified as fertility and fecundity, pregnancy outcomes, transgenerational exposure and effects. RESULTS Epidemiological studies on EDCs are not always consistent, in part due to limitations imposed by practical constraints. In order to make progress in this field, we recommend taking advantage of biomonitoring and biobanks, including the development of appropriate biomarkers, and taking into greater consideration modulating factors such as genetic polymorphisms and dietary habits. Further human studies are warranted with particular focus on impaired fertility/fecundity associated with currently widespread ED (e.g. bisphenol A, phthalates and polybrominated flame retardants). CONCLUSIONS A detailed appraisal of compounds specifically related to adverse reproductive outcomes is very important for prevention and risk-communication strategies. Besides research needs, the current evidence is sufficient to prompt precautionary actions to protect women's reproductive health.
Cecil KM, Dietrich KN, Altaye M, Egelhoff JC, Lindquist DM, Brubaker CJ, Lanphear BP. Proton magnetic resonance spectroscopy in adults with childhood lead exposure. Environ Health Perspect. 2011 Mar;119(3):403-8.
BACKGROUND: Childhood lead exposure adversely affects neurodevelopment. However, few studies have examined changes in human brain metabolism that may underlie known adverse cognitive and behavioral outcomes. OBJECTIVE: We examined the association between mean childhood blood lead levels and in vivo brain metabolite concentrations as adults, determined by proton magnetic resonance spectroscopy (MRS) in a birth cohort with documented low-to-moderate lead exposure. METHODS: Adult participants from the Cincinnati Lead Study [n = 159; mean age (+/- SD), 20.8 +/- 0.9 years] completed a quantitative, short-echo proton MRS protocol evaluating seven regions to determine brain concentrations of N-acetyl aspartate (NAA), creatine and phosphocreatine (Cr), cholines (Cho), myo-inositol, and a composite of glutamate and glutamine (GLX). Correlation and multiple linear regression analyses were conducted. RESULTS: Mean childhood blood lead levels were associated with regionally specific brain metabolite concentrations adjusted for age at imaging and Full-Scale intelligence quotient. Adjusted analyses estimated for a unit (micrograms per deciliter) increase in mean childhood blood lead concentrations, a decrease of NAA and Cr concentration levels in the basal ganglia, a decrease of NAA and a decrease of Cho concentration levels in the cerebellar hemisphere, a decrease of GLX concentration levels in vermis, a decrease of Cho and a decrease of GLX concentration levels in parietal white matter, and a decrease of Cho concentration levels in frontal white matter. CONCLUSIONS: Gray-matter NAA reductions associated with increasing childhood blood lead levels suggest that sustained childhood lead exposure produces an irreversible pattern of neuronal dysfunction, whereas associated white-matter choline declines indicate a permanent alteration to myelin architecture.
Chan E, Burstyn I, Cherry N, Bamforth F, Martin JW. Perfluorinated acids and hypothyroxinemia in pregnant women. Environ Res. 2011 Feb;.
Study Synopsis: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA and PFOS. In this study, researchers measured these chemicals in the blood of 96 pregnant women with low levels of the thyroid hormone free T4 and in 175 controls with normal free T4. Women with low free T4 and controls had similar levels of PFOA and PFOS. These results do not support a relationship between exposure to these chemicals and thyroid hormone levels in pregnant women.
Scientific abstract:
Perfluorinated acids (PFAs) are prominent and widespread contaminants of human blood. In animal studies there is evidence that suggests certain PFAs can disrupt thyroid hormone homeostasis. A commonly reported condition in exposed animals is hypothyroxinemia, whereby serum free thyroxine (fT4) is decreased despite normal thyroid stimulating hormone (TSH) concentrations. We designed an individually matched case-control study to investigate whether exposure to perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) was associated with hypothyroxinemia in pregnant women from Edmonton, Alberta, Canada, in 2005-2006, who underwent a "triple screen" blood test at 15-20 weeks gestation as part of ante-natal care. Thyroid hormones, fT4 and TSH, were measured in serum from 974 women, and from these we measured PFAs in the sera of 96 hypothyroxinemic cases (normal TSH, the lowest 10th percentile of fT4) and 175 controls (normal TSH, fT4 between the 50th and 90th percentiles) matched on age and referring physician. Analyses by conditional logistic regression indicated that the concentrations of PFAs in this population were not associated with hypothyroxinemia among pregnant women. The current findings do not support a causal link between PFA exposure and maternal hypothyroxinemia in the studied population.
Chan E, Burstyn I, Cherry N, Bamforth F, Martin JW. Perfluorinated acids and hypothyroxinemia in pregnant women. Environ Res. 2011 May;111(4):559-64.
Study Synopsis: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA and PFOS. In this study, researchers measured these chemicals in the blood of 96 pregnant women with low levels of the thyroid hormone free T4 and in 175 controls with normal free T4. Women with low free T4 and controls had similar levels of PFOA and PFOS. These results do not support a relationship between exposure to these chemicals and thyroid hormone levels in pregnant women.
Scientific abstract:
Perfluorinated acids (PFAs) are prominent and widespread contaminants of human blood. In animal studies there is evidence that suggests certain PFAs can disrupt thyroid hormone homeostasis. A commonly reported condition in exposed animals is hypothyroxinemia, whereby serum free thyroxine (fT4) is decreased despite normal thyroid stimulating hormone (TSH) concentrations. We designed an individually matched case-control study to investigate whether exposure to perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) was associated with hypothyroxinemia in pregnant women from Edmonton, Alberta, Canada, in 2005-2006, who underwent a "triple screen" blood test at 15-20 weeks gestation as part of ante-natal care. Thyroid hormones, fT4 and TSH, were measured in serum from 974 women, and from these we measured PFAs in the sera of 96 hypothyroxinemic cases (normal TSH, the lowest 10th percentile of fT4) and 175 controls (normal TSH, fT4 between the 50th and 90th percentiles) matched on age and referring physician. Analyses by conditional logistic regression indicated that the concentrations of PFAs in this population were not associated with hypothyroxinemia among pregnant women. The current findings do not support a causal link between PFA exposure and maternal hypothyroxinemia in the studied population.
Chauvigne F, Plummer S, Lesne L, Cravedi JP, Dejucq-Rainsford N, Fostier A, Jegou B. Mono-(2-ethylhexyl) phthalate directly alters the expression of Leydig cell genes and cyp17 lyase activity in cultured rat fetal testis. PLoS ONE. 2011;6(11):e27172.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating of some drugs, food packaging and vinyl flooring. In this study, researchers exposed specialized cells found in testicles called Leydig cells to a type of phthalate called monoethylhexyl phthalate (MEHP). A function of Leydig cells is to produce the male hormone testosterone. Exposure to MEHP was found to lead to a decrease in testosterone production by Leydig cells that was dose-related. This effect was due to the inhibition of the activity of a gene coding for an enzyme essential to the production of testosterone called CYP17a1. Other genes were also affected, including those encoding insulin-like factor 3, which is involved in controlling the descent of testicles into the scrotum, a normal developmental process in males. These results thus suggest that MEHP alters the function of Leydig cells, resulting in lower testosterone production which is mediated through the inhibition of the CYP17a1 gene in rat cells. MEHP may also affect testicular descent.
Scientific abstract:
Exposure to phthalates in utero alters fetal rat testis gene expression and testosterone production, but much remains to be done to understand the mechanisms underlying the direct action of phthalate within the fetal testis.We aimed to investigate the direct mechanisms of action of mono-(2-ethylhexyl) phthalate (MEHP) on the rat fetal testis, focusing on Leydig cell steroidogenesis in particular.We used an in vitro system based on the culture for three days, with or without MEHP, of rat fetal testes obtained at 14.5 days post-coitum.Exposure to MEHP led to a dose-dependent decrease in testosterone production. Moreover, the production of 5 alpha-dihydrotestosterone (5alpha-DHT) (-68%) and androstenedione (-54%) was also inhibited by 10 microM MEHP, whereas 17 alpha-hydroxyprogesterone (17alpha-OHP) production was found to increase (+41%). Testosterone synthesis was rescued by the addition of androstenedione but not by any of the other precursors used. Thus, the hormone data suggested that steroidogenesis was blocked at the level of the 17,20 lyase activity of the P450c17 enzyme (CYP17), converting 17alpha-OHP to androstenedione. The subsequent gene expression and protein levels supported this hypothesis. In addition to Cyp17a1, microarray analysis showed that several other genes important for testes development were affected by MEHP. These genes included those encoding insulin-like factor 3 (INSL3), which is involved in controlling testicular descent, and Inha, which encodes the alpha subunit of inhibin B.These findings indicate that under in vitro conditions known to support normal differentiation of the fetal rat testis, the exposure to MEHP directly inhibits several important Leydig cell factors involved in testis function and that the Cyp17a1 gene is a specific target to MEHP explaining the MEHP-induced suppression of steroidogenesis observed.
Chen A, Chung E, Defranco EA, Pinney SM, Dietrich KN. Serum PBDEs and age at menarche in adolescent girls: analysis of the National Health and Nutrition Examination Survey 2003-2004. Environ Res. 2011 Aug;111(6):831-7.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, funiture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers used data on the blood levels of PBDEs and information about age at the onset of menarche based on questionnaires from the National Health and Nutrition Examination Survey (NHANES), a survey using a sample representative of the U.S. population. They found that among 271 adolescent girls aged 12-19 years, every doubling in PBDE concentration in their blood (approximately) was associated with a 60% increase in the likelihood of experiencing menarche before age 12 years. Results suggest that exposure to PBDEs is related to earlier onset of puberty as measured based on age at menarche.
Scientific abstract:
BACKGROUND: Polybrominated diphenyl ethers (PBDEs), widely used as flame retardants since the 1970s, have exhibited endocrine disruption in experimental studies. Tetra- to hexa-BDE congeners are estrogenic, while hepta-BDE and 6-OH-BDE-47 are antiestrogenic. Most PBDEs also have antiandrogenic activity. It is not clear, however, whether PBDEs affect human reproduction. OBJECTIVES: The analysis was designed to investigate the potential endocrine disruption of PBDEs on the age at menarche in adolescent girls. METHODS: We analyzed the data from a sample of 271 adolescent girls (age 12-19 years) in the National Health and Nutrition Examination Survey (NHANES), 2003-2004. We estimated the associations between individual and total serum BDEs (BDE-28, -47, -99, -100, -153, and -154, lipid adjusted) and mean age at menarche. We also calculated the risk ratios (RRs) and 95% confidence intervals (CI) for menarche prior to age 12 years in relation to PBDE exposure. RESULTS: The median total serum BDE concentration was 44.7ng/g lipid. Higher serum PBDE concentrations were associated with slightly earlier ages at menarche. Each natural log unit of total BDEs was related to a change of -0.10 (95% CI: -0.33, 0.13) years of age at menarche and a RR of 1.60 (95% CI: 1.12, 2.28) for experiencing menarche before 12 years of age, after adjustment for potential confounders. CONCLUSION: These data suggest high concentrations of serum PBDEs during adolescence are associated with a younger age of menarche.
Chevrier C, Limon G, Monfort C, Rouget F, Garlantezec R, Petit C, Durand G, Cordier S. Urinary biomarkers of prenatal atrazine exposure and adverse birth outcomes in the PELAGIE birth cohort. Environ Health Perspect. 2011 Jul;119(7):1034-41.
Background: Despite evidence of atrazine toxicity on developing organisms from experimental studies, only few studies - and fewer epidemiological investigations - have examined the potential effects of prenatal exposure. Objectives: We sought to assess the association between adverse birth outcomes and urinary biomarkers of prenatal atrazine exposure, while taking into account exposures to other herbicides used on corn crops (simazine, alachlor, metolachlor, and acetochlor). Methods: This study used a case-cohort design nested in a prospective birth cohort conducted in the Brittany region from 2002 through 2006. It collected maternal urine samples to examine pesticide exposure biomarkers before the 19th week of gestation. Results: Quantifiable levels of atrazine or atrazine mercapturate were found in urine samples from 5.5% of 579 pregnant women, and dealkylated and hydroxylated triazine metabolites were identified in 20% and 40% of samples, respectively. The presence versus absence of quantifiable levels of atrazine or a specific atrazine metabolite was associated with fetal growth restriction (OR=1.5; 95% CI: 1.0-2.2) and small head circumference for sex and gestational age (OR=1.7; 95% CI: 1.0-2.7). Associations with major congenital anomalies were not evident with atrazine or its specific metabolites. Head circumference was inversely associated with the presence of quantifiable urinary metolachlor. Conclusions: This study is the first to assess associations of birth outcomes with multiple urinary biomarkers of exposure to triazine and chloroacetanilide herbicides. Evidence of associations with adverse birth outcomes raises particular concerns for countries where atrazine is still in use.
Chevrier J, Harley KG, Bradman A, Sjodin A, Eskenazi B. Prenatal exposure to polybrominated diphenyl ether flame retardants and neonatal thyroid-stimulating hormone levels in the CHAMACOS Study. Am J Epidemiol. 2011 Nov;174(10):1166-74.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, funiture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. Although thyroid hormones play an essential role in brain development, few studies have investigated relations between prenatal exposure to PBDEs and neonatal thyroid hormone levels, and none have measured thyroid-stimulating hormone (TSH) levels in newborns. In this study, researchers measured the concentration of PBDEs in 289 pregnant women living in California's Salinas Valley and obtained data on levels of TSH in their newborn children from medical records. They found no significant association between PBDE concentrations and TSH after analyzing the data in several different manners. Results suggest that prenatal exposure to PBDEs is not related to TSH levels in newborns.
Scientific abstract:
Studies published in the last 3 decades have demonstrated global human exposure to polybrominated diphenyl ether (PBDE) flame retardants. A growing body of literature suggests that PBDEs may disrupt thyroid hormone homeostasis. Although thyroid hormones play an essential role in brain development, few studies have investigated relations between prenatal exposure to PBDEs and neonatal thyroid hormone levels, and none have measured thyroid-stimulating hormone (TSH) levels in neonates. The authors measured 10 PBDE congeners in serum collected between October 1999 and October 2000 from 289 pregnant women living in California's Salinas Valley and abstracted TSH levels from their children's medical records. Individual PBDE congeners showed null or weak nonsignificant inverse relations with neonatal TSH. Total serum PBDE was not associated with neonatal TSH (beta = 0.00, 95% confidence interval: -0.06, 0.06). Except for brominated diphenyl ether 153, a higher serum PBDE level was related to elevated odds of high TSH (>/=80th percentile), but associations were not statistically significant. Associations were not modified by infant sex, age at TSH measurement, maternal serum polychlorinated biphenyl concentration, or mode of delivery. Results were robust to sensitivity analysis. The authors found no conclusive evidence that prenatal exposure to PBDEs at levels similar to those of the general US population is related to neonatal TSH.
Christensen KY, Maisonet M, Rubin C, Holmes A, Calafat AM, Kato K, Flanders WD, Heron J, Mcgeehin MA, Marcus M. Exposure to polyfluoroalkyl chemicals during pregnancy is not associated with offspring age at menarche in a contemporary British cohort. Environ Int. 2011 Jan;37(1):129-35.
Study Synopsis: Polyfluoroalkyl compounds (PFCs) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFCs. In this study, researchers collected blood samples from pregnant women and followed their daughters from birth to adolescence. They identified 218 girls who had early menarche (before 11.5 years of age) and 230 girls with normal age at menarche and measured the levels of 8 PFCs in their mothers' blood to estimate fetal exposure. Although fetal exposure to some PFCs were different between girls with early and normal onset of menarche, researchers determined that results may have been due to chance. Findings do not clearly support associations between fetal exposure to PFCs and age at menarche.
Scientific abstract:
INTRODUCTION: Polyfluoroalkyl chemicals (PFCs) are commercially synthesized chemicals used in consumer products. Exposure to certain PFCs is widespread, and some PFCs may act as endocrine disruptors. We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) in the United Kingdom to conduct a nested case-control study examining the association between age at menarche, and exposure to PFCs during pregnancy. METHODS: Cases were selected from female offspring in the ALSPAC who reported menarche before the age of 11.5 years (n = 218), and controls were a random sample of remaining girls (n = 230). Serum samples taken from the girls' mothers during pregnancy (1991-1992) were analyzed using on-line solid-phase extraction coupled to isotope dilution high-performance liquid chromatography-tandem mass spectrometry for 8 PFCs. Logistic regression was used to determine association between maternal serum PFC concentrations, and odds of earlier age at menarche. RESULTS: PFOS and PFOA were the predominant PFCs (median serum concentrations of 19.8 ng/mL and 3.7 ng/mL). All but one PFC were detectable in most samples. Total PFC concentration varied by number of births (inverse association with birth order; p-value < 0.0001) and race of the child (higher among whites; p-value = 0.03). The serum concentrations of carboxylates were associated with increased odds of earlier age at menarche; concentrations of perfluorooctane sulfonamide, the sulfonamide esters and sulfonates were all associated with decreased odds of earlier age at menarche. However, all confidence intervals included the null value of 1.0. CONCLUSIONS: ALSPAC study participants had nearly ubiquitous exposure to most PFCs examined, but PFC exposure did not appear to be associated with altered age at menarche of their offspring.
Cohn BA, Cirillo PM, Sholtz RI, Ferrara A, Park JS, Schwingl PJ. Polychlorinated biphenyl (PCB) exposure in mothers and time to pregnancy in daughters. Reprod Toxicol. 2011 Apr;31(3):290-6.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. PCBs persist in the environment, accumulate in human fatty tissue and are detected in the blood of virtually all human populations. Exposure to PCBs has been associated with a number of adverse health effects. In this study, researchers measured the levels of PCBs in blood samples collected from 289 mothers between one and three days after giving birth to a girl. They found that daughters whose mother was exposed to higher levels of certain PCBs (congeners 99, 156 and 187) took longer to become pregnant. The probability of conceiving fell by 38% and the risk of infertility increased by 30% among women whose mothers were exposed to higher levels of the PCBs mentioned above. However, women whose mothers had higher blood levels of other PCBs (congeners 105, 138 and 183) took less time to become pregnant. Results of this study suggest that prenatal exposure to PCBs is related with altered fecundability and fertility in women.
Scientific abstract:
Developmental exposure to polychlorinated biphenyls (PCBs) disrupts reproduction in animals. Human data are lacking. We measured PCBs in preserved mothers' serum samples collected during 1960-1963, 1-3 days after their daughters' birth. We recorded time to pregnancy (TTP) in 289 daughters 28-31 years later. PCB congeners 187, 156, and 99 in mother's serum were associated with longer TTP in their daughters while PCB congeners 105, 138 and 183 were associated shorter TTP. Probability of pregnancy fell by 38% (95% CI 17-53%) and infertility was higher (30% not pregnant after 13 cycles versus 11% not pregnant after 13 cycles) among women whose mothers had a higher proportion of PCB congeners associated with longer TTP (75th percentile versus 25th percentile). This study demonstrates, for the first time, that developmental exposure to PCBs may disrupt pregnancy in humans.
Cook MB, Trabert B, Mcglynn KA. Organochlorine compounds and testicular dysgenesis syndrome: human data. Int J Androl. 2011 Aug;34(4 Pt 2):e68-84; discussion e-5.
Study Synopsis: Organochlorines are chemicals that were primarily used as pesticides from the 1940s to the 1970s when they were banned due to concerns about their persistence in the environment, bioaccumulation in fat tissues and potential adverse health effects on wildlife and in humans. This paper reviews the literature on the possible link between exposure to organochlorines and hypospadias (abnormal location of the urethra), cryptorchidism (undescended testes), fertility and testicular cancer which are beleived to have common causes. Authors find no clear evidence of associations between organochlorines and these outcomes. They however underscore that may other environmental chemicals that have the potential to alter the male reproductive system have still not been investigated.
Scientific abstract:
Cryptorchidism, hypospadias, subfertility and testicular germ-cell tumour have been suggested to comprise a testicular dysgenesis syndrome (TDS) based on the premise that each may derive from perturbations of embryonal programming and gonadal development during foetal life. Endocrine-disrupting chemicals have been hypothesized to be associated with these disorders, given the importance of sex steroid hormones in urogenital development and homeostasis. Organochlorines are one such set of compounds which are defined as containing between one and ten covalently bonded chlorine atoms. These compounds are persistent pollutants with long half-lives, accumulate in adipose tissue when ingested, bioaccumulate and biomagnify, and have complex and variable toxicological profiles. Examples of organochlorines include dichloro-diphenyl-trichloroethane and its metabolites, polychlorinated biphenyls, and chlordane. In this comprehensive review of human epidemiologic studies which have tested for associations between organochlorines and facets of TDS, we find evidence for associations between the exposures p,p'-DDE, cis-nonachlor and trans-nonachlor with testicular germ-cell tumour. The sum of the evidence from human epidemiological studies does not indicate any association between specific organochlorines studied and cryptorchidism, hypospadias or fertility. Many other endocrine-disrupting chemicals, including additional organochlorines, have yet to be assessed in relation to disorders associated with TDS, yet study of such chemicals has strong scientific merit given the relevance of such hypotheses to urogenital development.
Costa LG, Giordano G. Is decabromodiphenyl ether (BDE-209) a developmental neurotoxicant?. Neurotoxicology. 2011 Jan;32(1):9-24.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this paper, authors review evidence of the potential effect of one form of PBDE, called BDE-209, on brain development.
Scientific abstract:
Polybrominated diphenyl ether (PBDE) flame retardants have become ubiquitous environmental pollutants. The relatively higher body burden in toddlers and children has raised concern for their potential developmental neurotoxicity, which has been suggested by animal studies, in vitro experiments, and recent human epidemiological evidence. While lower brominated PBDEs have been banned in several countries, the fully brominated decaBDE (BDE-209) is still utilized, though manufacturers will discontinue production in the U.S.A. in 2013. The recent decision by the U.S. Environmental Protection Agency to base the reference dose (RfD) for BDE-209 on a developmental neurotoxicity study has generated some controversy. Because of its bulky configuration, BDE-209 is poorly absorbed and does not easily penetrate the cell wall. Its acute and chronic toxicities are relatively low, with the liver and the thyroid as the primary targets, though there is some evidence of carcinogenicity. A few animal studies have indicated that BDE-209 may cause developmental neurotoxicity, affecting motor and cognitive domains, as seen for other PBDEs. Limited in vivo and in vitro studies have also evidenced effects of BDE-209 on thyroid hormone homeostasis and direct effects on nervous cells, again similar to what found with other lower brominated PBDEs. In contrast, a recent developmental neurotoxicity study, carried out according to international guidelines, has provided no evidence of adverse effects on neurodevelopment, and this should be considered in a future re-evaluation of BDE-209. While estimated exposure to BDE-209 in children is believed to be several orders of magnitude below the most conservative RfD proposed by the USEPA, questions remain on the extent and relevance of BDE-209 metabolism to lower brominated PBDEs in the environment and in humans.
Atrazine is the most commonly used herbicide in the U.S. and a wide-spread groundwater contaminant. Epidemiologic and laboratory evidence exists that atrazine disrupts reproductive health and hormone secretion. We examined the relationship between exposure to atrazine in drinking water and menstrual cycle function including reproductive hormone levels. Women 18-40 years old residing in agricultural communities where atrazine is used extensively (Illinois) and sparingly (Vermont) answered a questionnaire (n=102), maintained menstrual cycle diaries (n=67), and provided daily urine samples for analyses of luteinizing hormone (LH), and estradiol and progesterone metabolites (n=35). Markers of exposures included state of residence, atrazine and chlorotriazine concentrations in tap water, municipal water and urine, and estimated dose from water consumption. Women who lived in Illinois were more likely to report menstrual cycle length irregularity (odds ratio (OR)=4.69; 95% confidence interval (CI): 1.58-13.95) and more than 6 weeks between periods (OR=6.16; 95% CI: 1.29-29.38) than those who lived in Vermont. Consumption of >2 cups of unfiltered Illinois water daily was associated with increased risk of irregular periods (OR=5.73; 95% CI: 1.58-20.77). Estimated "dose" of atrazine and chlorotriazine from tap water was inversely related to mean mid-luteal estradiol metabolite. Atrazine "dose" from municipal concentrations was directly related to follicular phase length and inversely related to mean mid-luteal progesterone metabolite levels. We present preliminary evidence that atrazine exposure, at levels below the US EPA MCL, is associated with increased menstrual cycle irregularity, longer follicular phases, and decreased levels of menstrual cycle endocrine biomarkers of infertile ovulatory cycles.
Craig ZR, Wang W, Flaws JA. Endocrine-disrupting chemicals in ovarian function: effects on steroidogenesis, metabolism and nuclear receptor signaling. Reproduction. 2011 Nov;142(5):633-46.
Study Synopsis: This paper reviews the potential effects of environmental chemcials, such as the pesticides dichlorodiphenyl trichloroethane (DDT), methoxychlor, bisphenol A and phthalates, on the function of ovaries. Authors identify two ways in which chemicals may interact with ovaries: by altering hormone levels or by interfering with hormone binding to their receptors.
Scientific abstract:
Endocrine-disrupting chemicals (EDCs) are exogenous agents with the ability to interfere with processes regulated by endogenous hormones. One such process is female reproductive function. The major reproductive organ in the female is the ovary. Disruptions in ovarian processes by EDCs can lead to adverse outcomes such as anovulation, infertility, estrogen deficiency, and premature ovarian failure among others. This review summarizes the effects of EDCs on ovarian function by describing how they interfere with hormone signaling via two mechanisms: altering the availability of ovarian hormones, and altering binding and activity of the hormone at the receptor level. Among the chemicals covered are pesticides (e.g. dichlorodiphenyltrichloroethane and methoxychlor), plasticizers (e.g. bisphenol A and phthalates), dioxins, polychlorinated biphenyls, and polycyclic aromatic hydrocarbons (e.g. benzo[a]pyrene).
Dann AB, Hontela A. Triclosan: environmental exposure, toxicity and mechanisms of action. J Appl Toxicol. 2011 May;31(4):285-311.
Study Synopsis: Triclosan is commonly used as an antibacterial and antifungal in a range of household products including soap, mouthwash, toothpaste, deodorants and hand sanitizers. This paper reviews the chemical and toxicological properties of triclosan. It discusses topics including environmental contamination, wildlife and human exposure, potential health effects as well as the chemical's efficacy and issues of antibacterial resistance.
Scientific abstract:
Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a broad spectrum antibacterial agent used in personal care, veterinary, industrial and household products. TCS is commonly detected in aquatic ecosystems, as it is only partially removed during the wastewater treatment process. Sorption, biodegradation and photolytic degradation mitigate the availability of TCS to aquatic biota; however the by-products such as methyltriclosan and other chlorinated phenols may be more resistant to degradation and have higher toxicity than the parent compound. The continuous exposure of aquatic organisms to TCS, coupled with its bioaccumulation potential, have led to detectable levels of the antimicrobial in a number of aquatic species. TCS has been also detected in breast milk, urine and plasma, with levels of TCS in the blood correlating with consumer use patterns of the antimicrobial. Mammalian systemic toxicity studies indicate that TCS is neither acutely toxic, mutagenic, carcinogenic, nor a developmental toxicant. Recently, however, concern has been raised over TCS's potential for endocrine disruption, as the antimicrobial has been shown to disrupt thyroid hormone homeostasis and possibly the reproductive axis. Moreover, there is strong evidence that aquatic species such as algae, invertebrates and certain types of fish are much more sensitive to TCS than mammals. TCS is highly toxic to algae and exerts reproductive and developmental effects in some fish. The potential for endocrine disruption and antibiotic cross-resistance highlights the importance of the judicious use of TCS, whereby the use of TCS should be limited to applications where it has been shown to be effective. Copyright (c) 2011 John Wiley & Sons, Ltd.
Dingemans MM, Van Den Berg M, Westerink RH. Neurotoxicity of brominated flame retardants: (in-)direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous system. Environ Health Perspect. 2011 July;119(7):900-7.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. This paper reviews the evidence from animal and molecular toxicology studies linking exposure to PBDEs and their breakdown products on brain development.
Scientific abstract:
Objective: Polybrominated diphenyl ethers (PBDEs) and hydroxylated (OH-) or methoxylated forms thereof have been detected in humans. As this raises concern about adverse effects on the developing brain, scientific literature on these mechanisms was reviewed. Data synthesis: Many rodent studies reported behavioral changes after developmental, neonatal or adult exposure to PBDEs. Other studies documented subtle structural and functional alterations in brains of PBDE-exposed animals. Functional effects were observed on synaptic plasticity and the glutamate-nitric oxide-cyclic guanosine monophosphate pathway. In the brain, changes were observed in the expression of genes and proteins involved in synapse and axon formation, neuronal morphology, cell migration, synaptic plasticity, ion channels and vesicular neurotransmitter release. Cellular and molecular mechanisms include effects on neuronal viability (via apoptosis and oxidative stress), neuronal differentiation and migration, neurotransmitter release/uptake, neurotransmitter receptors and ion channels, calcium homeostasis and intracellular signaling pathways. Discussion: Bioactivation of PBDEs by hydroxylation has been observed for several endocrine endpoints. This has also been observed for mechanisms related to neurodevelopment: binding to thyroid hormone receptors and transport proteins, disruption of Ca2+ homeostasis and modulation of GABA and nACh receptor function. Conclusions: The increased hazard for developmental neurotoxicity by OH-PBDEs compared to their parent congeners via direct neurotoxicity and thyroid disruption clearly warrants further investigation into: 1) the role of oxidative metabolism in producing active metabolites of PBDEs and their impact on brain development; 2) concentrations of parent and OH-PBDEs in the brain; and 3) interactions between different environmental contaminants during exposure to mixtures, which may increase neurotoxicity.
Dingemans MM, Van Den Berg M, Westerink RH. Neurotoxicity of brominated flame retardants: (in)direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous system. Environ Health Perspect. 2011 Jul;119(7):900-7.
Scientific abstract:
BACKGROUND/OBJECTIVE: Polybrominated diphenyl ethers (PBDEs) and their hydroxylated (OH-) or methoxylated forms have been detected in humans. Because this raises concern about adverse effects on the developing brain, we reviewed the scientific literature on these mechanisms. DATA SYNTHESIS: Many rodent studies reported behavioral changes after developmental, neonatal, or adult exposure to PBDEs, and other studies documented subtle structural and functional alterations in brains of PBDE-exposed animals. Functional effects have been observed on synaptic plasticity and the glutamate-nitric oxide-cyclic guanosine monophosphate pathway. In the brain, changes have been observed in the expression of genes and proteins involved in synapse and axon formation, neuronal morphology, cell migration, synaptic plasticity, ion channels, and vesicular neurotransmitter release. Cellular and molecular mechanisms include effects on neuronal viability (via apoptosis and oxidative stress), neuronal differentiation and migration, neurotransmitter release/uptake, neurotransmitter receptors and ion channels, calcium (Ca(2)) homeostasis, and intracellular signaling pathways. DISCUSSION: Bioactivation of PBDEs by hydroxylation has been observed for several endocrine end points. This has also been observed for mechanisms related to neurodevelopment, including binding to thyroid hormone receptors and transport proteins, disruption of Ca(2) homeostasis, and modulation of GABA and nicotinic acetylcholine receptor function. CONCLUSIONS: The increased hazard for developmental neurotoxicity by hydroxylated (OH-)PBDEs compared with their parent congeners via direct neurotoxicity and thyroid disruption clearly warrants further investigation into a) the role of oxidative metabolism in producing active metabolites of PBDEs and their impact on brain development; b) concentrations of parent and OH-PBDEs in the brain; and c) interactions between different environmental contaminants during exposure to mixtures, which may increase neurotoxicity.
Dobrzynska MM, Tyrkiel EJ, Pachocki KA. Developmental toxicity in mice following paternal exposure to di-n-butyl-phthalate (DBP). Biomed Environ Sci. 2011 Oct;24(5):569-78.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating of some drugs, food packaging and vinyl flooring. In this study, researchers exposed male rats to dibutyl phthalate (DBP) to daily doses of 500 mg/kg or 2,000 mg/kg over an 8-week period and mated them with unexposed females. They found that offspring of exposed males suffered from growth retardation. Rats exposed to the lower dose fathered almost twice as many males as females and female offspring reached puberty later than offspring of unexposed control rats. Exposure at the higher dose resulted in an increase in sperm abnormalities in male offpsring. Rats from the second generation, whose parents were not exposed but whose grandfathers were, had normal development and reproductive function parameters. These results suggest that paternal exposure to DBP in rats affects offspring growth, sex ratio, onset of puberty in females and sperm quality in males at high doses.
Scientific abstract:
OBJECTIVE: The aim of the present study was to investigate the effects of paternal Di-N-butyl-phthalate (DBP) exposure pre- and postnatally on F1 generation offspring, and prenatally on F2 generation offspring. METHODS: Male mice were exposed to either 500 mg/kg or 2 000 mg/kg of DBP for 8 weeks, and mated with non-exposed females. Three-quarters of the females were sacrificed a day prior to parturition, and examined for the number of living and dead implantations, and incidence of gross malformations. Pups from the remaining females were assessed for developmental markers, growth parameters, as well as sperm quantity and quality. RESULTS: There were no changes in the fertility of parents and in intrauterine development of the offspring. Pups of DBP-exposed males demonstrated growth-retardation. Following paternal exposure to 500 mg/kg bw of DBP, there were almost twice the number of males than females born in the F1 generation. F1 generation females had a 2.5-day delay in vaginal opening. Paternal exposure to 2 000 mg/kg bw of DBP increased the incidence of sperm head malformations in F1 generation males; however, there were no changes in the fertility and viability of foetuses in the F2 generation. CONCLUSION: Paternal DBP exposure may disturb the sex ratio of the offspring, delay female sexual maturation, and deteriorate the sperm quality of F1 generation males.
BACKGROUND: Bisphenol A (BPA) is an estrogenic endocrine disruptor commonly used in manufacture of polycarbonate plastics and epoxy resins. Due to its ubiquitous presence in the environment, health concerns are increasing. Earlier studies from our group have shown that neonatal exposure of male rats to BPA affected spermatogenesis leading to impairment in fertility during adulthood. Further we also observed an altered gene expression of ERalpha and ERbeta in adult testis upon BPA exposure. Based on these results, we hypothesized that apart from endocrine action, BPA might mediate perturbations in expression of ERs via epigenetic mechanism. OBJECTIVES: The present study was undertaken to determine the effect of exposure of neonatal male rats to BPA on DNA methylation profile of estrogen receptor promoter region and on DNA methylation machinery. METHODS: In order to test this hypothesis, neonatal male rats were subcutaneously injected with 2.4mug of BPA/day for the first five days of life, i.e., on postnatal days (PND) 1-5, while control group received vehicle (sesame oil). Animals were sacrificed during adulthood (PND-125) and testes were dissected out for analysis. Methylation pattern of promoter region of ERalpha and ERbeta was analyzed in the testis by bisulfite sequencing and expression levels of DNA methyltransferases by quantitative RT-PCR and Western blotting respectively. RESULTS: Bisulfite sequencing revealed significant hypermethylation of ERalpha promoter to varying extents from 40% to 60%, and ERbeta promoter region with varying extent from 20% to 65%. Approximately 2-fold increase in Dnmt3a and Dnmt3b expression at transcript and protein level was also observed. CONCLUSION: The experimental evidence demonstrated that the neonatal exposure of rats to BPA led to aberrant DNA methylation in testis, indicating methylation mediated epigenetic changes as one of the possible mechanisms of BPA induced adverse effects on spermatogenesis and fertility.
Eggesbo M, Thomsen C, Jorgensen JV, Becher G, Odland JO, Longnecker MP. Associations between brominated flame retardants in human milk and thyroid-stimulating hormone (TSH) in neonates. Environ Res. 2011 Aug;111(6):737-43.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, funiture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. Hexabromocyclododecane (HBCD) is another type of flame retardant primarily used in polystyrene insulation and textiles. In this study, researchers measured the concentration of PBDEs and HBCD in the breast milk of 239 Norwegian women and determined the levels of thyroid-stimulating hormone (TSH) in their children shortly after birth. They found no relation between the levels of the flame retardants in breast milk and neonatal TSH. Levels measured in this study were however approximately one order of magnitude lower than those reported in Canada or the United States. Results do not support an association between prenatal exposure to PBDEs and HBCD, as assessed based on breast milk concentrations, and neonatal TSH at the low levels measured in this study.
Scientific abstract:
BACKGROUND: Brominated flame retardants (BFRs) have been in widespread use in a vast array of consumer products since the 1970s. The metabolites of some BFRs show a structural similarity to thyroid hormones and experimental animal studies have confirmed that they may interfere with thyroid hormone homeostasis. A major concern has been whether intrauterine exposure to BFRs may disturb thyroid homeostasis since the fetal brain is particularly susceptible to alterations in thyroid hormones. However, few reports on newborns have been published to date. OBJECTIVES: To evaluate the association between BFRs and neonatal thyroid-stimulating hormone (TSH). METHODS: We studied six polybrominated diphenyl ethers (PBDEs) measured in milk samples from 239 women who were part of the "Norwegian Human Milk Study" (HUMIS), 2003-2006. Hexabromocyclododecane (HBCD) and BDE-209 were measured in a subset of the women (193 and 46 milk samples, respectively). The milk was sampled at a median of 33 days after delivery. TSH was measured in babies three days after delivery as part of the routine national screening program for early detection of congenital hypothyroidism. Additional information was obtained through the Medical Birth Registry and questionnaires to the mothers. RESULTS: The PBDE concentrations in human milk in Norway were comparable to concentrations reported from other European countries and Asia, but not the US and Canada where levels are approximately one order of higher magnitude. We observed no statistically significant associations between BDE-47, 99, 153, 154, 209 and HBCD in human milk and TSH in models adjusted for possible confounders and other environmental toxicants including polychlorinated biphenyls (PCBs). CONCLUSIONS: We did not observe an association between TSH and exposure to HBCD and PBDEs within the exposure levels observed.
Erkekoglu P, Zeybek ND, Giray B, Asan E, Arnaud J, Hincal F. Reproductive toxicity of di(2-ethylhexyl) phthalate in selenium-supplemented and selenium-deficient rats. Drug Chem Toxicol. 2011 Oct;34(4):379-89.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating of some drugs, food packaging and vinyl flooring. A number of animal studies suggest that exposure to phthalates affect the reproductive system in males. Selenium is essential to normal development and function of the male reproductive system and selenium deficiency is common in many parts of the world. Researchers therefore tested the hypothesis that selenium deficiency may enhance the adverse effect of phthalates. To do so, they exposed male rats daily to diethylhexyl phthalate (DEHP) at a dose of 1,000 mg/kg over 10 days. In order to investigate whether selenium deficiency may alter the effect of DEHP, rats were split in three groups. The first group received a normal healthy diet, a second group received a diet deficient in selenium (<= 0.05 mg/kg) and a third group received a diet supplemented with selenium (1 mg/kg) for 5 weeks. Rats exposed to DEHP showed abnormalities in the cellular structure of testes, poorer sperm quality, lower levels of the male hormone testosterone and of leutinizing hormone (LH) and follicle-stimulating hormone (FSH) which are essential for the normal function of the reproductive system. The effects of DEHP were found to be more prononced in rats fed a diet deficient in selenium while those who had a diet supplemented with selenium had better outcomes. These results suggest that exposure to high doses of DEHP affects the reproductive sytem in male rats and that selenium is protective against this effect..
Scientific abstract:
Phthalates are abundantly produced plasticizers, and di(ethylhexyl) phthalate (DEHP) is the most widely used derivative in various consumer products and medical devices. Animal studies show that DEHP and various other phthalates cause reproductive and developmental toxicity. Although the evidences are limited, it seems reasonable that DEHP may have a potential for similar adverse effects in humans. Such concerns are increasing, particularly for the developing reproductive system of male infants and children. By taking into account the essentiality of selenium (Se) in testicular structure and functions and the high prevalence of inadequate Se intake in various part of the world, this study was designed to investigate the testicular toxicity of DEHP in Se-deficient male rats and to examine the possible preventive effects of Se supplementation on phthalate toxicity. Se deficiency was generated by feeding 3-week-old Sprague-Dawley rats with a top of page / modify search terms
Freire C, Lopez-Espinosa MJ, Fernandez M, Molina-Molina JM, Prada R, Olea N. Prenatal exposure to organochlorine pesticides and TSH status in newborns from Southern Spain. Sci Total Environ. 2011 Aug;409(18):3281-7.
Study Synopsis: Organochlorines are chemicals that were primarily used as pesticides from the 1940s to the 1970s when they were banned due to concerns about their persistence in the environment, bioaccumulation in fat tissues and potential adverse health effects on wildlife and in humans. In this study, researchers measured 17 organochlorine pesticides in the placenta of 220 boys born in Southern Spain. They found that higher exposure to endrin, and possibly to DDT's breakdown product dichlorodiphenyl dichloroethylene (DDE), were more likely to have high (>= 5 mIU/L) thyroid-stimulating hormone (TSH), a marker for a condition called congenital hypothyroidism. This condition is related to growth and brain development impairment. In addition higher exposure to endosulfan-sulfate was associated with a protective effect (reduced odds) of high TSH. Neonates exposed to higher levels of the fungicide hexachlorobenzene prenatally also had a tendency to have lower TSH levels but this results may have been due to chance. In summary, these results suggest that prenatal exposure to endrin, and possibly DDE is related to higher odds of markers suggesting congenital hypothyroidism. On the other hand, exposure to hexachlorobenzene and endosulfan-sulfate may be protective.
Scientific abstract:
OBJECTIVE: To investigate the association between prenatal exposure to organochlorine pesticides (OCPs) and thyroid-stimulating hormone (TSH) levels in male newborns. METHODS: Exposure to 17 OCPs was analyzed in 220 placentas from a male birth cohort in Southern Spain, and TSH was measured in the umbilical cord blood. OCP concentrations were quantified by gas chromatography and mass spectrometry. Multivariate regression analysis was conducted to examine the association between pesticide exposure and neonatal TSH levels, adjusting for confounders. RESULTS: Newborn boys with higher exposure to endrin in placenta had higher odds of TSH cord blood levels >/= 5 mU/L (80th percentile) (OR=2.05; 95% CI=1.01, 4.18; p=0.05), whereas higher prenatal exposure to endosulfan-sulfate was associated with lower odds of TSH >/= 5 mU/L (OR=0.36; 95% CI=0.17, 0.77; p=0.008). A marginally significant negative association was found between TSH and hexachlorobenzene levels (beta=-0.15; 95% CI=-0.31, 0.02; p=0.09), and exposure to p,p'-DDE showed a marginally-significant higher odds of TSH >/= 5 mU/L (OR=1.32; 95% CI=0.95, 1.83; p=0.09). No association was found between TSH and the remaining pesticides. CONCLUSIONS: Early exposure to certain environmental chemicals with endocrine-disruption activity may interfere with neonatal thyroid hormone status; however, the pattern of interference is not yet clearly elucidated.
Frye C, Bo E, Calamandrei G, Calza L, Dessi-Fulgheri F, Fernandez M, Fusani L, Kah O, Kajta M, Le Page Y, Patisaul HB, Venerosi A, Wojtowicz AK, Panzica GC. Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behavior and neuroendocrine systems. J Neuroendocrinol. 2011 Sep;.
Study Synopsis: This paper reviews the sources, effects and actions of chemicals that have the potential to interact with hormones. These so-called endocrine disruptor chemicals include the pesticide dichlorodiphenyl trichloroethane (DDT) and its breakdown products such as dichlorodiphenyl dichloroethylene (DDE), plastic components, such as bisphenol A, pharmaceuticals and dietary components. Chemicals discussed as part of the International Congress on Steroids on the Nervous System are reviewed in more details. Health outcome reviewed include reproductive and neurodevelopmental effects. Authors emphasize that exposure to endocrine disruptor chemicals may be of greater concern when they occur during critical periods when hormones play a curcial role in human development such as prenatally and during puberty. Effects in adulthood are also discussed.
Scientific abstract:
Some environmental contaminants interact with hormones and may exert adverse consequences due to their actions as endocrine disrupting chemicals (EDCs). Exposure in people is typically due to contamination of the food chain, inhalation of contaminated house dust, or occupational exposure. EDCs include pesticides and herbicides (such as diphenyl-dichloro-trichloroethane, DDT, or its metabolites), methoxychlor, biocides, heat stabilizers and chemical catalysts (such as tributyltin, TBT), plastic contaminants (e.g. bisphenol A, BPA), pharmaceuticals (i.e. diethylstilbestrol, DES; 17alpha-ethynilestradiol, EE2), or dietary components (such as phytoestrogens). The goal of this review is to address sources, effects and actions of EDCs, with an emphasis on topics discussed at the International Congress on Steroids and the Nervous System. EDCs may alter reproductively-relevant or non-reproductive, sexually-dimorphic behaviors. In addition, EDCs may have significant effects on neurodevelopmental processes, influencing morphology of sexually-dimorphic cerebral circuits. Exposure to EDCs is more dangerous if it occurs during specific "critical periods" of life, such as intrauterine, perinatal, juvenile or puberty periods, when organisms are more sensitive to hormonal disruption, than in other periods. However, exposure to EDCs in adulthood also can alter physiology. Several EDCs are xenoestrogens, may alter serum lipid concentrations, or metabolism enzymes that are necessary for converting cholesterol to steroid hormones, ultimately altering production of E(2) and/or other steroids. Finally, many EDCs may have actions via, or independent of, classic actions at cognate steroid receptors. EDCs may have effects through numerous other substrates, such as the aryl hydrocarbon receptor (AhR), the peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR), signal transduction pathways, calcium influx, and/or neurotransmitter receptors. Thus, EDCs, from varied sources, may have organizational effects during development, and/or activational effects in adulthood, that influence sexually-dimorphic, reproductively-relevant processes or other functions, by mimicking, antagonizing, or altering steroidal actions.
Gascon M, Vrijheid M, Martinez D, Forns J, Grimalt JO, Torrent M, Sunyer J. Effects of pre and postnatal exposure to low levels of polybromodiphenyl ethers on neurodevelopment and thyroid hormone levels at 4 years of age. Environ Int. 2011 Jan;37(3):605-11.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers measured the concentration of PBDEs in the cord blood of 88 children at birth and in the blood of 244 four-year-olds. Children with detectable levels of the PBDE congener BDE-47 at four years of age were 80% more likely to exhibit attention deficits and 160% more likely to have poorer social competence. No relationship was found with thyroid hormone levels in 4-year-olds. This study suggests that postnatal exposure to BDE-47 may be related to impaired attention and poorer social competence at 4 years of age.
Scientific abstract:
There are at present very few studies of the effects of polybromodiphenyl ethers (PBDEs), used as flame retardants in consumer products, on neurodevelopment or thyroid hormone levels in humans. The present study aims to examine the association between pre and postnatal PBDE concentrations and neurodevelopment and thyroid hormone levels in children at age 4 years and isolate the effects of PBDEs from those of PCBs, DDT, DDE and HCB. A prospective birth cohort in Menorca (Spain) enrolled 482 pregnant mothers between 1997 and 1998. At 4 years, children were assessed for motor and cognitive function (McCarthy Scales of Children's Abilities), attention-deficit, hyperactivity and impulsivity (ADHD-DSM-IV) and social competence (California Preschool Social Competence Scale). PBDE concentrations were measured in cord blood (N=88) and in serum of 4 years olds (N=244). Among all congeners analyzed only PBDE 47 was quantified in a reasonable number of samples (LOQ=0.002ng/ml). Exposure to PBDE 47 was analyzed as a dichotomous variable: concentrations above the LOQ (exposed) and concentrations below (referents). Scores for cognitive and motor functions were always lower in children pre and postnatally exposed to PBDE47 than in referents, but none of these associations was statistically significant (beta coefficient (95%CI) of the total cognition score: -2.7 (-7.0, 1.6) for postnatal exposure, and -1.4 (-9.2, 6.5) for prenatal exposure). Postnatal exposure to PBDE 47 was statistically significantly related to an increased risk of symptoms on the attention deficit subscale of ADHD symptoms (RR (95%CI)=1.8 (1.0, 3.2)) but not to hyperactivity symptoms. A statistically significant higher risk of poor social competence symptoms was observed as a consequence of postnatal PBDE 47 exposure (RR (95%CI)=2.6 (1.2, 5.9)). Adjustment for other organochlorine compounds did not influence the results. Levels of thyroid hormones were not associated to PBDE exposure. This study highlights the importance of assessing the effects of PBDE exposure not just prenatally but also during the early years of life. In the light of current evidence a precautionary approach towards PBDE exposure of both mothers and children seems warranted.
Hannas BR, Furr J, Lambright CS, Wilson VS, Foster PM, Gray LE, Jr. Dipentyl phthalate dosing during sexual differentiation disrupts fetal testis function and postnatal development of the male Sprague-Dawley rat with greater relative potency than other phthalates. Toxicol Sci. 2011 Mar;120(1):184-93.
Phthalate esters (PEs) constitute a large class of plasticizer compounds that are widely used for many consumer product applications. Ten or more members of the PE class of compounds are known to induce male fetal endocrine toxicity and postnatal reproductive malformations by disrupting androgen production during the sexual differentiation period of development. An early study conducted in the rat pubertal model suggested that dipentyl phthalate (DPeP) may be a more potent testicular toxicant than some more extensively studied phthalates. Regulatory agencies require dose-response and potency data to facilitate risk assessment; however, very little data are currently available for DPeP. The goal of this study was to establish a more comprehensive data set for DPeP, focusing on dose-response and potency information for fetal and postnatal male reproductive endpoints. We dosed pregnant rats on gestational day (GD) 17 or GD 14-18 and subsequently evaluated fetal testicular testosterone (T) production on GD 17.5 and GD 18, respectively. We also dosed pregnant rats on GD 8-18 and evaluated early postnatal endpoints in male offspring. Comparison of these data to data previously obtained under similar conditions for di (2-ethylhexyl) phthalate indicates that DPeP is approximately eightfold more potent in reducing fetal T production and two- to threefold more potent in inducing development of early postnatal male reproductive malformations. Additionally, fetal testicular T production was more sensitive to inhibitory effects of DPeP exposure than was gene expression of target genes involved in male reproductive development, supporting the use of this endpoint as a critical effect in the risk assessment process.
Huang LP, Lee CC, Hsu PC, Shih TS. The association between semen quality in workers and the concentration of di(2-ethylhexyl) phthalate in polyvinyl chloride pellet plant air. Fertil Steril. 2011 Jul;96(1):90-4.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating of some drugs, food packaging and vinyl flooring. In this study, researchers measured the concentration of diethylhexyl phthalate (DEHP) in air samples collected from 45 workers in a chemical plant producing polyvinyl chloride (PVC) in Taiwan. Workers exposed to DEHP levels above the median had lower semen quality, includinng reduced sperm motility and more DNA abnormalities in sperm heads relative to workers with exposure below the median. These results suggest that respiratory exposure to DEHP may be related to reduced semen quality at exposure levels experienced by workers employed in a PVC manufacturing plant.
Scientific abstract:
OBJECTIVE: To investigate potential associations between semen quality in workers and the concentrations of di(2-ethylhexyl) phthalate (DEHP) in personal air collected from polyvinyl chloride (PVC) plants. DESIGN: Cross-sectional study. SETTING: PVC plants in Taiwan. PATIENT(S): Forty-five male workers employed in two PVC pellet plants. INTERVENTION(S): None. MAIN OUTCOME MEASUREMENT(S): Sperm concentration, motility, morphology, and chromatin DNA integrity were accessed. RESULT(S): The workers were divided into low- and high-DEHP-exposed groups in accordance with the median levels of DEHP (23.7 mug/m(3)) in personal air. In the high-DEHP-exposed group, significant increases were found in the tendency for sperm DNA denaturation (alphaT) induction, the DNA fragmentation index (DFI), and propensity for coffee drinking. After adjusting for coffee drinking, cigarette smoking, and age, personal air concentrations of DEHP showed positive associations with alphaT (beta = 0.038) and DFI (beta = 0.140) and negative associations with sperm motility (beta = -0.227). CONCLUSION(S): This is the first study to demonstrate a link between DEHP concentration in ambient air and the adverse effects in sperm motility and chromatin DNA integrity. Given the current wide use of these PVC products, the implications for phthalates toxicity and occupational health could be considerable.
Ibhazehiebo K, Iwasaki T, Kimura-Kuroda J, Miyazaki W, Shimokawa N, Koibuchi N. Disruption of thyroid hormone receptor-mediated transcription and thyroid hormone-induced purkinje cell dendrite arborization by polybrominated diphenyl ethers. Environ Health Perspect. 2011 Feb;119(2):168-75.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. A number of studies suggest that PBDEs may affect brain development. This may occur through the disruption of thyroid hormone, which are essential to normal brain development. In this study, researchers exposed brain cells to PBDEs and found that the chemicals interfered with thyroid hormone action by preventing the thyroid hormone receptor from binding to DNA sequences called thyroid hormone response elements. They found that this prevented the normal development of brain cells. These results suggest PBDEs affects thyroid action on brain cells, which may in turn disrupt brain development.
Scientific abstract:
Background: Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants and are becoming a ubiquitous environmental contaminant. Adverse effects in the developing brain are of great health concern.Objective: We investigated the effect of PBDEs/hydroxylated PBDEs (OH-PBDEs) on thyroid hormone (TH) receptor (TR)-mediated transcription and on TH-induced dendrite arborization of cerebellar Purkinje cells.Methods: We examined the effect of PBDEs/OH-PBDEs on TR action using a transient transfection-based reporter gene assay. TR-cofactor binding was studied by the mammalian two-hybrid assay, and TR-DNA [TH response element (TRE)] binding was examined by the liquid chemiluminescent DNA pull-down assay. Chimeric receptors generated from TR and glucocorticoid receptor (GR) were used to identify the functional domain of TR responsible for PBDE action. The change in dendrite arborization of the Purkinje cell in primary culture of newborn rat cerebellum was also examined.Results: Several PBDE congeners suppressed TR-mediated transcription. The magnitude of suppression correlated with that of TR-TRE dissociation. PBDEs suppressed transcription of chimeric receptors containing the TR DNA binding domain (TR-DBD). We observed no such suppression with chimeras containing GR-DBD. In the cerebellar culture, PBDE significantly suppressed TH-induced Purkinje cell dendrite arborization.Conclusions: Several PBDE congeners may disrupt the TH system by partial dissociation of TR from TRE acting through TR-DBD and, consequently, may disrupt normal brain development.
Jedrychowski W, Perera F, Maugeri U, Miller RL, Rembiasz M, Flak E, Mroz E, Majewska R, Zembala M. Intrauterine exposure to lead may enhance sensitization to common inhalant allergens in early childhood: a prospective prebirth cohort study. Environ Res. 2011 Jan;111(1):119-24.
BACKGROUND: Several in vivo and in vitro studies have shown that metal-rich particles may enhance allergic responses to house dust mites and induce an increased release of allergy-related cytokines. OBJECTIVES: The main goal of this analysis is to define the possible association of intrauterine exposure to lead and mercury with the occurrence of skin sensitization to common aeroallergens in early childhood. MATERIAL AND METHODS: The present study refers to a sample of 224 women in the second trimester of pregnancy recruited from Krakow inner city area who had full term pregnancies and whose children underwent skin prick testing (SPT) at the age of 5. Lead and mercury levels were assessed in cord blood and retested in children at age of 5 years. Aeroallergen concentrations in house dust were measured at the age of 3 years. The main health outcome (atopic status) was defined as the positive SPT to at least one common aeroallergen (Der f1, Der p1, Can f1 and Fel d1) at the age of 5 years. In the statistical analysis of the association between atopic status of children and exposure to metals, the study considered a set of covariates such as maternal characteristics (age, education, atopy), child's gender, number of older siblings, prenatal (measured via cord blood cotinine) and postnatal environmental tobacco smoke together with exposure to polycyclic aromatic hydrocarbons (PAH) as measured by PAH-DNA adducts. RESULTS AND CONCLUSION: In the binary regression analysis, which controlled for the confounders, the risk ratio (RR) estimate for atopic sensitization was significantly associated with the lead exposure (RR=2.25, 95%CI: 1.21-4.19). In conclusion, the data suggest that even very low-level of prenatal lead exposure may be implicated in enhancing sensitization to common aeroallergens in early childhood.
Jung EM, An BS, Choi KC, Jeung EB. Potential estrogenic activity of triclosan in the uterus of immature rats and rat pituitary GH3 cells. Toxicol Lett. 2011 Oct;.
Scientific abstract:
Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS) is used as an antimicrobial agent in personal care, pharmaceutical, industrial, and household products. In this study, we established an in vivo model for screening estrogenic activity of TCS in the uteri of immature rats. In addition, we employed temporarily transfected cells with plasmids containing estrogen response element (ERE) and progesterone (P4) response element (PRE) sequences. We found that uterine weight was significantly increased by 17alpha-ethinylestradiol (EE) as a positive control and TCS at doses of 7.5, 37.4, and 187.5mg/kg. In addition, the expressions of calbindin-D(9k) (CaBP-9k) and complement C3 (C3) were significantly induced by EE and TCS in the uteri of immature rats, indicating that TCS can induce their expression mediated by estrogenic activity. Co-treatment with steroid antagonists ICI 182,780 (ICI) and RU 486 in conjunction with TCS (37.5mg/kg) reversed TCS-induced uterine weight and CaBP-9k mRNA and protein expression increases in immature rats. Moreover, ERE and PRE luciferase activity was evaluated in GH3 cells following treatment with TCS. Concentrations of TCS at increasing doses (10(-9), 10(-7), and 10(-5)M) resulted in a significant increase in ERE luciferase activity compared to control; however, no difference was observed in PRE luciferase activity following TCS treatment. To confirm that ER signaling is involved in TCS-induced CaBP-9k expression, we treated GH3 cells with the anti-estrogen ICI, which can block TCS-induced up-regulation of CaBP-9k in these cells. Taken together, these results indicate that TCS has an estrogen-like property, which may be mediated through an ER-involved signaling pathway in both in vivo and in vitro models.
Kim S, Choi K, Ji K, Seo J, Kho Y, Park J, Park S, Hwang I, Jeon J, Yang H, Giesy JP. Trans-placental transfer of thirteen perfluorinated compounds and relations with fetal thyroid hormones. Environ Sci Technol. 2011 Sep;45(17):7465-72.
Study Synopsis: Polyfluoroalkyl compounds (PFCs) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFCs. In this study, researchers measured the concentration of 4 PFCs in the blood of 44 pregnant women as well as in cord blood and breast milk. They found that increasing maternal blood levels of perfluorotridecanoic acid (PFTDA) was associated with reduced concentrations of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) in cord blood and that maternal perfluorooctane sulfate (PFOS) was related to decreasing levels of T3 in cord blood. Results are of particular significance due to the important role played by thyroid hormone in fetal growth and brain development. In summary, results suggest that exposure to some PFCs may be related to decreases in the concentration of the thyroid hormones T3 and/or T4 in cord blood.
Scientific abstract:
While the results of animal studies have shown that perfluorinated compounds (PFCs) can modulate concentrations of thyroid hormones in blood, limited information is available on relationships between concentrations of PFCs in human blood serum and fetal thyroid hormones. The relationship between concentrations of PFCs in blood and fetal thyroid hormone concentrations or birth weight, and ratios of major PFCs between maternal and fetal serum were determined. Concentrations of PFCs were measured in blood serum of pregnant women (n = 44), fetal cord blood serum (n = 43) and breast milk (n = 35). Total concentrations of thyroxin (T4), triiodothyronin (T3) and thyroid stimulating hormone (TSH) in blood serum were also quantified. The ratios of major PFCs in maternal versus fetal serum were 1:1.93, 1.02, 0.72, and 0.48 for perfluorotridecanoic acid (PFTrDA), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS), respectively. Fetal PFOS, PFOA, PFTrDA and maternal PFTrDA were correlated with fetal total T4 concentrations, but after adjusting for major covariates, most of the relationships were no longer statistically significant. However, the significant negative correlations between maternal PFOS and fetal T3, and maternal PFTrDA and fetal T4 and T3 remained. Since thyroid hormones are crucial in the early development of the fetus, its clinical implication should be evaluated. Given the observed trans-placental transfer of PFCs, efforts should be also made to elucidate the exposure sources among pregnant women.
Kim SH, Chun S, Jang JY, Chae HD, Kim CH, Kang BM. Increased plasma levels of phthalate esters in women with advanced-stage endometriosis: a prospective case-control study. Fertil Steril. 2011 Jan;95(1):357-9.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured the blood levels of two phthalates, namely monoethylhexyl phthalate (MEHP) and diethylhexyl phthalate (DEHP), in the blood of 97 Korean women with endometriosis and in 169 healthy controls. Endometriosis is a condition characterized by the growth of tissue normally found in the uterus on other organs or structures. This may cause infertility, abdominal pain and abnormal menses. Higher blood concentration of both MEP and DEP were found in women with endometriosis relative to controls. These results suggest that exposure to phthalates may be related to endometriosis.
Scientific abstract:
We performed the present prospective case-control study to evaluate whether the plasma concentrations of phthalate esters are elevated in women with advanced-stage endometriosis in a Korean population. Measuring plasma levels of monoethylhexyl phthalate and di-(2-ethylhexyl) phthalate in 97 women with advanced-stage endometriosis and 169 control women by liquid chromatography-tandem mass spectrometry, we found that the concentrations of monoethylhexyl phthalate, as well as di-(2-ethylhexyl) phthalate, are significantly higher in those with advanced-stage endometriosis, which supports the hypothesis that exposure to phthalate might play a role in the establishment of endometriosis.
Knox SS, Jackson T, Javins B, Frisbee SJ, Shankar A, Ducatman AM. Implications of early menopause in women exposed to perfluorocarbons. J Clin Endocrinol Metab. 2011 Jun;96(6):1747-53.
Study Synopsis: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA and PFOS. In this study, researchers measured PFOA and PFOS in the blood of 25,957 women aged 18 to 65 years. Odds of having reached menopause were between 1.4 and 2.1 times higher among women in the highest quintile of PFOS relative to those in the lowest quintile. Women with higher blood levels of PFOS also had lower levels of the female hormone estradiol. No associations were found with PFOA blood levels. These results suggest that exposure to PFOS, but not PFOA, may be related with earlier menopause and lower estradiol blood levels in women.
Scientific abstract:
Context: Perfluorocarbons (PFC) are man-made chemicals used in numerous household products. They have a long half-life in humans and complex animal toxicity, and accumulating evidence points toward associations with multiple human health endpoints. Objective: Our objective was to investigate whether PFC are associated with endocrine disruption in women. Design: Cross-sectional analyses were made between quintiles of serum PFC, serum estradiol, and menopause onset. Setting: The C8 Health Project, with cohort of 69,030 adults and children, was conducted due to PFC contamination of drinking water from six water districts in two states. Participants: Participants included 25,957 women aged 18-65 yr. Main Outcome Measures: Serum estradiol levels and onset of menopause were assessed. The survey was the result of a class action suit, and survey designers (an independent corporation) had no a priori hypotheses. All hypotheses have been formulated by other investigators after data collection. Results: After excluding women who reported hysterectomy and adjusting for age within the group, smoking, alcohol consumption, body mass index, and exercise, the odds of having experienced menopause were significantly higher in the highest quintile relative to the lowest quintile of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) in the perimenopausal [PFOS odds = 1.4, confidence interval (CI) = 1.1-1.8; PFOA odds =1.4, CI = 1.1-1.8] and menopausal age groups (PFOS odds = 2.1, CI=1.6-2.8; PFOA odds = 1.7, CI = 1.3-2.3). After appropriate exclusions and adjustment for covariates, there was a significant inverse association between PFOS and estradiol in perimenopausal (beta = -3.65; P < 0.0001) and menopausal age groups (beta = -0.83; P = 0.007) but not between PFOA and estradiol. Conclusions: These data suggest that PFC are associated with endocrine disruption in women and that further research on mechanisms is warranted.
Korrick SA, Lee MM, Williams PL, Sergeyev O, Burns JS, Patterson DG, Turner WE, Needham LL, Altshul L, Revich B, Hauser R. Dioxin exposure and age of pubertal onset among Russian boys. Environ Health Perspect. 2011 Sep;119(9):1339-44.
Study Synopsis: Dioxins are highly toxic chemicals that are higly persistent in the environment and bioaccumulate in humans' fat. Some evidence suggests that chemicals such as dioxins may disrupt hormones and alter the timing of puberty. In this study, researchers measured the serum concentration of dioxins in 499 boys who lived in Chapaevsk, Russia, a region contaminated with dioxins. Boys were enrolled at age 8-9 years and followed until age 12. Pubertal onset was assessed based on genitalia and testicular development. Dioxin concentration and toxic equivalents, which combines the levels of chemicals similar to dioxins (such as furans and polychlorinated biphenyls), were associated with later onset of puberty based on testicular development but not based on genitalia development. Results suggest that relatively high exposure to dioxins is related to delayed puberty in boys
Scientific abstract:
BACKGROUND: Animal data demonstrate associations of dioxin, furan, and polychlorinated biphenyl (PCB) exposures with altered male gonadal maturation. It is unclear whether these associations apply to human populations. OBJECTIVES: We investigated the association of dioxins, furans, PCBs, and corresponding toxic equivalent (TEQ) concentrations with pubertal onset among boys in a dioxin-contaminated region. METHODS: Between 2003 and 2005, 499 boys 8-9 years of age were enrolled in a longitudinal study in Chapaevsk, Russia. Pubertal onset [stage 2 or higher for genitalia (G2+) or testicular volume (TV) > 3 mL] was assessed annually between ages 8 and 12 years. Serum levels at enrollment were analyzed by the Centers for Disease Control and Prevention, Atlanta, Georgia, USA. We used Cox proportional hazards models to assess age at pubertal onset as a function of exposure adjusted for potential confounders. We conducted sensitivity analyses excluding boys with pubertal onset at enrollment. RESULTS: The median (range) total serum TEQ concentration was 21 (4-175) pg/g lipid, approximately three times higher than values in European children. At enrollment, boys were generally healthy and normal weight (mean body mass index, 15.9 kg/m2), with 30% having entered puberty by G2+ and 14% by TV criteria. Higher dioxin TEQs were associated with later pubertal onset by TV (hazard ratio = 0.68, 95% confidence interval, 0.49-0.95 for the highest compared with the lowest quartile). Similar associations were observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin concentrations for TV but not G2+. Results were robust to sensitivity analyses. CONCLUSIONS: Findings support an association of higher peripubertal serum dioxin TEQs and concentrations with later male pubertal onset reflected in delayed testicular maturation.
Korrick SA, Lee MM, Williams PL, Sergeyev O, Burns JS, Patterson DJ, Turner WE, Needham LL, Altshul L, Revich B, Hauser R. Dioxin exposure and age of pubertal onset among Russian boys. Environ Health Perspect. 2011 Apr ;.
Study Synopsis: Dioxins are highly toxic chemicals that persist in the environment, accumulate in human fatty tissue and concentrate up the food chain. Furans and polychlorinated biphenyls (PCBs) are closely related chemicals that have toxicological properties that are similar to those of dioxins. In this study, researchers measured dioxins, furans and PCBs in the blood of 489 boys aged 8 to 9 years and evaluated pubertal development based on testicular volume and genitalia development. They found that those with higher blood levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic dioxin, and total dioxins entered puberty later when testicular volume was used as the criteria. Similar results were obtained when exposure was summarized based on the relative toxicity of all the chemicals measured. Results suggest that exposure to dioxins is related with delayed puberty in boys.
Scientific abstract:
Background: Animal data demonstrate associations of dioxin, furan, and PCB exposures with altered male gonadal maturation. It is unclear whether these associations apply to human populations. Objectives: We investigated the association of dioxins, furans, PCBs and corresponding toxic equivalent (TEQ) concentrations with pubertal onset among boys in a dioxin-contaminated region. Methods: Between 2003-2005, 489 boys were enrolled at ages 8-9 years in a longitudinal study in Chapaevsk, Russia. Pubertal onset - stages 2 or higher for genitalia (G2+) or testicular volume (TV) > 3 ml - was assessed annually between ages 8-12 years. Serum levels at enrollment were analyzed by the Centers for Disease Control and Prevention, Atlanta, GA. Cox proportional hazards models were used to assess age at pubertal onset as a function of exposure adjusted for potential confounders. Sensitivity analyses were conducted excluding boys with pubertal onset at enrollment. Results: The median (range) total serum TEQ concentration was 21 (4-175) pg/g lipid, approximately three times higher than values in European children. At enrollment, boys were generally healthy and normal weight (mean BMI 15.9 kg/m2), with 30% having entered puberty by G2+ and 14% by TV criteria. Higher dioxin TEQs were associated with later pubertal onset by TV, hazard ratio = 0.68, 95% CI: 0.49-0.95 for the highest compared with the lowest quartile. Similar associations were observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin concentrations for TV but not G2+. Results were robust to sensitivity analyses. Conclusions: Findings support an association of higher peri-pubertal serum dioxin TEQs and concentrations with later male pubertal onset reflected in delayed testicular maturation.
Kraugerud M, Zimmer KE, Ropstad E, Verhaegen S. Perfluorinated compounds differentially affect steroidogenesis and viability in the human adrenocortical carcinoma (H295R) in vitro cell assay. Toxicol Lett. 2011 Aug;205(1):62-8.
Study Synopsis: Perfluorinated compounds (PFCs), including perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS) and perfluorononanoic acid (PFNA) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFCs. In this study, researchers exposed cells from the adrenal cortex to PFCs. The adrenal cortex is one of the site of production of sex hormones such as the male hormone testosterone and the female hormone estradiol. High doses of PFOS was found to increase estradiol, testosterone and progesterone production. The expression of a gene involved (cytochrome 11A) in the synthesis of these hormones was however not affected by PFOS. Exposure of the cells to other PFCs such as PFOA and PFNA had minimal effects on hormone production. These results suggest that PFOS in high concentrations affects the production of hormones by the adrenal cortex by a mechanism that does not involve a change in gene expression.
Scientific abstract:
Perfluorinated compounds (PFCs) comprise a large class of man-made chemicals of which some are persistent and present throughout the ecosystem. This raises concerns about potential harmful effects of such PFCs on humans and the environment. In order to investigate the effects of potentially harmful PFCs on steroid hormone production, human adrenocortical H295R cells were exposed to three persistent PFCs including perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) at six different concentrations (6nM to 600muM) for 48h. Exposure to 600muM PFOS resulted in a dose-responsive increase in oestradiol as well as a smaller dose-responsive increase in progesterone and testosterone secretion measured using radioimmunoassay. The aromatase activity was not significantly altered by PFOS. Only small changes in hormone secretion were detected following exposure to PFOA and PFNA. Gene expression of CYP11A, quantified using qRT-PCR was decreased by all exposure doses of PFOA, whereas HMGR expression was decreased by 60nM PFNA. The viability markedly decreased by exposure to 600muM of PFOA or PFNA, but not PFOS. Flow cytometric analysis demonstrated a significant increase in apoptosis following exposure to PFNA at the highest concentration. We conclude that PFOS is capable of altering steroidogenesis in the H295R in vitro model by a mechanism other than changes in gene expression or activity of aromatase. Additionally, PFCs appear to differentially affect cell viability with induction of cell death via apoptosis at high doses of PFNA.
Kusk KO, Kruger T, Long M, Taxvig C, Lykkesfeldt AE, Frederiksen H, Andersson AM, Andersen HR, Hansen KM, Nellemann C, Bonefeld-Jorgensen EC. Endocrine potency of wastewater: contents of endocrine disrupting chemicals and effects measured by in vivo and in vitro assays. Environ Toxicol Chem. 2011 Feb;30(2):413-26.
Study Synopsis: Endocrine disrupting compounds (EDCs) are chemicals that are suspected of affecting hormone systems in humans and wildlife. Industrial and municipal effluents may be an important source of EDCs in the aquatic environment. In this study, researchers examined the efficiency of two typical urban Danish sewage treatment plants in removing EDCs from wastewater. They found that treatment plants substantially reduced the concentration of some EDCs but that treated water still had hormonal effects. These results suggest that the treatment plants tested only partially removed EDCs from water.
Scientific abstract:
Industrial and municipal effluents are important sources of endocrine disrupting compounds (EDCs) discharged into the aquatic environment. This study investigated the endocrine potency of wastewater and the cleaning efficiency of two typical urban Danish sewage treatment plants (STPs), using chemical analysis and a battery of bioassays. Influent samples, collected at the first STP grate, and effluent samples, collected after the sewage treatment, were extracted using solid phase extraction. Extracts were analyzed for the content of a range of industrial chemicals with endocrine disrupting properties: phthalate metabolites, parabens, industrial phenols, ultraviolet screens, and natural and synthetic steroid estrogens. The endocrine disrupting bioactivity and toxicity of the extracts were analyzed in cell culture assay for the potency to affect the function of the estrogen, androgen, aryl hydrocarbon, and thyroid receptors as well as the steroid hormone synthesis. The early-life stage (ELS) development was tested in a marine copepod. The concentrations of all analyzed chemicals were reduced in effluents compared with influents, and for some to below the detection limit. Influent as well as effluent samples from both STPs were found to interact with all four receptors and to interfere with the steroid hormone synthesis showing the presence of measured EDCs. Both influent samples and one of the effluent samples inhibited the development of the copepod Acartia tonsa. In conclusion, the presence of EDCs was reduced in the STPs but not eliminated, as verified by the applied bioassays that all responded to the extracts of effluent samples. Our data suggest that the wastewater treatment processes are not efficient enough to prevent contamination of environmental surface waters.
Lambertino A, Turyk M, Anderson H, Freels S, Persky V. Uterine leiomyomata in a cohort of Great Lakes sport fish consumers. Environ Res. 2011 May;111(4):565-72.
Scientific abstract:
Diet and endocrine disrupting persistent organic pollutants (POPs) have been associated with gynecologic conditions including uterine leiomyomata (UL), endometriosis, and ovarian cysts. Great Lakes sport fish consumption is a source of exposure to POPs such as p,p'-diphenyldichloroethene (DDE) and polychlorinated biphenyls (PCBs). This study was designed to examine retrospectively the effects Great Lakes sport fish consumption on the incidence of UL and to examine the effects of DDE and PCB serum levels on prevalent UL in women participating in the Great Lakes Fish Consumption Study. We hypothesized that associations of exposures with UL would be modified by breastfeeding status. Years of sport fish consumption, demographic, health, and reproductive data were assessed by survey. In a subgroup, serum was collected and tested for DDE and PCB levels. Effects of years of Great Lakes sport fish and sport fish consumption were modeled using time-dependent Cox proportional hazards regression and effects of POP exposures on UL were modeled using multiple logistic regression. Years of sport fish consumption were associated with UL, with an incidence rate ratio of 1.2 (95% CI 1.0-1.3) for each 10-year increment of fish consumption. Summary measures of POP exposures in the overall group were not associated with UL. In the subgroup of women who never breastfed and in whom PCB measurements were available, however, UL was significantly associated with PCBs and groupings of estrogenic, antiestrogenic, and dioxin-like PCBs. These findings support the possibility that PCB exposures from fish consumption may increase the risk of UL and highlight the importance of additional studies exploring biologic pathways by which they could be acting.
Li S, Dai J, Zhang L, Zhang J, Zhang Z, Chen B. An association of elevated serum prolactin with phthalate exposure in adult men. Biomed Environ Sci. 2011 Feb;24(1):31-9.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is commone due to their widespread use. In this study, researchers measured two phthalates named dibutyl phthalate (DBP) and diethylhexyl phthalate (DEHP) in semen and blood samples collected from 118 men suspected of infertility. They also measured several hormones in their blood including follicle-stimulating hormone, luteinizing hormone, testosterone, estradiol and prolactin. Researchers found that men with higher levels of DBP and DEHP in blood, and those with higher concentration of DEHP in semen, had increased levels of the hormone prolactin. For instance, men with higher blood DEHP levevls had 4.7 times the odds of having elevated prolactin relative to those who had low DEHP levels. Higher serum concentration of DEHP was also related with increased estradiol levels. These results suggest that exposure to phthalates may be related to changes in hormone levels in men.
Scientific abstract:
OBJECTIVE: To investigate the associations of hormone circulation with phthalate exposure in adult men. METHODS: Semen and serum samples were collected from 118 men who were suspected of infertility. Phthalate diesters including dibutyl phthalate (DBP) and diethylhexyl phthalate (DEHP) in both semen and serum samples were measured, along with serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E(2)) and prolactin (PRL). RESULTS: Serum PRL was positively associated with serum DBP and DEHP and semen DEHP in all models of Spearman correlation, linear regression and binary logistic regression. In linear regression models adjusted for potential confounders and excluding subjects with undetectable phthalates, a 10-fold increase in semen DEHP was associated with a 23% increase in serum PRL, as well as a 26% increase in serum DBP and a 20% increase in serum DEHP. In logistic regression models all subjects demonstrated a dose-response relationship between above reference value PRL and semen DEHP (odds ratio per tertile adjusted for potential confounders = 1.0, 1.70, 3.50; P for trend = 0.01), and serum DBP (1.0, 1.10, 2.62; P for trend = 0.04), and serum DEHP (1.0, 1.46, 4.69; P for trend < 0.01). A positive correlation between serum estradiol and semen DEHP (linear regression), and an inverse correlation between semen DBP and serum testosterone and T:E(2) ratio (Spearman correlation) were also established. CONCLUSION: Serum PRL is suggested to be positively associated with both DBP and DEHP exposure in adult men.
Lin LC, Wang SL, Chang YC, Huang PC, Cheng JT, Su PH, Liao PC. Associations between maternal phthalate exposure and cord sex hormones in human infants. Chemosphere. 2011 Jan ;83(8):1192-9.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is commone due to their widespread use. In this study, researchers measured the concentration of phthalate residues in the urine of 155 pregnant women and measured hormones in umbelical cord blood. They found that, among women who gave birth to a girl, those with higher exposure to a type of phthalate called diethylhexyl phthalate (DEHP) had lower cord free testosterone. No such association was found among male newborns. These results suggest that maternal exposure to DEHP may be related with reduced cord free testosterone in female newborns.
Scientific abstract:
It has been speculated that maternal phthalate exposure may affect reproductive development in human newborns. However, the mechanism awaits further investigation. The aim is to evaluate the association between maternal phthalate exposure and cord sex steroid hormones in pregnant women and their newborns from the general population. A total of 155 maternal and infant pair were recruited and analyzed. Levels of urinary phthalate metabolites and sex steroid hormones were determined using liquid chromatography/electrospray tandem mass spectrometry (LC-ESI-MS/MS) and radioimmunoassay (RIA), respectively. No significant correlation was found between each steroid hormones and phthalate metabolites for male newborns, except MMP was marginally significantly correlated with E(2). After adjusting for maternal age, estradiol (E(2)) levels in cord serum from male newborns were not correlated with maternal urinary phthalate metabolites. In female newborns, the maternal urinary levels of mono-(2-ethylhexyl) phthalate (MEHP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (5OH-MEHP) were negatively correlated with the free testosterone (fT) and fT/E(2) levels in cord serum with Pearson correlation coefficients ranging between -0.24 and -0.29 (p<0.05). Additionally, after gestational age was adjusted, the maternal urinary level of DEHP was negatively correlated with the free testosterone (fT) and fT/E(2) levels in cord serum. We suggest that maternal exposure to phthalates may affect sex steroid hormones status in fetal and newborn stage.
Lin SM, Chen FA, Huang YF, Hsing LL, Chen LL, Wu LS, Liu TS, Chang-Chien GP, Chen KC, Chao HR. Negative associations between PBDE levels and thyroid hormones in cord blood. Int J Hyg Environ Health. 2011 Mar;214(2):115-20.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers measured the blood concentration of PBDEs in the cord blood of 54 women shortly after they gave birth. They found that higher levels of some types of PBDEs, namely BDE-153 and BDE-183, were related to lower levels of the thyroid hormone free triiodothyronine (T3) in cord blood. Increasing concentrations of BDE-154 were also associated with lower total T3. These results agree with those reported by experimental studies conducted in rodents but contrast with results found in prior human studies.
Scientific abstract:
Polybrominated diphenyl ethers (PBDEs) causing thyroidal effects have been demonstrated in in vivo and in vitro studies. PBDEs with structural similarities to thyroid hormones have increased recently, but the health effects for thyroid hormones have not been well studied. The study aimed to determine PBDE levels in cord blood and further to explore associations between prenatal PBDE exposures and thyroid hormones in cord blood. Fifty-four cord blood samples were collected after delivery. Cord-blood levels of BDE-15, 28, 47, 99, 100, 153, 154, and 183 were analyzed using a high resolution gas chromatograph with a high resolution mass spectrometer. Thyroid hormones were determined by an automated chemiluminescence analyzer. The mean, median, and standard deviation of SigmaPBDEs were 4.72, 3.49, and 6.36ng/g lipid, respectively. To adjust for confounding by maternal age, pre-pregnant BMI and gestational age, stepwise multiple linear regression was used after log(2) transformation of the exposure variables. A doubling of BDE-154 was associated with 0.043ng/mL lower triiodothyronine (T3) values (adjusted r=-0.245, p=0.043). Likewise a doubling of BDE-153 was associated with 0.143ng/mL lower free T3 (FT3) values and a doubling of BDE-183 with 0.084ng/mL lower FT3 values (adjusted r=-0.487, p=0.023). In contrast, the T4 (thyroxine)/T3 ratio increased by 4.93 (adjusted r=0.277, p=0.017) when doubling BDE-100 exposure. No significant associations with BDE-47 or any other of the PBDEs was found. Our findings of an inverse relationship between BDE-153, BDE-154 or BDE-184 and thyroid hormones confirm the results of animal experiments but are in contrast to most epidemiological studies.
Liu L, Bao H, Liu F, Zhang J, Shen H. Phthalates exposure of Chinese reproductive age couples and its effect on male semen quality, a primary study. Environ Int. 2011 25-Apr;.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured the residues of six phthalates in the urine of 150 male patients from a fertility clinic. Sperm quality parameters were measured including semen volume, and sperm concentration and motility. They found that urine levels of one of the residues, named monobutyl phthalate, was related to lower sperm concentration. These results suggest that urine levels of phthalate residues may be associated with poorer semen parameters.
Scientific abstract:
Phthalates are suspected of having adverse effects on androgen-regulated reproductive development in animals and may be toxic for human sperm. The purposes of our study were to investigate the general exposure of a Chinese reproductive age cohort to these ubiquitous pollutants and to assess their potential effect on semen quality. Six phthalate metabolites, monomethyl phthalate (MMP), monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono-2-ethylhexyl phthalate (MEHP), and mono-2-ethyl-5-oxohexyl phthalate (MEOHP) were measured in spot urines of 150 individuals recruited from a Chongqing, China, reproductive institute. The questionnaire and clinical data were evaluated, and the correlations of phthalate exposure and semen qualities like semen volume, sperm concentration, motility and sperm motion parameters, were determined by multiple logistic regression analysis. The creatinine adjusted average concentrations for MMP, MEP, MBP, MBzP, MEHP and MEOHP were 41.3, 300, 41.0, 0.78, 2.99 and 3.90mug/g, respectively. After adjustment for age, body mass index (BMI), abstinence, smoking, drinking, and education, there was a borderline-significant dose-response relationship between MBP and sperm concentration, with odd ratios (ORs) 1.0, 6.8 and 12.0 for increasing exposure tertiles (p=0.05). Although the dose-response relationships for MMP and MEP versus sperm concentration were not significant, a significant positive correlation between MEP and straight-line velocity of sperm motion was observed. The present data may imply some effects of phthalate exposure on semen. However, due to the small sample size, our finding needs to be confirmed on a larger population.
Lopez-Espinosa MJ, Fletcher T, Armstrong B, Genser B, Dhatariya K, Mondal D, Ducatman A, Leonardi G. Association of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with age of puberty among children living near a chemical plant. Environ Sci Technol. 2011 2-May;.
Study Synopsis: Perfluorochemicals (PFCs) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of two PFCs, namely perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS). In this study, researchers measured the blood concentration of PFOA and PFOS in 3,076 boys and 2,931 girls aged 8-18 years and evaluated relationships with sexual maturation based on hormone levels (testosterone or estradiol) or menarche onset. They found that girls with higher levels of PFOS or PFOA reached menarche later while boys with higher blood levels of PFOS took longer for their testosterone to raise (an indicator of puberty onset). These results thus suggest that blood levels of PFCs may be associated with delayed sexual maturation in boys and girls.
Scientific abstract:
Animal studies suggest that perfluorocarbons (PFCs) may alter sexual maturation. Relationships of human PFC exposure with puberty are not clear. We conducted a cross-sectional study to investigate whether perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) were associated with indicators of sexual maturation in a 2005-2006 survey of residents with PFOA water contamination from the Mid-Ohio Valley. Participants were 3076 boys and 2931 girls aged 8-18 years. They were classified as having reached puberty based on either hormone levels (total >50 ng/dL and free >5 pg/mL testosterone in boys and estradiol >20 pg/mL in girls) or onset of menarche. We estimated the odds of having reached puberty classified by these criteria and the fitted median age of reaching puberty in relation to serum PFOA and PFOS concentrations measured when puberty status was assigned. For boys, there was a relationship of reduced odds of reached puberty (raised testosterone) with increasing PFOS (delay of 190 days between the highest and lowest quartile). For girls, higher concentrations of PFOA or PFOS were associated with reduced odds of postmenarche (130 and 138 days of delay, respectively). In conclusion, our study showed a later age of puberty in this population correlated with PFC concentrations.
Madrigano J, Baccarelli A, Mittleman MA, Wright RO, Sparrow D, Vokonas PS, Tarantini L, Schwartz J. Prolonged exposure to particulate pollution, genes associated with glutathione pathways, and DNA methylation in a cohort of older men. Environ Health Perspect. 2011 Mar ;.
Background and Objective: DNA methylation is a potential pathway linking environmental exposures to disease. Exposure to particulate air pollution has been associated with increased cardiovascular morbidity and mortality, and lower blood DNA methylation has been found in processes related to cardiovascular morbidity. We hypothesized that prolonged exposure to particulate pollution would be associated with hypomethylation of repetitive DNA elements and that this association would be modified by genes involved in glutathione metabolism and other host characteristics. Methods: DNA methylation of the Long Interspersed Nucleotide Element-1 (LINE-1) and the short interspersed nucleotide element, Alu, were measured by quantitative PCR-Pyrosequencing in 1406 blood samples from 706 elderly participants in the Normative Aging Study (NAS). We estimated changes in repetitive element DNA methylation associated with ambient particles (PM2.5), black carbon and sulfates, with mixed models. We examined multiple exposure windows (one to six months) prior to DNA methylation measurement. We investigated whether this association was modified by genotype and phenotype. Results: An increase of an interquartile range in black carbon over a 90-day period was associated with a decrease of 0.31% 5-methylcytosine (5-mC) (95% CI: 0.12%, 0.50%) in Alu. An increase in an interquartile range of sulfate over a 90-day period was associated with a decrease of 0.27% 5mC (0.02%, 0.52%) in LINE-1. The GSTM1 null genotype strengthened the association between black carbon and Alu hypomethylation. Conclusion: Prolonged exposure to black carbon and sulfate particles was associated with hypomethylation of two types of repetitive elements.
Martinez-Arguelles DB, Guichard T, Culty M, Zirkin BR, Papadopoulos V. In utero exposure to the antiandrogen di-(2-ethylhexyl) phthalate decreases adrenal aldosterone production in the adult rat. Biol Reprod. 2011 Jul;85(1):51-61.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. Prior studies found that exposure to diethylhexyl phthalate (DEHP) reduced the blood levels of testosterone in rats. In this study, researchers exposed pregnant rats to different levels of DEHP and measured the blood concentration of the hormones corticosterone and aldosterone in the blood of their offspring. Aldosterone stimulates the production of the male hormone testosterone. Exposure to DEHP resulted in a decrease in the levels of aldosterone but not corticosterone 60 days after birth. These results suggest that the decrease in testosterone observed after exposing rats to DEHP may be due to a reduction in blood aldosterone.
Scientific abstract:
We previously reported that in utero exposure of the male fetus to the plasticizer di-(2-ethylhexyl) phthalate (DEHP) resulted in decreased circulating levels of testosterone in the adult without affecting Leydig cell numbers, luteinizing hormone levels, or steroidogenic enzyme expression. Fetal exposure to DEHP resulted in reduced mineralocorticoid receptor (MR; NR3C2) expression in adult Leydig cells. In the present studies, treatment of pregnant Sprague-Dawley dams from Gestational Day 14 until birth with 20, 50, 100, 300, or 750 mg kg(-1) day(-1) of DEHP resulted in significant sex-specific decreases in serum aldosterone but not corticosterone levels at Postnatal Day 60 (PND60) but not at PND21. There was no effect on circulating levels of potassium, angiotensin II or adrenocorticotropin hormone (ACTH). However, there was reduced expression of AT receptor Agtr1a, Agtr1b, and Agtr2 mRNAs. The mRNA levels of proteins and enzymes implicated in aldosterone biosynthesis were not affected by in utero DEHP treatment except for Cyp11b2, which was decreased at high (>/= 500 mg kg(-1) day(-1)) doses. The data presented herein, together with our previous observation that aldosterone stimulates testosterone production via an MR-mediated mechanism, suggest that in utero exposure to DEHP causes reduction in both adrenal aldosterone synthesis and MR expression in Leydig cells, leading to reduced testosterone production in the adult. Moreover, these results suggest the existence of a DEHP-sensitive adrenal-testis axis regulating androgen formation.
Marvin CH, Tomy GT, Armitage JM, Arnot JA, Mccarty L, Covaci A, Palace V. Hexabromocyclododecane: current understanding of chemistry, environmental fate and toxicology and implications for global management. Environ Sci Technol. 2011 Oct;45(20):8613-23.
Study Synopsis: Hexabromocyclododecane (HBCD) is a flame retardant used in polystyrene insulation and textiles. Although a growing number of studies have examined the potential health effects of other flame retardants, such as polybrominated diphenyl ethers (PBDEs), few human studies have examined the effect of exposure to HBCD. This paper reviews the current knowledge on the health effects of this chemical.
Scientific abstract:
Hexabromocyclododecane (HBCD) is a globally produced brominated flame retardant (BFR) used primarily as an additive FR in polystyrene and textile products and has been the subject of intensified research, monitoring and regulatory interest over the past decade. HBCD is currently being evaluated under the Stockholm Convention on Persistent Organic Pollutants. HBCD is hydrophobic (i.e., has low water solubility) and thus partitions to organic phases in the aquatic environment (e.g., lipids, suspended solids). It is ubiquitous in the global environment with monitoring data generally exhibiting the expected relationship between proximity to known sources and levels; however, temporal trends are not consistent. Estimated degradation half-lives, together with data in abiotic compartments and long-range transport potential indicate HBCD may be sufficiently persistent and distributed to be of global concern. The detection of HBCD in biota in the Arctic and in source regions and available bioaccumulation data also support the case for regulatory scrutiny. Toxicity testing has detected reproductive, developmental and behavioral effects in animals where exposures are sufficient. Recent toxicological advances include a better mechanistic understanding of how HBCD can interfere with the hypothalamic-pituitary-thyroid axis, affect normal development, and impact the central nervous system; however, levels in biota in remote locations are below known effects thresholds. For many regulatory criteria, there are substantial uncertainties that reduce confidence in evaluations and thereby confound management decision-making based on currently available information.
Meeker JD, Ferguson KK. Relationship between urinary phthalate and bisphenol A concentrations and serum thyroid measures in U.S. adults and adolescents from the National Health and Nutrition Examination Survey (NHANES) 2007-2008. Environ Health Perspect. 2011 Oct;119(10):1396-402.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to these chemicals is common due to their widespread use. In this study, researchers used data from the National Health and Nutrition Examination Survey (NHANES), a large study using a sample that is representative of the U.S. population. The concentrations of phthalates and BPA were measured in the urine of 1,346 adults aged 20 years and older and 329 adolescents between the ages of 12 and 19 years by NHANES staff. Among adults, increasing urine levels of breakdown products of diethylhexyl phthalate (DEHP) was related to lower blood levels of the thyroid hormones thyroxine (T4) and triiodothyronine (T3), and increasing levels of thyroid-stimulating hormone (TSH), consistent with a medical condition called hypothyroidism. Conversely, in adolescents, DEHP breakdown products were associated with increasing T3. There was limited evidence that BPA urine levels were related to reduced T4 and TSH. These results suggest that urine levels of DEHP are related to changes in thyroid hormone levels consistent with hypothyroidism in adults but not in adolescents.
Scientific abstract:
BACKGROUND: Limited animal, in vitro, and human studies have reported that exposure to phthalates or bisphenol A (BPA) may affect thyroid signaling. OBJECTIVE: We explored the cross-sectional relationship between urinary concentrations of metabolites of di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and BPA with a panel of serum thyroid measures among a representative sample of U.S. adults and adolescents. METHODS: We analyzed data on urinary biomarkers of exposure to phthalates and BPA, serum thyroid measures, and important covariates from 1,346 adults (ages >/= 20 years) and 329 adolescents (ages 12-19 years) from the National Health and Nutrition Examination Survey (NHANES) 2007-2008 using multivariable linear regression. RESULTS: Among adults, we observed significant inverse relationships between urinary DEHP metabolites and total thyroxine (T4), free T4, total triiodothyronine (T3), and thyroglobulin, and positive relationships with thyroid-stimulating hormone (TSH). The strongest and most consistent relationships involved total T4, where adjusted regression coefficients for quintiles of oxidative DEHP metabolites displayed monotonic dose-dependent decreases in total T4 (p-value for trend < 0.0001). Suggestive inverse relationships between urinary BPA and total T4 and TSH were also observed. Conversely, among adolescents, we observed significant positive relationships between DEHP metabolites and total T3. Mono(3-carboxypropyl) phthalate, a secondary metabolite of both DBP and di-n-octyl phthalate, was associated with several thyroid measures in both age groups, whereas other DBP metabolites were not associated with thyroid measures. CONCLUSIONS: These results support previous reports of associations between phthalates-and possibly BPA--and altered thyroid hormones. More detailed studies are needed to determine the temporal relationships and potential clinical and public health implications of these associations.
Meeker JD, Maity A, Missmer SA, Williams PL, Mahalingaiah S, Ehrlich S, Berry KF, Altshul L, Perry MJ, Cramer DW, Hauser R. Serum concentrations of polychlorinated biphenyls (PCBs) in relation to in vitro fertilization (IVF) outcomes. Environ Health Perspect. 2011 Feb;.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. PCBs persist in the environment, accumulate in human fatty tissue and are detected in the blood of virtually all human populations. Exposure to PCBs has been associated with a number of adverse health effects. In this study, PCBs were measured in blood samples collected from 765 women undergoing in vitro fertilization between 1994 and 2003. Women with elevated (highest quartile) blood levels of total PCBs had 70% higher odds of failed implantation than those with low PCB levels (lower quartile). Most of the relationship appeared to be driven by one type of PCB (congener number 153). Women with elevated levels of this congener had twice the odds of failed implantation relative to those with low levels. No relation was found with the odds of reaching clinical pregnancy or with the risk of spontaneous abortion. Results suggest that blood levels of PCBs are related with elevated odds of failed implantation among women undergoing in vitro fertilization.
Scientific abstract:
Background: Human exposure to polychlorinated biphenyls (PCBs) remains widespread. PCBs have been associated with adverse reproductive health outcomes including reduced fecundability and increased risk of pregnancy loss, though the human data remain largely inconclusive. Objective: To explore the relationship between serum PCB concentrations and early pregnancy loss among a large cohort of women undergoing in vitro fertilization (IVF) between 1994 and 2003. Methods: Concentrations of 57 PCB congeners were measured in serum samples collected during 827 IVF/ICSI cycles from 765 women. Joint statistical models that accommodate multiple outcomes and multiple cycles per woman were used to assess the relationship between serum PCB quartiles and implantation failure, chemical pregnancies (human chorionic gonadotropin [hCG] level greater than 5.0 mIU/ml) that did not result in clinical pregnancy, or spontaneous abortion while also adjusting for confounders. Results: PCB 153 was the congener present in the highest concentration (median 46.2 ng/g lipid). Increasing quartiles of PCB 153 and total PCBs were associated with significantly elevated dose-dependent odds of failed implantation. Adjusted odds ratios (95% confidence interval) for highest versus lowest quartile were 2.0 (1.2, 3.4) for PCB 153 and 1.7 (1.0, 2.9) for total PCBs. There were suggestive trends for increased odds of implantation failure for PCB 118 and CYP-inducing congeners (p values for trend=0.06). No statistically significant associations between PCBs and chemical pregnancy or spontaneous abortion were found. Conclusions: Serum PCB concentrations at levels similar to the US general population were associated with failed implantation among women undergoing IVF. These findings may help explain previous reports of reduced fecundability among women exposed to PCBs.
BACKGROUND: Human exposure to polychlorinated biphenyls (PCBs) remains widespread. PCBs have been associated with adverse reproductive health outcomes including reduced fecundability and increased risk of pregnancy loss, although the human data remain largely inconclusive. OBJECTIVE: Our goal was to explore the relationship between serum PCB concentrations and early pregnancy loss among a large cohort of women undergoing in vitro fertilization (IVF) between 1994 and 2003. METHODS: Concentrations of 57 PCB congeners were measured in serum samples collected during 827 IVF/intracytoplasmic sperm injection cycles from 765 women. Joint statistical models that accommodate multiple outcomes and multiple cycles per woman were used to assess the relationship between serum PCB quartiles and implantation failure, chemical pregnancies (human chorionic gonadotropin level > 5.0 mIU/mL) that did not result in clinical pregnancy, or spontaneous abortion, while also adjusting for confounders. RESULTS: PCB-153 was the congener present in the highest concentration (median, 46.2 ng/g lipid). Increasing quartiles of PCB-153 and the sum of all measured PCB congeners (SigmaPCBs) were associated with significantly elevated dose-dependent odds of failed implantation. Adjusted odds ratios (95% confidence interval) for highest versus lowest quartile were 2.0 (1.2-3.4) for PCB-153 and 1.7 (1.0-2.9) for SigmaPCBs. There were suggestive trends for increased odds of implantation failure for PCB-118 and cytochrome P450-inducing congeners (p-values for trend = 0.06). No statistically significant associations between PCBs and chemical pregnancy or spontaneous abortion were found. CONCLUSIONS: Serum PCB concentrations at levels similar to the U.S. general population were associated with failed implantation among women undergoing IVF. These findings may help explain previous reports of reduced fecundability among women exposed to PCBs.
Miodovnik A, Engel SM, Zhu C, Ye X, Soorya LV, Silva MJ, Calafat AM, Wolff MS. Endocrine disruptors and childhood social impairment. Neurotoxicology. 2011 Mar;32(2):261-7.
Prenatal exposure to endocrine disruptors has the potential to impact early brain development. Neurodevelopmental toxicity in utero may manifest as psychosocial deficits later in childhood. This study investigates prenatal exposure to two ubiquitous endocrine disruptors, the phthalate esters and bisphenol A (BPA), and social behavior in a sample of adolescent inner-city children. Third trimester urines of women enrolled in the Mount Sinai Children's Environmental Health Study between 1998 and 2002 (n=404) were analyzed for phthalate metabolites and BPA. Mother-child pairs were asked to return for a follow-up assessment when the child was between the ages of 7 and 9 years. At this visit, mothers completed the Social Responsiveness Scale (SRS) (n=137), a quantitative scale for measuring the severity of social impairment related to Autistic Spectrum Disorders (ASD) in the general population. In adjusted general linear models increasing log-transformed low molecular weight (LMW) phthalate metabolite concentrations were associated with greater social deficits (beta=1.53, 95% CI 0.25-2.8). Among the subscales, LMWP were also associated with poorer Social Cognition (beta=1.40, 95% CI 0.1-2.7); Social Communication (beta=1.86, 95% CI 0.5-3.2); and Social Awareness (beta=1.25, 95% CI 0.1-2.4), but not for Autistic Mannerisms or Social Motivation. No significant association with BPA was found (beta=1.18, 95% CI -0.75, 3.11). Prenatal phthalate exposure was associated with childhood social impairment in a multiethnic urban population. Even mild degrees of impaired social functioning in otherwise healthy individuals can have very important adverse effects over a child's lifetime. These results extend our previous finding of atypical neonatal and early childhood behaviors in relation to prenatal phthalate exposure.
Mocarelli P, Gerthoux PM, Needham LL, Patterson DG, Limonta G, Falbo R, Signorini S, Bertona M, Crespi C, Sarto C, Scott PK, Turner WE, Brambilla P. Perinatal exposure to low doses of dioxin can permanently impair human semen quality. Environ Health Perspect. 2011 May;119(5):713-8.
Background: In recent decades, young men in some industrialized areas have reportedly experienced a decrease in semen quality.Objective: We examined effects of perinatal dioxin exposure on sperm quality and reproductive hormones.Methods: We investigated sperm quality and hormone concentrations in 39 sons (mean age, 22.5 years) born between 1977 and 1984 to mothers exposed to dioxin after the accident in Seveso, Italy (1976), and 58 comparisons (mean age, 24.6 years) born to mothers exposed only to background dioxin. Maternal dioxin levels at conception were extrapolated from the concentrations measured in 1976 serum samples.Results: The 21 breast-fed sons whose exposed mothers had a median serum dioxin concentration as low as 19 ppt at conception had lower sperm concentration (36.3 vs. 86.3 million/mL; p = 0.002), total count (116.9 vs. 231.1; p = 0.02), progressive motility (35.8 vs. 44.2%; p = 0.03), and total motile count (38.7 vs. 98 million; p = 0.01) than did the 36 breast-fed comparisons. The 18 formula-fed exposed and the 22 formula-fed and 36 breast-fed comparisons (maternal dioxin background 10 ppt at conception) had no sperm-related differences. Follicle-stimulating hormone was higher in the breast-fed exposed group than in the breast-fed comparisons (4.1 vs. 2.63 IU/L; p = 0.03) or the formula-fed exposed (4.1 vs. 2.6 IU/L; p = 0.04), and inhibin B was lower (breast-fed exposed group, 70.2; breast-fed comparisons, 101.8 pg/mL, p = 0.01; formula-fed exposed, 99.9 pg/mL, p = 0.02).Conclusions: In utero and lactational exposure of children to relatively low dioxin doses can permanently reduce sperm quality.
Moral R, Santucci-Pereira J, Wang R, Russo IH, Lamartiniere CA, Russo J. In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats. Environ Health. 2011;10(1):5.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers exposed pregnant rats daily to benzyl phthalate (BBP) at doses varying between 0 and 500 mg per kg body weight and examined their female offspring. They found that exposure to BBP caused delayed vaginal opening, a marker of pubertal onset, as well as alterations in the morphology of the mammary gland. In addition, the expression of genes related to immune function and cell proliferation were altered, suggesting an increased susceptibility to cancers. These results suggest that prenatal exposure to BBP may delay puberty, interfere with the development of the mammary gland and alter gene expression.
Scientific abstract:
ABSTRACT: BACKGROUND: Environmental estrogens are exogenous estrogen-mimicking compounds that can interfere with endogenous endocrine systems. Several of these endocrine disruptors have been shown to alter normal development and influence tumorigenesis in experimental models. N-butyl benzyl phthalate (BBP), a widely used plasticizer, is a well-known endocrine disruptor. The aim of this study was to elucidate the effect of prenatal exposure to BBP on the morphology, proliferative index, and genomic signature of the rat mammary gland at different ages. METHODS: In utero exposure was performed by gavage of pregnant Sprague Dawley CD rats with 120mg or 500mg BBP/kg/day from day 10 post-conception to delivery. Female litters were euthanized at 21, 35, 50 and 100 days. The morphology and proliferative index of the mammary gland were studied from whole mount preparations and BrdU incorporation, respectively. Gene expression profile was assessed by microarrays. Several genes found differentially expressed and related to different functional categories were further validated by real time RT-PCR. RESULTS: Prenatal exposure of BBP induced delayed vaginal opening and changes in the post-natal mammary gland long after the end of the treatment, mainly by 35 days of age. Exposure to the high dose resulted in modifications in architecture and proliferative index of the mammary gland, mostly affecting the undifferentiated terminal end buds. Moreover, the expression profiles of this gland in the exposed rats were modified in a dose-dependent fashion. Analysis of functional categories showed that modified genes were related to immune function, cell signaling, proliferation and differentiation, or metabolism. CONCLUSIONS: Our data suggest that in utero exposure to BBP induced a delayed pubertal onset and modified morphology of the mammary gland. These alterations were accompanied by modifications in gene expression previously associated with an increased susceptibility to carcinogenesis.
Naile JE, Wiseman S, Bachtold K, Jones PD, Giesy JP. Transcriptional effects of perfluorinated compounds in rat hepatoma cells. Chemosphere. 2011 Nov;.
Study Synopsis: Polyfluoroalkyl compounds (PFCs), such as perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA), are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFCs. While PFOS and PFOA have been extensively studied in animal and in vitro studies, other PFCs including replacement chemicals such as perfluorobutanesulfonate (PFBS) and perfluorobutyric acid (PFBA), have not been well characterized. It has generally been assumed that the effects of other PFCs were similar to those of PFOS and that minor differences in effects were due to molecular characteristics such as their size. This study compared the effects of 10 PFCs routinely found in the environment on the expression of 7 genes known or suspected of being affected by PFOS such as the synthesis of certain types of fats (fatty acids and cholesterol) and thyroid development. Although significant changes in gene expression were noted, effects of the different PFCs were very different and could not be attributed to molecular characteristics.
Scientific abstract:
Perfluorooctanesulfonate (PFOS) is the terminal degradation product of many commercially used perfluorinated compounds, and most of the toxicity testing to date has focused on its potential biological effects. While PFOS has been extensively studied, other PFCs including replacement chemicals such as perfluorobutanesulfonate (PFBS) and perfluorobutyric acid (PFBA), have not been well characterized. Despite the relative lack of data available on these other PFCs it has been assumed that they will cause similar or lesser effects than PFOS. This study compared the effects of 10 PFCs routinely found in the environment on mRNA abundance of 7 genes related to processes known to be affected by PFOS, such as fatty acid and cholesterol synthesis, and thyroid development. Rat H4IIE hepatoma cells were exposed and changes in mRNA abundance were quantified by real-time PCR. Significant changes in mRNA abundance were observed. The effects caused by the shorter chain replacement chemicals differed significantly from those caused by PFOS or PFOA. Furthermore, not all of the PFCs caused the same effects, and changes could not simply be attributed to chain-length or functional group. These differences could mean that these replacement chemicals do not act through the same mechanisms as the more studied PFOS and PFOA.
Ren A, Qiu X, Jin L, Ma J, Li Z, Zhang L, Zhu H, Finnell RH, Zhu T. Association of selected persistent organic pollutants in the placenta with the risk of neural tube defects. Proc Natl Acad Sci U S A. 2011 Aug;108(31):12770-5.
Study Synopsis: Persistent Organic Pollutants (POPs) are ubiquitous synthetic chemicals that persist in the environment and in humans, accumulate in fat and are generally found at higher concentration in animals situated higher in the food chain. Twelve POPs were banned internationally by the Stockholm Convention on POPs in 2001; nine chemicals were added to the list in 2009. Polycyclic aromatic hydrocarbons (PAH), on the other hand, are by-products of the combustion of fuel and other products. In this study, researchers measured the concentration of organochlorine pesticides, including dichlorodiphenyl trichloroethane (DDT) and DDT's breakdown product dichlorodiphenyl dichloroethylene (DDE), the industrial chemicals polychlorinated biphenyls (PCBs) and the flame retardants polybrominated diphenylethers (PBDEs) in the placenta of 80 fetuses or neonates with neural tube defects and 50 healthy controls. The median concentrations of DDT, DDE, hexachlorocyclohexane and endosulfan were higher in cases compared with controls. Having levels of PAH above the median in the placenta was associated with a 4.5-fold increase in the risk of neural tube defect. When specific neural tube defects were investigated, risks of anencephaly (birth with part of the brain and/or skull missing) were increased by 5.8 times and risks of spina bifida (malformation of the spine) were 3.7 times higher among those with higher concentrations of PAH in the placenta relative to controls. These results suggest that elevated levels of DDT, DDE, hexachlorocyclohexane, endosulfan and PAH in the placenta are related to increased risks of neural tube defects.
Scientific abstract:
Persistent organic pollutants (POPs) have been associated with a wide range of adverse health effects. Our case-control study was performed to explore the association between placental levels of selected POPs and risks for neural tube defects (NTDs) in a Chinese population with a high prevalence of NTDs. Cases included 80 fetuses or newborns with NTDs, whereas the controls were 50 healthy, nonmalformed newborn infants. Placental concentrations of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers were analyzed by gas chromatography-mass spectrometry. The medians of PAHs, o,p'-isomers of dichlorodiphenyltrichloroethane (DDT) and metabolites, alpha- and gamma-hexachlorocyclohexane (HCH), and alpha-endosulfan were significantly higher in case placentas than in controls. PAH concentrations above the median were associated with a 4.52-fold [95% confidence interval (CI), 2.10-9.74) increased risk for any NTDs, and 5.84- (95% CI, 2.28-14.96) and 3.71-fold (95% CI, 1.57-8.79) increased risks for anencephaly and spina bifida, respectively. A dose-response relationship was observed between PAH levels and the risk of NTDs, with odds ratios for the second, third, and fourth quartiles, compared with the first, of 1.77- (95% CI, 0.66-4.76), 3.83- (95% CI, 1.37-10.75), and 11.67-fold (95% CI, 3.28-41.49), respectively. A dose-response relationship was observed for anencephaly and spina bifida subtypes. Similar results were observed for o,p'-DDT and metabolites, alpha-HCH, gamma-HCH, and alpha-endosulfan, whereas no dose-response relationship was observed for the last two pollutants. Elevated placental concentrations of PAHs, o,p'-DDT and metabolites, and alpha-HCH were associated with increased risks of NTDs in this population.
Shah A, Coburn CG, Watson-Siriboe A, Whitley R, Shahidzadeh A, Gillard ER, Nichol R, Leon-Olea M, Gaertner M, Kodavanti PR, Curras-Collazo MC. Altered cardiovascular reactivity and osmoregulation during hyperosmotic stress in adult rats developmentally exposed to polybrominated diphenyl ethers (PBDEs). Toxicol Appl Pharmacol. 2011 Oct;256(2):103-13.
Scientific abstract:
Polybrominated diphenyl ethers (PBDEs) and the structurally similar chemicals polychlorinated biphenyls (PCBs) disrupt the function of multiple endocrine systems. PCBs and PBDEs disrupt the secretion of vasopressin (VP) from the hypothalamus during osmotic activation. Since the peripheral and central vasopressinergic axes are critical for osmotic and cardiovascular regulation, we examined whether perinatal PBDE exposure could impact these functions during physiological activation. Rats were perinatally dosed with a commercial PBDE mixture, DE-71. Dams were given 0 (corn oil control), 1.7 (low dose) or 30.6 mg/kg/day (high dose) in corn oil from gestational day (GD) 6 through postnatal day (PND) 21 by oral gavage. In the male offspring exposed to high dose PBDE plasma thyroxine and triiodothyronine levels were reduced at PND 21 and recovered to control levels by PND 60 when thyroid stimulating hormone levels were elevated. At 14-18 months of age, cardiovascular responses were measured in four groups of rats: Normal (Oil, normosmotic condition), Hyper (Oil, hyperosmotic stress), Hyper PBDE low (1.7 mg/kg/day DE-71 perinatally, hyperosmotic stress), and Hyper PBDE high (30.6 mg/kg/day DE-71 perinatally, hyperosmotic stress). Systolic blood pressure (BP), diastolic BP, and heart rate (HR) were determined using tail cuff sphygmomanometry and normalized to pretreatment values (baseline) measured under basal conditions. Hyperosmotic treatment yielded significant changes in systolic BP in PBDE exposed rats only. Hyper PBDE low and high dose rats showed 36.1 and 64.7% greater systolic BP responses at 3h post hyperosmotic injection relative to pretreatment baseline, respectively. No treatment effects were measured for diastolic BP and HR. Hyper and Hyper PBDE rats showed increased mean plasma osmolality values by 45 min after injection relative to normosmotic controls. In contrast to Hyper rats, Hyper PBDE (high) rats showed a further increase in mean plasma osmolality at 3h (358.3+/-12.4mOsm/L) relative to 45 min post hyperosmotic injection (325.1+/-11.4mOsm/L). Impaired osmoregulation in PBDE-treated animals could not be attributed to decreased levels of plasma vasopressin. Our findings suggest that developmental exposure to PBDEs may disrupt cardiovascular reactivity and osmoregulatory responses to physiological activation in late adulthood.
Shekharyadav C, Bajpai M, Kumar V, Ahmed RS, Gupta P, Banerjee BD. Polymorphism in CYP1A1, GSTMI, GSTT1 genes and organochlorine pesticides in the etiology of hypospadias. Hum Exp Toxicol. 2011 Oct;30(10):1464-74.
Study Synopsis: Organochlorines are chemicals that were primarily used as pesticides from the 1940s to the 1970s when they were banned due to concerns about their persistence in the environment, bioaccumulation in fat tissues and potential adverse health effects on wildlife and in humans. In this study, researchers measured the the levels of organochlorine pesticides in the blood of 80 boys with hypospadias (abnormal location of the urethra) and 120 controls. They found that cases had higher blood levels of beta-hexachlorohexane (HCH), gamma-HCH, and p,p'-dichlorodiphenyl-dichloroethylene (p,p'-DDE) relative to controls. Genes involved in the elimination of these chemicals were not related to the risk of hypospadias. Results suggest that exposure to some organochlorine pesticides may be related to increased risk of hypospadias.
Scientific abstract:
Exposure to endocrine-disrupting chemicals (EDCs) and maternal endogenous estrogen may cause hypospadias, common congenital anomaly. Several organochlorine pesticides (OCPs) have been reported to possess an endocrine-disrupting potential. Cytochrome P4501A1 (CYP1A1) and glutathione S-transferases (GSTM1 and GSTT1) of xenobiotic metabolizing enzyme family are involved in the metabolism of various environmental toxicants and steroidal hormones. Hence, the present study was designed to evaluate the role of CYP1A1, GSTM1, GSTT1 genes polymorphism, OCPs levels and risk of hypospadias. A total of 80 hypospadiac and 120 age-matched control boys were included. OCP levels in blood were determined using Gas Chromatograph equipped with electron capture detector (GC-ECD) and polymorphism in CYP1A1, GSTM1 and GSTT1 genes was evaluated by RFLP and multiplex PCR method. We observed significant high levels of beta-hexachlorohexane (HCH), gamma-HCH, and p,p'-dichlorodiphenyl-dichloroethylene (p,p'-DDE) in the cases. CYP1A1 polymorphisms were not significantly different among cases and controls, whereas concomitant deletion of GSTM1 and GSTT1 genotypes was significantly higher in cases as compared to controls. However, after adjusting for low birth weight and maternal occupational exposure, the results did not remain significant but odds of risk was higher (OR = 1.72, p = 0.14) among cases. In conclusion, our study suggests irrespective of genetic predisposition, higher level of some OCPs may be associated with increased risk of hypospadias.
Suh CH, Cho NK, Lee CK, Lee CH, Kim DH, Kim JH, Son BC, Lee JT. Perfluorooctanoic acid-induced inhibition of placental prolactin-family hormone and fetal growth retardation in mice. Mol Cell Endocrinol. 2011 Jan;337(1-2):7-15.
Study Synopsis: Perfluorooctanoic acid (PFOA) is a highly persistent water and oil repellent used in products such as Teflon, Scotchguard and Gore-Tex. It has been measured in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA. In this study, researchers exposed pregnant rats daily to PFOA at doses ranging from 0 to 25 mg/kg body weight over 6 days. Exposure to PFOA caused reductions in fetal and placental weights and increases in fetal deaths and miscarriages. Changes in placental tissue as well as alterations in the expression of genes regulating placental hormones were also observed in exposed animals. These results suggest that exposure to high doses of PFOA during pregnancy affect fetal development and placental function in mice.
Scientific abstract:
Perfluorooctanoic acid (PFOA) is a persistent pollutant worldwide and even found in human cord blood and breast milk. Some animal studies have reported that PFOA causes developmental toxicity such as fetal weight loss, but the mechanism is still unclear. This study focused on developmental toxicity of PFOA, particularly impacts of PFOA on placental endocrine function such as placental prolactin (PRL)-family hormone gene expression and fetal growth in mouse. Time-mated CD-1 mice were dosed by gavage with 0, 2, 10 and 25mg/kg B.W/day of PFOA (n=10) dissolved with de-ionized water from gestational day (GD) 11-16. During treatment, body weight of each pregnant mouse was measured daily. On day 16, caesarean sections were performed and developmental data were observed. Three placentas from three different pregnant mice were assigned to each of the following experiments. The mRNA levels of mouse placental lactogen (mPL)-II, prolactin like protein (mPLP)-E, -F and Pit-1alpha and beta isotype mRNAs, a transacting factor of mPLs and mPLPs genes, were analyzed using northern blot, in situ hybridization and RT-PCR, respectively. Maternal body weight gain was significantly declined from GD 13 in the PFOA treated groups compared to control. Developmental data such as fetal and placental weights were significantly decreased in accordance with PFOA dosage. Number of dead fetuses and post-implantation losses were significantly increased in the PFOA-exposed groups. In addition, placental efficiency (fetal weight/placental weight) was significantly reduced in PFOA treated groups in accordance with PFOA dosage. Histopathologic changes were observed in placenta. Dose dependent necrotic changes were observed in both 10mg and 25mg PFOA treated groups. Cell frequency of glycogen trophoblast cell and parietal trophoblast giant cell were decreased dose dependently in the junctional zone. In the labyrinth zone, sinusoidal trophoblast giant cell frequency was decreased in the 25mg PFOA treated group. Also, morphological change such as crushed nuclear (atrophy) of trophoblast cells was observed in 25mg PFOA treated group. Finally, mRNA levels of the mPL-II, mPLP-E, -F and Pit-1alpha and beta were significantly reduced in the PFOA treated groups dose dependently. In addition, the changing pattern between mPL-II, mPLP-E, -F mRNA levels and fetal body weight showed positive relationship. In conclusion, the inhibitory effects of PFOA on the placental prolactin-family hormone genes expression may be secondary effects to insufficient trophoblast cell type differentiation and/or increased trophoblast cell necrosis. The impacts of PFOA on placental development and endocrine function reduced the placental efficiency and partly contributed to the fetal growth retardation in the mouse.
Suh CH, Cho NK, Lee CK, Lee CH, Kim DH, Kim JH, Son BC, Lee JT. Perfluorooctanoic acid-induced inhibition of placental prolactin-family hormone and fetal growth retardation in mice. Mol Cell Endocrinol. 2011 30-Apr;337(1-2):7-15.
Study Synopsis: Perfluorooctanoic acid (PFOA) is a highly persistent water and oil repellent used in products such as Teflon, Scotchguard and Gore-Tex. It has been measured in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA. In this study, researchers exposed pregnant mice to different doses of PFOA during six days. They found that exposure reduced maternal weight gain and that the weight of fetuses and of their placenta was decreased in a dose-dependent manner. In addition, exposure to PFOA was related to an increase in fetal death and post-implantation losses. Finally, PFOA altered the tissue structure of the placenta and the expression of genes associated with hormones that are essential to the normal development of the fetus. These results suggest that maternal exposure to PFOA affects fetal growth and survival, which may be caused by alterations in placental development and hormone synthesis in mice.
Scientific abstract:
Perfluorooctanoic acid (PFOA) is a persistent pollutant worldwide and even found in human cord blood and breast milk. Some animal studies have reported that PFOA causes developmental toxicity such as fetal weight loss, but the mechanism is still unclear. This study focused on developmental toxicity of PFOA, particularly impacts of PFOA on placental endocrine function such as placental prolactin (PRL)-family hormone gene expression and fetal growth in mouse. Time-mated CD-1 mice were dosed by gavage with 0, 2, 10 and 25mg/kg B.W/day of PFOA (n=10) dissolved with de-ionized water from gestational day (GD) 11-16. During treatment, body weight of each pregnant mouse was measured daily. On day 16, caesarean sections were performed and developmental data were observed. Three placentas from three different pregnant mice were assigned to each of the following experiments. The mRNA levels of mouse placental lactogen (mPL)-II, prolactin like protein (mPLP)-E, -F and Pit-1alpha and beta isotype mRNAs, a transacting factor of mPLs and mPLPs genes, were analyzed using northern blot, in situ hybridization and RT-PCR, respectively. Maternal body weight gain was significantly declined from GD 13 in the PFOA treated groups compared to control. Developmental data such as fetal and placental weights were significantly decreased in accordance with PFOA dosage. Number of dead fetuses and post-implantation losses were significantly increased in the PFOA-exposed groups. In addition, placental efficiency (fetal weight/placental weight) was significantly reduced in PFOA treated groups in accordance with PFOA dosage. Histopathologic changes were observed in placenta. Dose dependent necrotic changes were observed in both 10mg and 25mg PFOA treated groups. Cell frequency of glycogen trophoblast cell and parietal trophoblast giant cell were decreased dose dependently in the junctional zone. In the labyrinth zone, sinusoidal trophoblast giant cell frequency was decreased in the 25mg PFOA treated group. Also, morphological change such as crushed nuclear (atrophy) of trophoblast cells was observed in 25mg PFOA treated group. Finally, mRNA levels of the mPL-II, mPLP-E, -F and Pit-1alpha and beta were significantly reduced in the PFOA treated groups dose dependently. In addition, the changing pattern between mPL-II, mPLP-E, -F mRNA levels and fetal body weight showed positive relationship. In conclusion, the inhibitory effects of PFOA on the placental prolactin-family hormone genes expression may be secondary effects to insufficient trophoblast cell type differentiation and/or increased trophoblast cell necrosis. The impacts of PFOA on placental development and endocrine function reduced the placental efficiency and partly contributed to the fetal growth retardation in the mouse.
Vrabie CM, Candido A, Van Den Berg H, Murk AJ, Van Duursen MB, Jonker MT. Specific in vitro toxicity of crude and refined petroleum products. 3. Estrogenic responses in mammalian assays. Environ Toxicol Chem. 2011 Jan;30(4):973-80.
Study Synopsis: Interest in the health effects of exposure to crude oils has substantially grown since the explosion of the Deepwater Horizon platform in the Gulf of Mexico. In this study, researchers exposed specialized cells to one of 11 crude and refined oils to determine whether they could mimic hormones. They found that 8 of the oils tested had effects that resembled those of the female hormone estrogen. Exposure to estrogen-like chemicals has been found to affect brain development, result in earlier puberty onset and increase breast cancer risk in animals. Some crude and refined oils may thus have similar health effects.
Scientific abstract:
Current petroleum risk assessment only considers narcosis as mode of action, but several studies have demonstrated that oils contain compounds with dioxin-like, (anti)estrogenic, and (anti)androgenic activities. The present study is the third in a series investigating the specific toxic effects of 11 crude oils and refined products. By employing recombinant mammalian cells stably transfected with the human estrogen receptor alpha (ERalpha) or beta (ERbeta), and expressing the luciferase protein (i.e., ERalpha-U2OS-Luc and ERbeta-U2OS-Luc assay), the (anti)estrogenicity of oils was studied. All oils, except for two refined and one crude oil, induced estrogenic responses. The calculated estrogenic potencies of the oils were 6 to 9 orders of magnitude lower than the potency of 17beta-estradiol (E2). Upon coexposure to a fixed concentration of E2 and increasing concentrations of oils, additive, antagonistic, and synergistic effects were revealed. One nautical fuel oil was tested in the human breast carcinoma cell line (MCF-7), where it induced cell proliferation up to 70% relative to the maximum induction by E2. At its minimum effect concentration of 25 mg/L, the oil was also capable of inducing mRNA expression of the estrogen-dependent protein pS2 by a factor of two. The present results indicate that oils naturally contain potentially endocrine disrupting compounds that are able to influence the estrogenicity of other compounds and may cause biological responses beyond receptor binding. (c) 2011 SETAC.
Wan H, Zhao Y, Wong M, Lee CK, Yeung WS, Giesy JP, Wong CK. Testicular signaling is the potential target of perfluorooctanesulfonate-mediated subfertility in male mice. Biol Reprod. 2011 May;84(5):1016-23.
Study Synopsis: Perfluorochemicals (PFCs) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of two PFCs, namely perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS). Although a number of studies have reported adverse effects on the male reproductive system in rodents following exposure to high doses of PFOS, the underlying toxicological mechanisms are still unclear. In this study, researchers exposed 8-week-old male mice to PFOS at doses varying between 0 and 10 mg/kg per day for 7 to 21 days. Blood levels of the male hormone testosterone and sperm counts were reduced in mice exposed to the highest dose of PFOS for 21 days. The expression of receptors for hormones such as gonadotropin, growth hormone and insulin-like growth factor-1 and of enzymes involved in the synthesis of steroid hormones such as testosterone were also reduced in mice testicles. These results suggest that PFOS alter the male reproductive system in mice by affecting testicular signaling.
Scientific abstract:
Perfluorooctanesulfonate (PFOS) was produced and used by various industries and consumer products. Due to its persistence, it is ubiquitous in air, water, soil, wildlife and humans. While the adverse effects of PFOS on male fertility are reported, the underlying mechanisms have not yet been elucidated. Here for the first time, effects of PFOS on testicular signaling, such as gonadotropin, growth hormone, insulin-like growth factor, and inhibins/activins were shown to be directly related to male subfertility. Sexually mature 8-week-old CD1 male mice were administered by gavages in corn oil with 0, 1, 5, or 10 mg PFOS/kg/day for 7, 14, or 21 days. Serum concentrations of testosterone and epididymal sperm counts were significantly less in the mice after 21 days of the exposure to the highest dose than that of the controls. The expression levels of testicular receptors for gonadotropin, growth hormone and insulin-like growth factor-1 were considerably reduced on Day 21 in mice exposed to 10 and/or 5 mg PFOS/kg/day. The transcript levels of the subunits of the testicular factors (i.e. inhibins and activins), Inha, Inhba, and Inhbb were significantly less on Day 21 of 10, 5 and/or 1mg/kg/day of PFOS exposure. The mRNA expression levels of steroidogenic enzymes (i.e. StAR, CYP11A1, CYP17A1, 3beta-HSD, 17beta-HSD) were notably reduced. Therefore PFOS-elicited subfertility in male mice is manifested as progressive deterioration of testicular signaling.
Wan HT, Zhao YG, Wong MH, Lee KF, Yeung WS, Giesy JP, Wong CK. Testicular signaling is the potential target of perfluorooctanesulfonate-mediated subfertility in male mice. Biol Reprod. 2011 May;84(5):1016-23.
Perfluorooctanesulfonate (PFOS) was produced and used by various industries and in consumer products. Because of its persistence, it is ubiquitous in air, water, soil, wildlife, and humans. Although the adverse effects of PFOS on male fertility have been reported, the underlying mechanisms have not yet been elucidated. Here, for the first time, the effects of PFOS on testicular signaling, such as gonadotropin, growth hormone, insulin-like growth factor, and inhibins/activins were shown to be directly related to male subfertility. Sexually mature 8-wk-old CD1 male mice were administered by gavages in corn oil daily with 0, 1, 5, or 10 mg/kg PFOS for 7, 14, or 21 days. Serum concentrations of testosterone and epididymal sperm counts were significantly lower in the mice after 21 days of the exposure to the highest dose compared with the controls. The expression levels of testicular receptors for gonadotropin, growth hormone, and insulin-like growth factor 1 were considerably reduced on Day 21 in mice exposed daily to 10 or 5 mg/kg PFOS. The transcript levels of the subunits of the testicular factors (i.e., inhibins and activins), Inha, Inhba, and Inhbb, were significantly lower on Day 21 of daily exposure to 10, 5, or 1 mg/kg PFOS. The mRNA expression levels of steroidogenic enzymes (i.e., StAR, CYP11A1, CYP17A1, 3beta-HSD, and 17beta-HSD) were notably reduced. Therefore, PFOS-elicited subfertility in male mice is manifested as progressive deterioration of testicular signaling.
Wells EM, Navas-Acien A, Herbstman JB, Apelberg BJ, Silbergeld EK, Caldwell KL, Jones RL, Halden RU, Witter FR, Goldman LR. Low-level lead exposure and elevations in blood pressure during pregnancy. Environ Health Perspect. 2011 May;119(5):664-9.
Background: Lead exposure is associated with elevated blood pressure during pregnancy; however, the magnitude of this relationship at low exposure levels is unclear.Objectives: Our goal was to determine the association between low-level lead exposure and blood pressure during late pregnancy.Methods: We collected admission and maximum (based on systolic) blood pressures during labor and delivery among 285 women in Baltimore, Maryland. We measured umbilical cord blood lead using inductively coupled plasma mass spectrometry. Multivariable models were adjusted for age, race, median household income, parity, smoking during pregnancy, prepregnancy body mass index, and anemia. These models were used to calculate benchmark dose values.Results: Geometric mean cord blood lead was 0.66 mug/dL (95% confidence interval, 0.61-0.70). Comparing blood pressure measurements between those in the highest and those in the lowest quartile of lead exposure, we observed a 6.87-mmHg (1.51-12.21 mmHg) increase in admission systolic blood pressure and a 4.40-mmHg (0.21-8.59 mmHg) increase in admission diastolic blood pressure after adjustment for confounders. Corresponding values for maximum blood pressure increase were 7.72 (1.83-13.60) and 8.33 (1.14-15.53) mmHg. Benchmark dose lower limit values for a 1-SD increase in blood pressure were < 2 mug/dL blood lead for all blood pressure end points.Conclusions: A significant association between low-level lead exposures and elevations in maternal blood pressure during labor and delivery can be observed at umbilical blood lead levels < 2 mug/dL.
Wong EW, Cheng CY. Impacts of environmental toxicants on male reproductive dysfunction. Trends Pharmacol Sci. 2011 Feb;32(5):290-9.
Study Synopsis: A number of environmental chemicals have been associated with adverse effects on the male reproductive system. This paper reviews the evidence regarding potential mechanims of action for such effects. Authors conclude by recommanding that additional studies be conducted to compare the health effects of high-level acute exposure versus low-level chronic exposure to environmental chemicals.
Scientific abstract:
Male infertility caused by exposure to environmental toxicants such as cadmium, mercury, bisphenol A (BPA) and dioxin is a global problem, particularly in industrialized countries. Studies in the testis and other organs have illustrated the importance of environmental toxicant-induced oxidative stress in mediating disruption to cell junctions. This, in turn, is regulated by the activation of PI3K/c-Src/FAK and MAPK signaling pathways, with the involvement of polarity proteins. This leads to reproductive dysfunction such as reduced sperm count and reduced quality of semen. In this review, we discuss how these findings can improve understanding of the modes of action of environmental toxicants in testicular dysfunction. Thus, specific inhibitors and/or antagonists against signaling molecules in these pathways may be able to 'reverse' and/or 'block' the disruptive effects of toxicant-induced damage. Additional studies comparing high-level acute exposure versus low-level chronic exposure to environmental toxicants are also needed to fully elucidate the underlying molecular mechanism(s) by which these toxicants disrupt male reproductive function.
Zhang F, Hu W, Yu H, Sun H, Shen O, Wang X, Liu H, Lam MH, Giesy JP, Zhang X. Endocrine disruption effects of 2,2',4,4',6-pentabromodiphenylether (BDE100) in reporter gene assays. J Environ Monit. 2011 5-Apr;13(4):850-4.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers evaluated the potential of one type of PBDE, namely BDE-100, to affect the hormonal system by using specialized cells in petri dishes. They found that BDE-100 had both antiestrogenic and antiandrogenic effects. Results thus suggest that BDE-100 may modulate the endocrine system in multiple ways.
Scientific abstract:
Polybrominated diphenyl ethers (PBDEs) constitute an important group of flame retardants. 2,2',4,4',6-Pentabromodiphenylether (BDE100) is a prominent PBDE congener in some human populations. The potential of BDE100 to modulate responses mediated by the estrogen (ER), thyroid hormone (ThR) or androgen receptors (AR) were investigated by use of transactivation reporter gene assays. The African green monkey kidney CV-1 cell transiently transfected with the constructed reporter gene plasmid ERE-TATA-Luc and pUAS-tk-Luc with luciferase (Luc) under control of the estrogen response (ERE), or thyroid hormone response (ThRE) elements were used to evaluate (anti)estrogen and thyroid effects of BDE100. The (anti)androgenic potency of BDE100 was also evaluated by use of MDA-kb2 cells, which were stably transfected with MMTV-luciferase. The assays displayed appropriate responses to known natural estrogen 17beta-estradiol (E2), ThR ligand triiodothyronine (T3), and the AR agonist 5alpha-dihydrotestosterone (DHT). 10 or 50 muM BDE100 significantly up-regulated expression of Luc under control of the ER. Antiestrogenic potency was observed for BDE100 (IC50 = 6.21 muM). Co-exposure to 50 muM BDE100 significantly enhanced expression of Luc caused by 5 nM T3. BDE100 was antiandrogenic at 10 and 50 muM with an IC50 of 28.60 muM BDE100. These results suggest that BDE100 can modulate the endocrine system in multiple ways by interfering with several hormonal signaling pathways simultaneously.
We evaluated in utero exposures to pesticides by measuring maternal and cord serum biomarkers in a New Jersey cohort of pregnant women and the birth outcomes of their neonates. The study was based on 150 women that underwent an elective cesarean delivery at term in a hospital in central New Jersey. We evaluated the following pesticide compounds in both maternal and umbilical cord sera: chlorpyrifos, diazinon, carbofuran, chlorothalonil, dacthal, metolachlor, trifluralin and diethyl-m-toluamide (DEET). Of these compounds, chlorpyrifos, carbofuran, chlorothalonil, trifluralin, metolachlor and DEET were the pesticides most frequently detected in the serum samples. We found high (> or =75th percentile) metolachlor concentrations in cord blood that were related to birth weight (3605 g in upper quartile vs 3399 g; p=0.05). We also observed an increase in abdominal circumference with increasing cord dichloran concentrations (p=0.031). These observations suggest that in utero exposures to certain pesticides may alter birth outcomes.
Boas M, Frederiksen H, Feldt-Rasmussen U, Skakkebaek NE, Hegedus L, Hilsted L, Juul A, Main KM. Childhood exposure to phthalates: associations with thyroid function, insulin-like growth factor I, and growth. Environ Health Perspect. 2010 Oct;118(10):1458-64.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to Phthalates is common due to their widespread use. In this study, researchers measured the concentration of 12 phthalate residues in the urine of 845 children aged between 4 and 9 years and quantified the levels of thyroid hormone in their blood. They also measured the levels of insulin-like growth factor (IGF-1) which is secreted by the liver and is involved in cell growth and development and may play a role in some diseases such as cancer and diabetes. Higher levels of phthalate residues in urine were associated with reduced levels of the thyroid hormone triiodothyronine (T3) in girls and with IGF-1 in boys. Most residues were also related with lower height, weight, body surface and growth in both sexes. These results suggest that exposure to phthalates may be related with adverse effects on thyroid hormone and growth parameters.
Scientific abstract:
BACKGROUND: Phthalates are widely used chemicals, and human exposure is extensive. Recent studies have indicated that phthalates may have thyroid-disrupting properties. OBJECTIVE: We aimed to assess concentrations of phthalate metabolites in urine samples from Danish children and to investigate the associations with thyroid function, insulin-like growth factor I (IGF-I), and growth. METHODS: In 845 children 4-9 years of age, we determined urinary concentrations of 12 phthalate metabolites and serum levels of thyroid-stimulating hormone, thyroid hormones, and IGF-I. RESULTS: Phthalate metabolites were detected in all urine samples, of which monobutyl phthalate was present in highest concentration. Phthalate metabolites were negatively associated with serum levels of free and total triiodothyronine, although statistically significant primarily in girls. Metabolites of di(2-ethylhexyl) phthalate and diisononyl phthalate were negatively associated with IGF-I in boys. Most phthalate metabolites were negatively associated with height, weight, body surface, and height gain in both sexes. CONCLUSIONS: Our study showed negative associations between urinary phthalate concentrations and thyroid hormones, IGF-I, and growth in children. Although our study was not designed to reveal the mechanism of action, the overall coherent negative associations between urine phthalate and thyroid and growth parameters may suggest causative negative roles of phthalate exposures for child health.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured the concentration of 12 phthalate residues in the urine of 845 children aged 4-9 years. They found that children with higher phthalate residues in their urine had lower levels of the thyroid hormone triiodothyronine (T3). These results were particularly significant in girls. Some phthalate residues (those of diethylhexyl and diisononyl phthalate) were related with lower levels of inlulin-like growth factor 1 (IGF-1). IGF-1 is secreted by the liver and is involved in cell growth and development and may play a role in some diseases such as cancer and diabetes. Finally, children with higher phthalate residues in their urine tended to be shorter, have a lower body weight, body surface and reduced growth. Results from this study suggest that exposure to phthalates may be related with alteration in thyroid hormone levels and growth in children.
Scientific abstract:
BACKGROUND: Phthalates are widely used chemicals, and human exposure is extensive. Recent studies have indicated that phthalates may have thyroid-disrupting properties. OBJECTIVE: We aimed to assess concentrations of phthalate metabolites in urine samples from Danish children and to investigate the associations with thyroid function, insulin-like growth factor I (IGF-I), and growth. METHODS: In 845 children 4-9 years of age, we determined urinary concentrations of 12 phthalate metabolites and serum levels of thyroid-stimulating hormone, thyroid hormones, and IGF-I. RESULTS: Phthalate metabolites were detected in all urine samples, of which monobutyl phthalate was present in highest concentration. Phthalate metabolites were negatively associated with serum levels of free and total triiodothyronine, although statistically significant primarily in girls. Metabolites of di(2-ethylhexyl) phthalate and diisononyl phthalate were negatively associated with IGF-I in boys. Most phthalate metabolites were negatively associated with height, weight, body surface, and height gain in both sexes. CONCLUSIONS: Our study showed negative associations between urinary phthalate concentrations and thyroid hormones, IGF-I, and growth in children. Although our study was not designed to reveal the mechanism of action, the overall coherent negative associations between urine phthalate and thyroid and growth parameters may suggest causative negative roles of phthalate exposures for child health.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured the concentration of 12 phthalate residues in the urine of 845 children aged 4-9 years. They found that children with higher phthalate residues in their urine had lower levels of the thyroid hormone triiodothyronine (T3). These results were particularly significant in girls. Some phthalate residues (those of diethylhexyl and diisononyl phthalate) were related with lower levels of insulin-like growth factor 1 (IGF-1). IGF-1 is secreted by the liver and is involved in cell growth and development and may play a role in some diseases such as cancer and diabetes. Finally, children with higher phthalate residues in their urine tended to be shorter, have a lower body weight, body surface and reduced growth. Results from this study suggest that exposure to phthalates may be related with alteration in thyroid hormone levels and growth in children.
Scientific abstract:
BACKGROUND: Phthalates are widely used chemicals, and human exposure is extensive. Recent studies have indicated that phthalates may have thyroid-disrupting properties. OBJECTIVE: We aimed to assess concentrations of phthalate metabolites in urine samples from Danish children and to investigate the associations with thyroid function, insulin-like growth factor I (IGF-I), and growth. METHODS: In 845 children 4-9 years of age, we determined urinary concentrations of 12 phthalate metabolites and serum levels of thyroid-stimulating hormone, thyroid hormones, and IGF-I. RESULTS: Phthalate metabolites were detected in all urine samples, of which monobutyl phthalate was present in highest concentration. Phthalate metabolites were negatively associated with serum levels of free and total triiodothyronine, although statistically significant primarily in girls. Metabolites of di(2-ethylhexyl) phthalate and diisononyl phthalate were negatively associated with IGF-I in boys. Most phthalate metabolites were negatively associated with height, weight, body surface, and height gain in both sexes. CONCLUSIONS: Our study showed negative associations between urinary phthalate concentrations and thyroid hormones, IGF-I, and growth in children. Although our study was not designed to reveal the mechanism of action, the overall coherent negative associations between urine phthalate and thyroid and growth parameters may suggest causative negative roles of phthalate exposures for child health.
Hormonally controlled vascular changes play a key role in endometrial development and in the differentiation process necessary for implantation. Vascular endothelial growth factor (VEGF) has emerged as one of the central regulators of the uterine vasculature. Hormonal perturbations during neonatal development may alter sex steroid-dependent regulation of VEGF and may ultimately affect fertility later in life. The aim of this study was to determine whether neonatal exposure to the environmental estrogenic chemical bisphenol A (BPA) affects the adult rat uterine response to hormonal stimuli. Newborn female rats were given s.c. injections of vehicle, BPA (0.05 mg/kg per day or 20 mg/kg per day) or diethylstilbestrol (0.2 Ī¼g/kg per day) on Postnatal Days 1, 3, 5, and 7. To evaluate the long-term effects, rats were ovariectomized at Postnatal Day 80 and submitted to hormonal replacement. Rats neonatally exposed to xenoestrogens showed a decreased induction of uterine endothelial proliferation and a decreased mRNA expression in response to ovarian steroid treatment. Also, although the estrogen receptor alpha (ESR1) expression was lower in subepithelial cells than in controls, a higher expression of silencing mediator of retinoic acid and thyroid hormone receptor (NCOR1, also known as SMRT) corepressor was evidenced in the same compartment. The results indicate that disturbed expression in BPA rats could be the result of changes in endocrine pathways, such as an altered induction of ESR1 and/or NCOR1 expression. Because of the importance of VEGF in the implantation process, our data suggest that neonatal BPA exposure might have negative consequences on female fertility.
Carmichael SL, Herring AH, Sjodin A, Jones R, Needham L, Ma C, Ding K, Shaw GM. Hypospadias and halogenated organic pollutant levels in maternal mid-pregnancy serum samples. Chemosphere. 2010 Jul;80(6):641-6.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. The objective of this study was to evaluate whether exposure to PBDEs, structurally similar polybrominated biphenyls (PCBs) and nine other persistent pesticides was related with increased risks of hypospadias, a congenital condition characterized by the abnormal location of the urethra opening. Researchers measured the concentration of the chemicals in the blood of 20 California women who delivered a son with hypospadias and in 28 women who delivered healthy infants. No association was found to be statistically significant. Results thus do not support the hypothesis that exposure to PBDEs, PCBs or other persistent pesticides is related with increased risk of hypospadias in the population under study.
Scientific abstract:
BACKGROUND: Environmental contaminants that disrupt endocrine function may contribute to hypospadias etiology. OBJECTIVE: To compare levels of selected halogenated organic pollutants in women delivering infants with and without hypospadias. METHODS: This study examined levels of nine polybrominated flame retardants (PBDEs), 30 polychlorinated biphenyls (PCBs) and nine persistent pesticides in mid-pregnancy serum samples from 20 women who delivered infants with hypospadias and 28 women who delivered unaffected infants, in California. Analytes were measured using isotope dilution high-resolution mass spectrometry. Values below individual limits of detection (LOD) for each analyte were imputed based on a truncated multivariate normal distribution. Levels of 17 analytes for which at least 50% of cases and controls had values above the LOD were compared using t-tests and by generating odds ratios from logistic regression analyses. RESULTS: Means were greater for cases than controls for 11 of the 17 reported analytes (4 of 5 PBDEs, 7 of 9 PCBs, and 0 of 3 other persistent pesticides), but none of the differences were statistically significant. Eleven of the 17 odds ratios exceeded one (the same analytes that had greater means), but none of the confidence intervals excluded one. After adjustment for sample processing time and foreign-born Hispanic race-ethnicity, only four of the odds ratios exceeded one. CONCLUSIONS: Levels of the PBDEs and PCBs were not statistically significantly different, but the sample size was small. The current study adds to a relatively limited knowledge base regarding the potential association of specific contaminants with hypospadias or other birth defects.
Background. Human exposure to polybrominated diphenylether (PBDE) flame retardants has increased exponentially over the last three decades. Animal and human studies suggest that PBDEs may disrupt thyroid function. Although thyroid hormone of maternal origin is essential to normal fetal brain development, there is a paucity of human data regarding associations between exposure to PBDEs and maternal thyroid hormone levels during pregnancy. Objectives. To determine whether PBDE serum concentrations are associated with thyroid hormone levels in pregnant women. Methods. We measured the concentration of 10 PBDE congeners, free thyroxine (T4), total T4 and thyroid-stimulating hormone (TSH) in 270 pregnant women around the 27th week of gestation. Results. Serum concentrations of individual PBDE congeners with detection frequencies >50% (BDE-28, 47, 99, 100 and 153) and their sum ( summation operatorPBDEs) were inversely associated with TSH levels. Decreases in TSH ranged between 10.9% (95%CI= -20.6, 0.0) and 18.7% (95%CI= -29.2, -4.5) for every 10-fold increase in individual congeners. Odds of subclinical hyperthyroidism (low TSH but normal T4) were also significantly elevated in participants in the highest quartile of summation operatorPBDEs, and BDE-100 and 153 relative to those in the first quartile. Associations between PBDEs and free and total T4 were not statistically significant. Results were not substantially altered after the removal of outliers, and were independent of the method used to adjust for blood lipid levels and to express summation operatorPBDEs. Conclusions. Results suggest that exposure to PBDEs is associated with lower TSH during pregnancy. Findings may have implications for maternal health and fetal development.
Study Synopsis: DDT is an insecticide that was banned by the U.S. Environmental Protection Agency (EPA) in the 1970s due to concerns about its persistence in the environment and toxic effects on wildlife and humans. DDT was banned internationally by the Stockholm Convention on Persistent Organic Pollutants, except to control insects that transmit human diseases such as malaria. In this study, researchers measured the concentration of DDT in the blood of 318 participants. They found that those with higher DDT blood levels had lower concentrations of the thyroid hormones free thyroxine (T4) and triiodothyronine (T3) and had altered levels of thyroid-stimulating hormone (TSH) and of transthyretin, a protein responsible for the transport of T4 and T3 in the blood. Depressed blood levels of retinol-binding protein, responsible for the transport of vitamin A, were also associated with higher levels of DDT. These results suggest that exposure to DDT may be related with alterations in thyroid function and vitamin A transport.
Scientific abstract:
Background: The insecticide dichloro-diphenyl-trichloroethane (DDT) has been used for malaria vector control in the northern and eastern parts of the Vhembe District of Limpopo Province, South Africa, since 1945. Bioaccumulation of DDT raises concern as it reportedly affects thyroid function. Objective: The objective was to investigate the association between DDT uptake, as reflected in plasma concentrations, and thyroid homeostasis, while considering related factors. Methods: Dietary intake, serum retinol-binding protein (RBP), transthyretin (TTR) and albumin concentrations and liver- and thyroid function were compared between cases with evidence of a body burden of DDT in the circulation (DDT concentration of any isomer >/=0.02 mug/g lipid ; n=278) and controls (DDT concentration of all isomers <0.02 mug/g lipid; n=40) in a cross-sectional study. Further analyses were performed to assess the relevance of changes in RBP status associated with DDT uptake. Results: RBP concentrations below the reference range were more prevalent in cases [54% versus 10% in controls; Chi-square 27.4 (p<0.001)], which could not be explained by nutrient intake. Significantly lower thyroid hormone concentrations were in observed cases (ptop of page / modify search terms
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured the blood levels of one type of phthalate called diethylhexyl phthalate (DEHP) and its main metabolite (monoethylhexyl phthalate or MEHP) in boys with breast enlargement, a condition called gynecomastia, and controls. They found that cases of gynecomastia had higher levels of both chemicals in their blood.
Scientific abstract:
OBJECTIVE: Several untoward health effects of phthalates, which are a group of industrial chemicals with many commercial uses including personal-care products and plastic materials, have been defined. The most commonly used, di-(2-ethylhexyl)-phthalate (DEHP), is known to have antiandrogenic or estrogenic effects or both. Mono-(2-ethylhexyl)-phthalate (MEHP) is the main metabolite of DEHP. In this study, we aimed to determine the plasma DEHP and MEHP levels in pubertal gynecomastia cases. PATIENTS AND METHODS: The study group comprised 40 newly diagnosed pubertal gynecomastia cases who were admitted to Hacettepe University Ihsan Do[g]ramac[i] Children's Hospital. The control group comprised 21 age-matched children without gynecomastia or other endocrinologic disorder. Plasma DEHP and MEHP levels were measured by using high-performance liquid chromatography. Serum hormone levels were determined in some pubertal gynecomastia cases according to the physician's evaluation. RESULTS: Plasma DEHP and MEHP levels were found to be statistically significantly higher in the pubertal gynecomastia group compared with the control group (P < .001) (DEHP, 4.66 {+/-} 1.58 and 3.09 {+/-} 0.90 {micro}g/mL, respectively [odds ratio: 2.77 (95% confidence interval: 1.48-5.21)]; MEHP, 3.19 {+/-} 1.41 and 1.37 {+/-} 0.36 {micro}g/mL [odds ratio: 24.76 (95% confidence interval: 3.5-172.6)]). There was a statistically significant correlation between plasma DEHP and MEHP levels (r: 0.58; P < .001). In the pubertal gynecomastia group, no correlation could be determined between plasma DEHP and MEHP levels and any of the hormone levels. CONCLUSIONS: DEHP, which has antiandrogenic or estrogenic effects, may be an etiologic factor in pubertal gynecomastia. These results may pioneer larger-scale studies on the etiologic role of DEHP in pubertal gynecomastia.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured phthalate metabolites in urine samples collected from 188 pregnant women during the third trimester of gestation. Their children's cognitive and behavioral development was assessed between 4 and 9 years of age. Higher levels of some metabolites were associated with more aggressive behaviors, conduct problems, attention problems and depression. Poorer emotional control was also related with higher urine levels of some phthalates. These results suggest that prenatal exposure to certain phthalates may be related with impaired behavioral development. The domains affected in this study are those commonly found in children clinically diagnosed with conduct or attention deficit hyperactivity disorders,
Scientific abstract:
BACKGROUND: Experimental and observational studies have reported biological consequences of phthalate exposure relevant to neurodevelopment. OBJECTIVE: Our goal was to examine the association of prenatal phthalate exposure with behavior and executive functioning at 4-9 years of age. METHODS: The Mount Sinai Children's Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urines were collected and analyzed for phthalate metabolites. Children (n = 188, n = 365 visits) were assessed for cognitive and behavioral development between the ages of 4 and 9 years. RESULTS: In multivariate adjusted models, increased loge concentrations of low molecular weight (LMW) phthalate metabolites were associated with poorer scores on the aggression [beta = 1.24; 95% confidence interval (CI), 0.15- 2.34], conduct problems (beta = 2.40; 95% CI, 1.34-3.46), attention problems (beta = 1.29; 95% CI, 0.16- 2.41), and depression (beta = 1.18; 95% CI, 0.11-2.24) clinical scales; and externalizing problems (beta = 1.75; 95% CI, 0.61-2.88) and behavioral symptom index (beta = 1.55; 95% CI, 0.39-2.71) composite scales. Increased loge concentrations of LMW phthalates were also associated with poorer scores on the global executive composite index (beta = 1.23; 95% CI, 0.09-2.36) and the emotional control scale (beta = 1.33; 95% CI, 0.18- 2.49). CONCLUSION: Behavioral domains adversely associated with prenatal exposure to LMW phthalates in our study are commonly found to be affected in children clinically diagnosed with conduct or attention deficit hyperactivity disorders.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers exposed Leydig cells extracted from mice testicles to diethylhexyl phthalate (DEHP), the most abundantly used phthalate or monoethylhexyl phthalate (MEHP), its main metabolite. Leydig cells produce the male hormone testosterone. Both DEHP and MEHP were found to be toxic to Leydig cells and to cause DNA damage. MEHP appeared to be more toxic than DEHP. However, exposure to selenium, a mineral essential to human health, was found to be protective against the deleterious effects of MEHP and DEHP. These results suggest that, under the experimental conditions created by researchers, DEHP and its metabolite MEHP are toxic to Leydig cells and cause DNA damage. Selenium supplementation appeared to protect against these effects.
Scientific abstract:
Di(2-ethylhexyl)-phthalate (DEHP) is the most abundantly used phthalate derivative, inevitable environmental exposure of which is suspected to contribute to the increasing incidence of testicular dysgenesis syndrome in humans. Oxidative stress and mitochondrial dysfunction in germ cells are suggested to contribute to phthalate-induced disruption of spermatogenesis in rodents, and Leydig cells are one of the main targets of phthalates' testicular toxicity. Selenium is known to be involved in the modulation of intracellular redox equilibrium, and plays a critical role in testis, sperm, and reproduction. This study was aimed to investigate the oxidative stress potential of DEHP and its consequences in testicular cells, and examine the possible protective effects of selenium using the MA-10 mouse Leydig tumor cell line as a model. In the presence and absence of selenium compounds [30 nM sodium selenite (SS), and 10 muM selenomethionine (SM)], the effects of exposure to DEHP and its main metabolite mono(2-ethylhexyl)-phthalate (MEHP) on the cell viability, enzymatic and non-enzymatic antioxidant status, ROS production, p53 expression, and DNA damage by alkaline Comet assay were investigated. The overall results of this study demonstrated the cytotoxicity and genotoxicity potential of DEHP, where MEHP was found to be more potent than the parent compound. SS and SM produced almost the same level of protection against antioxidant status modifying effects, ROS and p53 inducing potentials, and DNA damaging effects of the two phthalate derivatives. It was thus shown that DEHP produced oxidative stress in MA-10 cells, and selenium supplementation appeared to be an effective redox regulator in the experimental conditions used in this study, emphasizing the critical importance of the appropriate selenium status.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers exposed Leydig cells extracted from mice testicles to diethylhexyl phthalate (DEHP), the most abundantly used phthalate or monoethylhexyl phthalate (MEHP), its main metabolite. Leydig cells produce the male hormone testosterone. Both DEHP and MEHP were found to be toxic to Leydig cells and to cause DNA damage. MEHP appeared to be more toxic than DEHP. However, exposure to selenium, a mineral essential to human health, was found to be protective against the deleterious effects of MEHP and DEHP. These results suggest that, under the experimental conditions created by researchers, DEHP and its metabolite MEHP are toxic to Leydig cells and cause DNA damage. Selenium supplementation appeared to protect against these effects.
Scientific abstract:
Di(2-ethylhexyl)-phthalate (DEHP) is the most abundantly used phthalate derivative, inevitable environmental exposure of which is suspected to contribute to the increasing incidence of testicular dysgenesis syndrome in humans. Oxidative stress and mitochondrial dysfunction in germ cells are suggested to contribute to phthalate-induced disruption of spermatogenesis in rodents, and Leydig cells are one of the main targets of phthalates' testicular toxicity. Selenium is known to be involved in the modulation of intracellular redox equilibrium, and plays a critical role in testis, sperm, and reproduction. This study was aimed to investigate the oxidative stress potential of DEHP and its consequences in testicular cells, and examine the possible protective effects of selenium using the MA-10 mouse Leydig tumor cell line as a model. In the presence and absence of selenium compounds [30 nM sodium selenite (SS), and 10 muM selenomethionine (SM)], the effects of exposure to DEHP and its main metabolite mono(2-ethylhexyl)-phthalate (MEHP) on the cell viability, enzymatic and non-enzymatic antioxidant status, ROS production, p53 expression, and DNA damage by alkaline Comet assay were investigated. The overall results of this study demonstrated the cytotoxicity and genotoxicity potential of DEHP, where MEHP was found to be more potent than the parent compound. SS and SM produced almost the same level of protection against antioxidant status modifying effects, ROS and p53 inducing potentials, and DNA damaging effects of the two phthalate derivatives. It was thus shown that DEHP produced oxidative stress in MA-10 cells, and selenium supplementation appeared to be an effective redox regulator in the experimental conditions used in this study, emphasizing the critical importance of the appropriate selenium status.
Eskenazi B, Warner M, Marks AR, Samuels S, Needham L, Brambilla P, Mocarelli P. Serum dioxin concentrations and time to pregnancy. Epidemiology. 2010 Mar;21(2):224-31.
Study Synopsis: Dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are highly toxic chemicals that bioaccumulate in humans' fat. In 1976, an explosion in a chemical manufacturing plant located in Seveso, Italy released large amounts of TCDD, resulting in the highest known exposure to TCDD in a residential community. In this study, researchers measured the levels of TCDD in the blood of 472 women who attempted to conceive after the accident. They found that women with higher blood levels of TCDD took longer to become pregnant and had almost twice the odds of being infertile (defined as taking more than 12 months to become pregnant). These results suggest that exposure to TCDD may affect female fertility.
Scientific abstract:
BACKGROUND: Pollution may play a role in population trends of declining semen quality and regional differences in time to pregnancy (TTP) in industrialized societies. Dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been suspected. In 1976, an explosion near Seveso, Italy resulted in the highest TCDD exposure known in residential populations. Twenty years later, we conducted a retrospective cohort study, the Seveso Women's Health Study. METHODS: Of 981 participants, 472 women attempted pregnancy after the explosion, and 278 delivered a livebirth not associated with contraceptive failure. Individual serum TCDD levels were measured from samples collected soon after the explosion and extrapolated to the conception attempt. We examined the relation of TCDD levels to time to pregnancy (parameterized as the monthly probability of conception within the first 12 months of trying) and to infertility (defined as conception after at least 12 months of trying). We modeled fecundability with discrete-time Cox proportional hazards regression, and we modeled fertility with logistic regression. We tested the sensitivity of the conclusions to differing definitions of eligibility and outcome. RESULTS: Median TCDD level was 50 parts per trillion, median time to pregnancy was 2 months, and 17% reported taking 12 or more months to conceive. For every 10-fold increase in serum TCDD, we observed a 25% increase in time to pregnancy (adjusted-fecundability odds ratio = 0.75 [95% confidence interval (CI) = 0.60-0.95]) and about a doubling in odds of infertility (adjusted odds ratio = 1.9 [95% CI = 1.1-3.2]). Results were similar for extrapolated TCDD and sensitivity analyses. CONCLUSIONS: We found dose-related increases in TTP and infertility associated with individual serum TCDD levels in the women from Seveso, Italy. These findings may have implications for fertility in industrialized areas.
Study Synopsis: Dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are highly toxic industrial by-products that are persistent in the environment and humans and bioaccumulate in fat. TCDD has been reported to interfere with thyroid hormones metabolism and signaling in the developing brain. Thyroid hormones are critical to normal brain development, including a process called myelination. This process comprises the formation of myelin, an insulating layer found around certain parts of brain cells. In this study, researchers exposed pregnant rats to a single dose of TCDD and examined offspring shortly (2-3 days) after birth and at age 14, 30 and 135 days. Researchers found significant alterations of the myelin both at age 2-3 days and 135 days, suggesting that exposure may have a long-term effect. Results suggest that prenatal exposure to TCDD may affect myelination.
Scientific abstract:
Polychlorinated dibenzo-dioxins, furans and dioxin-like polychlorinated biphenyls are ubiquitous in foodstuffs of animal origin and accumulate in the fatty tissues of animals and humans. The most toxic congener is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a lipophilic endocrine-disrupting molecule that accumulates in adipose tissue, placenta and milk. polychlorinated biphenyls and TCDD are known to interfere with thyroid hormone metabolism and signaling in the developing brain. As thyroid hormone is critical in the myelination process during development, we investigated the effect of a single dose of TCDD prenatal exposure (gestational day 18) on the myelination process. A semi-quantitative analysis of oligodendrocyte markers at different stages of maturation was performed in the offspring's medulla oblongata, cerebellum, diencephalon and telenchephalon at different postnatal days (2/3, 14, 30 and 135). The most significant alterations observed were: (i) cerebellum and medulla oblongata: altered expression of oligodendroglial lineage and platelet-derived growth factor alpha receptor, myelin basic protein (MBP) mRNAs (P2/3, P135) and MBP protein (P135); (ii) diencephalon: increase in platelet- derived growth factor alpha receptor mRNA level (P2/3); (iii) telenchephalon: decrease in MBP mRNA expression. The oligodendroglial generation capability of adult neural stem/precursor cells obtained ex vivo from TCDD and vehicle-treated dams was then explored. TCDD impairs neurosphere proliferation and retards CNPase-positive cell generation from adult neurospheres.
Study Synopsis: Dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are highly toxic industrial by-products that are persistent in the environment and humans and bioaccumulate in fat. TCDD has been reported to interfere with thyroid hormones metabolism and signaling in the developing brain. Thyroid hormones are critical to normal brain development, including a process called myelination. This process comprises the formation of myelin, an insulating layer found around certain parts of brain cells. In this study, researchers exposed pregnant rats to a single dose of TCDD and examined offspring shortly (2-3 days) after birth and at age 14, 30 and 135 days. Researchers found significant alterations of the myelin both at age 2-3 days and 135 days, suggesting that exposure may have a long-term effect. Results suggest that prenatal exposure to TCDD may affect myelination.
Scientific abstract:
Polychlorinated dibenzo-dioxins, furans and dioxin-like polychlorinated biphenyls are ubiquitous in foodstuffs of animal origin and accumulate in the fatty tissues of animals and humans. The most toxic congener is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a lipophilic endocrine-disrupting molecule that accumulates in adipose tissue, placenta and milk. polychlorinated biphenyls and TCDD are known to interfere with thyroid hormone metabolism and signaling in the developing brain. As thyroid hormone is critical in the myelination process during development, we investigated the effect of a single dose of TCDD prenatal exposure (gestational day 18) on the myelination process. A semi-quantitative analysis of oligodendrocyte markers at different stages of maturation was performed in the offspring's medulla oblongata, cerebellum, diencephalon and telenchephalon at different postnatal days (2/3, 14, 30 and 135). The most significant alterations observed were: (i) cerebellum and medulla oblongata: altered expression of oligodendroglial lineage and platelet-derived growth factor alpha receptor, myelin basic protein (MBP) mRNAs (P2/3, P135) and MBP protein (P135); (ii) diencephalon: increase in platelet- derived growth factor alpha receptor mRNA level (P2/3); (iii) telenchephalon: decrease in MBP mRNA expression. The oligodendroglial generation capability of adult neural stem/precursor cells obtained ex vivo from TCDD and vehicle-treated dams was then explored. TCDD impairs neurosphere proliferation and retards CNPase-positive cell generation from adult neurospheres.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. In this study, researchers injected female rats with different doses BPA on a daily basis from birth to 10 days of age and investigated impacts on reproductive parameters. The found that exposure to BPA was related with increased blood levels of the hormones testosterone and estradiol (an estrogen) and reduced progesterone in adulthood. BPA also altered the secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. GnRH pulse activity is essential to normal reproductive function. Finally, exposure to BPA affected female fertility with rats exposed to the highest dose having abnormal ovaries and being infertile. Results show that neonatal exposure to high doses of BPA affect the reproductive system in female rats.
Scientific abstract:
Background: Bisphenol A (BPA), an endocrine disruptor, is a component of polycarbonate plastics, epoxy resins and polystyrene. Several studies have reported potent in vivo effects, as BPA acts like an estrogen agonist and/or antagonist and androgen and thyroid hormone antagonist. Objectives: We investigated the effects of neonatal exposure to BPA on the reproductive axis in adult Sprague-Dawley females. Methods: Females were injected subcutaneously, daily, from postnatal day 1 (PND1) to PND10 with BPA, 500 microg/50microl (BPA500, ~10-4 M, a dose higher than the LOAEL=50 mg/kg), 50 microg/50microl (BPA50), 5 microg/50microl (BPA5) in castor oil (both doses lower than the LOAEL) or vehicle. We studied in adults: GnRH release from hypothalamic explants, serum sexual hormone levels, ovarian morphology, ovulation and fertility. Results: Neonatal exposure to BPA was associated with increased serum testosterone and estradiol levels and reduced progesterone in adulthood, and with altered in vitro GnRH secretion. Animals exposed to BPA500 had altered ovarian morphology, showing a large number of cysts. Animals exposed to BPA50 had reduced fertility, without changes in the number of oocytes on the morning of estrus, whereas animals exposed to BPA500 showed infertility. Conclusions: Exposure to high doses of BPA during the period of brain sexual differentiation altered the hypothalamic-pituitary-gonadal axis in Sprague-Dawley females. These results have the potential to link the neonatal exposure to high doses of BPA in rats with the development of PCOS. Studies of doses and routes of administration more consistent with human exposures are needed to determine the relevance of these findings to human health.
Guerra MT, Scarano WR, De Toledo FC, Franci JA, Kempinas Wde G. Reproductive development and function of female rats exposed to di-eta-butyl-phthalate (DBP) in utero and during lactation. Reprod Toxicol. 2010 Jan;29(1):99-105.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers exposed pregnant rats to high doses (100 mg/kg per day) of dietabutyl phthalate (DBP) during gestation and lactation. DBP did not appear to adversely affect the development and function of the reproductive system of female offspring. These results suggest that pre and postnatal exposure to DBP does not impair the female reproductive system in rats under the experimental conditions of this study.
Scientific abstract:
Phthalates are environmental contaminants used in the production of plastics, cosmetics and medical devices. Studies on the effects of phthalates on female reproductive health are particularly sparse and mostly restricted to high-dose exposure in rats. In the present study, pregnant rats were treated with 100mg/kg-d of di-eta-butyl-phthalate (DBP) or only the vehicle (control group), from GD 12 to GD 20 for evaluation of reproductive outcomes and fetal gonads analysis (F0), and from GD 12 to PND 21 to evaluate reproductive development and function on F1 female offspring. Results showed that all parameters were comparable between groups, although there was a significant increase in the fetal weight after DBP exposure. However, the body weight at birth was normal. Based on these data we can conclude that, in these experimental conditions, DBP did not disturb the reproductive development or function of female rats.
Background: Exposure to polybrominated diphenyl ether (PBDE) flame retardants is widespread, with 97% of Americans having detectable levels. Although PBDEs have been associated with reproductive and hormonal effects in animals, no human studies have examined their association with fertility. Objectives: To determine whether maternal concentrations of PBDEs in serum collected during pregnancy are associated with time to pregnancy and menstrual cycle characteristics. Methods: Pregnant women (N = 223) living in a low-income, predominantly Mexican-immigrant community in California were interviewed to determine how many months they took to become pregnant. Blood samples were collected and analyzed for PBDEs. PBDE concentrations were lipid-adjusted and log10-transformed. Analyses were limited to PBDE congeners detected in >75% of the population (BDE-47, -99, -100, -153). Cox proportional hazards models modified for discrete time were used to obtain fecundability odds ratios (fOR) for the association of PBDEs and time to pregnancy. Results: All four congeners were detected in more than 95% of women. Increasing levels of BDE-47, -99, -100, -153 and the sum of these 4 congeners were all associated with longer time to pregnancy. Significantly reduced fORs were observed for BDE-100 (adjusted fOR = 0.6, 95% confidence interval (CI): 0.4, 0.9), BDE-153 (adjusted fOR = 0.5, 95% CI: 0.3, 0.8), and the sum of the 4 congeners (adjusted fOR = 0.7, 95% CI: 0.5. 1.0). PBDEs were not associated with menstrual cycle characteristics.
Conclusions: We found significant decreases in fecundability associated with PBDE exposure in women. Future studies are needed to replicate and confirm this finding.
Herbstman JB, Sjodin A, Kurzon M, Lederman SA, Jones RS, Rauh V, Needham LL, Tang D, Niedzwiecki M, Wang RY, Perera F. Prenatal exposure to PBDEs and neurodevelopment. Environ Health Perspect. 2010 May;118(5):712-9.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers measured PBDE in the cord blood of 210 women who delivered in one of three hospitals in lower Manhattan, New York after September 11, 2001. They found that women with higher cord blood levels of PBDEs scored lower on tests of mental and physical development between 1 and 6 years of age. Associations were significant with mental development at 1-3 years of age, and with measures of the intellectual quotient (IQ) at 4 (verbal, performance and full scale IQ), and 6 years (performance IQ). These results suggest that prenatal exposure to PBDEs may be related with impaired neurodevelopment.
Scientific abstract:
BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardant compounds that are persistent and bioaccumulative and therefore have become ubiquitous environment contaminants. Animal studies suggest that prenatal PBDE exposure may result in adverse neurodevelopmental effects. OBJECTIVE: In a longitudinal cohort initiated after 11 September 2001, including 329 mothers who delivered in one of three hospitals in lower Manhattan, New York, we examined prenatal PBDE exposure and neurodevelopment when their children were 12-48 and 72 months of age. METHODS: We analyzed 210 cord blood specimens for selected PBDE congeners and assessed neurodevelopmental effects in the children at 12-48 and 72 months of age; 118, 117, 114, 104, and 96 children with available cord PBDE measurements were assessed at 12, 24, 36, 48, and 72 months, respectively. We used multivariate regression analyses to evaluate the associations between concentrations of individual PBDE congeners and neurodevelopmental indices. RESULTS: Median cord blood concentrations of PBDE congeners 47, 99, and 100 were 11.2, 3.2, and 1.4 ng/g lipid, respectively. After adjustment for potential confounders, children with higher concentrations of BDEs 47, 99, or 100 scored lower on tests of mental and physical development at 12-48 and 72 months. Associations were significant for 12-month Psychomotor Development Index (BDE-47), 24-month Mental Development Index (MDI) (BDE-47, 99, and 100), 36-month MDI (BDE-100), 48-month full-scale and verbal IQ (BDE-47, 99, and 100) and performance IQ (BDE-100), and 72-month performance IQ (BDE-100). CONCLUSIONS: This epidemiologic study demonstrates neurodevelopmental effects in relation to cord blood PBDE concentrations. Confirmation is needed in other longitudinal studies.
Huang PC, Tsai EM, Li WF, Liao PC, Chung MC, Wang YH, Wang SL. Association between phthalate exposure and glutathione S-transferase M1 polymorphism in adenomyosis, leiomyoma and endometriosis. Hum Reprod. 2010 Apr;25(4):986-94.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers compared the urine levels of seven phthalate residues between healthy controls and women diagnosed with endometriosis (growth of endometrium outside the uterus), adenomyosis (growth of endometrium in the muscular layer of the uterus) or leiomyoma (noncancerous tumors of the uterus). Patients with endometriosis had urine levels of the phthalate residue monobutyl phthalate (MBP) that were 62% higher than controls. Leiomyoma cases, on the other hand, had urine levels of monoethylhexyl phthalate (MEHP) that were 1.8 times higher than controls. These findings suggest that exposure to phthalates may be related to endometriosis and leiomyoma. It is however important to note that this study had a small sample size and differences in the urine levels of phthalates may be due to differences in phthalate metabolism between cases and healthy women rather than differences in exposure. This study thus needs to be replicated.
Scientific abstract:
BACKGROUND: Phthalates are known to have estrogenic effects in cell models and experimental animals. However, the evidence regarding the effects of phthalates on human reproduction is still limited. We conducted a case-control study to determine whether estrogen-dependent diseases are associated with phthalate exposure and how the glutathione S-transferase M1 (GSTM1; a major detoxification enzyme) genotype modulates the risk. METHODS: We recruited subjects who underwent laparotomy and had pathologic confirmation of endometriosis (EN) (n = 28), adenomyosis (AD) (n = 16) and leiomyoma (LEI) (n = 36) from the Department of Obstetrics and Gynecology at a medical center in Taiwan between 2005 and 2007. Controls (n = 29) were patients without any of the three aforementioned gynecologic conditions. Urine samples were collected before surgery and analyzed for seven phthalate metabolites using liquid chromatography-tandem mass spectrometry. Peripheral lymphocytes were used for GSTM1 genotype determination. RESULTS: Patients with LEIs had significantly higher levels of total urinary mono-ethylhexyl phthalate (SigmaMEHP; 52.1 versus 18.9 microg/g creatinine, P < 0.05) than the controls, whereas patients with EN had an increased level of urinary mono-n-butyl phthalate (94.1 versus 58.0 microg/g creatinine, P < 0.05). Subjects with GSTM1 null genotype had significantly increased odds for AD relative to those with GSTM1 wild genotype [odds ratio (OR) = 5.30; 95% CI, 1.22-23.1], even after adjustment for age and phthalate exposure. Subjects who carried the GSTM1 null genotype and had a high urinary level of SigmaMEHP showed a significantly increased risk for AD (OR = 10.4; 95% CI, 1.26-85.0) and LEIs (OR = 5.93; 95% CI, 1.10-31.9) after adjustment for age, compared with those with GSTM1 wild-type and low urinary level of SigmaMEHP. CONCLUSIONS: These results suggest that both GSTM1 null and phthalate exposure are associated with AD and LEI. Larger studies are warranted to investigate potential interaction between GSTM1 null and phthalate exposure in the etiology of estrogen-dependent gynecologic conditions.
Study Synopsis: Hexabromocyclododecane (HBCD) is a flame retardant used in polystyrene insulation and textiles. Although a growing number of studies have examined the potential health effects of other flame retardants, such as polybrominated diphenyl ethers (PBDEs), few studies have examined the effect of exposure to HBCD. In this study, researchers exposed cells to HBCD and found that the chemical supressed the effect of thyroid hormones and altered the development of neurons called Purkinje cells which is usually induced by thyroid hormones. Results suggest that exposure to HBCD may interfere with thyroid hormone action and alter brain development.
Scientific abstract:
1,2,5,6,9,10-alphaHexabromocyclododecane (HBCD) is a nonaromatic, brominated cyclic alkane used as an additive flame retardant. It bioaccumulates, persists in the environment, and has been detected in humans and wildlife. Its developmental neurotoxicity is of great concern. We investigated the effect of HBCD on thyroid hormone (TH) receptor (TR)-mediated transcription using transient transfection-based reporter gene assays and found that a low-dose (10(-10) M) HBCD suppressed TR-mediated transcription. We further examined the effect of HBCD on interaction of TR with TH response element (TRE) and found a partial dissociation of TR from TRE. HBCD did not dissociate steroid receptor coactivator-1 from TR in the presence of TH; neither did it recruit corepressors (N-CoR and SMRT) to TR in the absence of TH. Furthermore, low-dose HBCD (10(-10) M) significantly suppressed TH-induced dendrite arborization of Purkinje cells in primary cerebellar culture derived from newborn rat. These results show that low-dose HBCD can potentially disrupt TR-mediated transactivation and impairs Purkinje cell dendritogenesis, suggesting that HBCD can interfere with TH action in target organs, including the developing brain.
Study Synopsis: Hexabromocyclododecane (HBCD) is a flame retardant used in polystyrene insulation and textiles. Although a growing number of studies have examined the potential health effects of other flame retardants, such as polybrominated diphenyl ethers (PBDEs), few studies have examined the effect of exposure to HBCD. In this study, researchers exposed cells to HBCD and found that the chemical suppressed the effect of thyroid hormones and altered the development of neurons called Purkinje cells which is usually induced by thyroid hormones. Results suggest that exposure to HBCD may interfere with thyroid hormone action and alter brain development.
Scientific abstract:
1,2,5,6,9,10-alphaHexabromocyclododecane (HBCD) is a nonaromatic, brominated cyclic alkane used as an additive flame retardant. It bioaccumulates, persists in the environment, and has been detected in humans and wildlife. Its developmental neurotoxicity is of great concern. We investigated the effect of HBCD on thyroid hormone (TH) receptor (TR)-mediated transcription using transient transfection-based reporter gene assays and found that a low-dose (10(-10) M) HBCD suppressed TR-mediated transcription. We further examined the effect of HBCD on interaction of TR with TH response element (TRE) and found a partial dissociation of TR from TRE. HBCD did not dissociate steroid receptor coactivator-1 from TR in the presence of TH; neither did it recruit corepressors (N-CoR and SMRT) to TR in the absence of TH. Furthermore, low-dose HBCD (10(-10) M) significantly suppressed TH-induced dendrite arborization of Purkinje cells in primary cerebellar culture derived from newborn rat. These results show that low-dose HBCD can potentially disrupt TR-mediated transactivation and impairs Purkinje cell dendritogenesis, suggesting that HBCD can interfere with TH action in target organs, including the developing brain.
Study Synopsis: Semen quality appears to have declined in recent decades in some populations. At the same time, couple fertility may have increased. This paper suggest hypotheses for this apparent inconsistency.
Scientific abstract:
Semen quality appears to have declined in recent decades in some populations, e.g. north-western Europe. At the same time, couple fertility may have increased. Hypotheses are suggested for this apparent inconsistency. Alongside the deterioration of spermatogenesis there is clear evidence of an increase in other related problems, notably testicular cancer. The sharply rising trend in this condition started a century ago--decades earlier than sometimes thought. This and other evidence clearly indicates an environmental origin, but there is also a definite genetic component. The relationship of genetics and environment is discussed in the context of the puzzle that infertility is inherited, which appears to be impossible from an evolutionary standpoint. Poor semen quality is related not only to testicular cancer but also to zygote development, in which cancer-like disruption of the genetic apparatus is observed, with serious implications for offspring health. This needs to be seen in the context that human reproduction is prone to a higher degree of impairment than that of other mammalian species, in relation to spermatogenesis, couple fertility, early pregnancy loss and embryonic aneuploidy; female- and male-mediated pathways are both implicated. It is unclear whether such human specificity originated on an evolutionary/genetic or a historico-social timescale, which is important in relation to pathogenesis. The evidence clearly indicates that the currently most popular explanation for male reproductive system impairment, the endocrine disruption hypothesis, cannot explain the main features of the descriptive epidemiology. An alternative pathogenesis is outlined, and some possible exposures considered that could be responsible.
Kim SH, Chun S, Jang JY, Chae HD, Kim CH, Kang BM. Increased plasma levels of phthalate esters in women with advanced-stage endometriosis: a prospective case-control study. Fertil Steril. 2010 Jan;95(1):357-9.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured the concentration of monoethylhexyl phthalate (MEHP) and diethylhexyl phthalate (DEHP) in the blood of 97 women with advanced-stage endometriosis, an outgrowth of tissue normally located inside the uterus, and 169 healthy controls. They found that the blood levels of these two chemicals were higher in endometriosis cases relative to controls. These results suggest that exposure to phthalates may be related to increased risk of endometriosis.
Scientific abstract:
We performed the present prospective case-control study to evaluate whether the plasma concentrations of phthalate esters are elevated in women with advanced-stage endometriosis in a Korean population. Measuring plasma levels of monoethylhexyl phthalate and di-(2-ethylhexyl) phthalate in 97 women with advanced-stage endometriosis and 169 control women by liquid chromatography-tandem mass spectrometry, we found that the concentrations of monoethylhexyl phthalate, as well as di-(2-ethylhexyl) phthalate, are significantly higher in those with advanced-stage endometriosis, which supports the hypothesis that exposure to phthalate might play a role in the establishment of endometriosis.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. Studies suggest that exposure to diethylhexyl phthalate (DEHP) may be related with increased risks of endometriosis, the growth of tissue normally lining the inside of the uterus (the endometrium) outside of the uterine cavity. In this study, researchers exposed two types of endometrial cells (endometrial stroma cells and Ishikawa cells) to DEHP and found that it increased their viability. These results suggest that DEHP may play a role in endometriosis.
Scientific abstract:
Based on the findings of several reports that have shown an increased plasma level of di-(2-ethylhexyl) phthalate (DEHP) in women with endometriosis, the present study was designed to evaluate whether in vitro treatment with DEHP can increase viability of endometrial cells. Utilizing 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay, fluorescent activated cell sorter analysis, and microscopic evaluation after Hoechst staining, we revealed that in vitro treatment with DEHP leads to increased viability of Ishikawa cells as well as endometrial stromal cells in serum-free condition and following exposure to hydrogen peroxide, which suggests that exposure to phthalate might play a role in the establishment of endometriosis.
Key Words: Cell Proliferation/drug effects, Cell Survival/drug effects, Cells, Cultured, Diethylhexyl Phthalate/ pharmacology, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Endometrium/ drug effects/physiology, Female, Humans, Plasticizers/pharmacology, Stromal Cells/ drug effects/physiology, Time Factors, Up-Regulation/drug effects
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. Studies suggest that exposure to diethylhexyl phthalate (DEHP) may be related with increased risks of endometriosis, the growth of tissue normally lining the inside of the uterus (the endometrium) outside of the uterine cavity. In this study, researchers exposed two types of endometrial cells (endometrial stroma cells and Ishikawa cells) to DEHP and found that it increased their viability. These results suggest that DEHP may play a role in endometriosis.
Scientific abstract:
Based on the findings of several reports that have shown an increased plasma level of di-(2-ethylhexyl) phthalate (DEHP) in women with endometriosis, the present study was designed to evaluate whether in vitro treatment with DEHP can increase viability of endometrial cells. Utilizing 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay, fluorescent activated cell sorter analysis, and microscopic evaluation after Hoechst staining, we revealed that in vitro treatment with DEHP leads to increased viability of Ishikawa cells as well as endometrial stromal cells in serum-free condition and following exposure to hydrogen peroxide, which suggests that exposure to phthalate might play a role in the establishment of endometriosis.
Key Words: Cell Proliferation/drug effects, Cell Survival/drug effects, Cells, Cultured, Diethylhexyl Phthalate/ pharmacology, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Endometrium/ drug effects/physiology, Female, Humans, Plasticizers/pharmacology, Stromal Cells/ drug effects/physiology, Time Factors, Up-Regulation/drug effects
Kodavanti PR, Coburn CG, Moser VC, Macphail RC, Fenton SE, Stoker TE, Rayner JL, Kannan K, Birnbaum LS. Developmental exposure to a commercial PBDE mixture, DE-71: neurobehavioral, hormonal, and reproductive effects. Toxicol Sci. 2010 Jul;116(1):297-312.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers exposed pregnant rats to different doses of the PBDE commercial mixture DE-71 and investigated neurobehavioral, hormonal and reproductive effects in offspring. DE-71 did not affect birth weight, body weight gain, the weight of reproductive tissues and serum concentrations of the male hormone testosterone. No substantial neurobehavioral effects were observed. Exposure however caused a large reduction in the blood levels of the thyroid hormone thyroxine (T4) both in dams and offspring. Anogenital distance, a marker of demasculinization of the male reproductive tract, and preputial separation, a marker of puberty onset in males, were also affected. Finally, the development of the mammary gland was altered in females. These results show that prenatal exposure to DE-71 affects thyroid hormone levels, puberty onset as well as the male and female reproductive tract in rats.
Scientific abstract:
Developmental effects of polybrominated diphenyl ethers (PBDEs) have been suspected due to their structural similarities to polychlorinated biphenyls (PCBs). This study evaluated neurobehavioral, hormonal, and reproductive effects in rat offspring perinatally exposed to a widely used pentabrominated commercial mixture, DE-71. Pregnant Long-Evans rats were exposed to 0, 1.7, 10.2, or 30.6 mg/kg/day DE-71 in corn oil by oral gavage from gestational day 6 to weaning. DE-71 did not alter maternal or male offspring body weights. However, female offspring were smaller compared with controls from postnatal days (PNDs) 35-60. Although several neurobehavioral endpoints were assessed, the only statistically significant behavioral finding was a dose-by-age interaction in the number of rears in an open-field test. Developmental exposure to DE-71 caused severe hypothyroxinemia in the dams and early postnatal offspring. DE-71 also affected anogenital distance and preputial separation in male pups. Body weight gain over time, reproductive tissue weights, and serum testosterone concentrations at PND 60 were not altered. Mammary gland development of female offspring was significantly affected at PND 21. Congener-specific analysis of PBDEs indicated accumulation in all tissues examined. Highest PBDE concentrations were found in fat including milk, whereas blood had the lowest concentrations on a wet weight basis. PBDE concentrations were comparable among various brain regions. Thus, perinatal exposure to DE-71 leads to accumulation of PBDE congeners in various tissues crossing blood-placenta and blood-brain barriers, causing subtle changes in some parameters of neurobehavior and dramatic changes in circulating thyroid hormone levels, as well as changes in both male and female reproductive endpoints. Some of these effects are similar to those seen with PCBs, and the persistence of these changes requires further investigation.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. In this study, researchers estimated exposure to BPA in factory workers based on air samples and expert judgment. They found that workers exposed to BPA had increased odds of low sexual desire, erectile difficulty, ejaculation difficulty and reduced satisfaction with their sex life. Results suggest that exposure to BPA may be related with adverse effects on male sexual function. This study is however limited by the fact that exposure was not directly measured for each worker.
Scientific abstract:
BACKGROUND: Animal studies have suggested that bisphenol-A (BPA) is a potential human endocrine disrupter; but evidence from human studies is needed. METHODS: We conducted an occupational cohort study to examine the effect of occupational exposure to BPA on the risk of male sexual dysfunction. Current workers from BPA-exposed and control factories were recruited. The exposed workers were exposed to very high BPA levels in their workplace. Male sexual function was ascertained through in-person interviews using a standard male sexual function inventory. RESULTS: BPA-exposed workers had consistently higher risk of male sexual dysfunction across all domains of male sexual function than the unexposed workers. After controlling for matching variables and potential confounders, exposed workers had a significantly increased risk of reduced sexual desire [odds ratios (OR) = 3.9, 95% confidence interval: 1.8-8.6), erectile difficulty (OR = 4.5, 95% CI 2.1-9.8), ejaculation difficulty (OR = 7.1, 95% CI 2.9-17.6), and reduced satisfaction with sex life (OR = 3.9, 95% CI 2.3-6.6). A dose-response relationship was observed with an increasing level of cumulative BPA exposure associated with a higher risk of sexual dysfunction. Furthermore, compared with the unexposed workers, BPA-exposed workers reported significantly higher frequencies of reduced sexual function within 1 year of employment in the BPA-exposed factories. CONCLUSIONS: Our findings provide the first evidence that exposure to BPA in the workplace could have an adverse effect on male sexual dysfunction.
Lomenick JP, Calafat AM, Melguizo Castro MS, Mier R, Stenger P, Foster MB, Wintergerst KA. Phthalate exposure and precocious puberty in females. J Pediatr. 2010 Feb;156(2):221-5.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers compared the urine concentration of nine phthalate metabolites in 28 girls with central precocious puberty and 28 girls of the same age and race but who had not reached puberty. No significant differences were observed between the two groups of girls. These results suggest that exposure to phthalates may not be related with central precocious puberty. However, the sample in this study was small, which may have limited this study's capability to detect differences.
Scientific abstract:
OBJECTIVE: To determine whether phthalate exposure is associated with precocious puberty in girls. STUDY DESIGN: This was a multicenter cross-sectional study in which 28 girls with central precocious puberty (CPP) and 28 age- and race-matched prepubertal females were enrolled. Nine phthalate metabolites and creatinine were measured in spot urine samples from these 56 children. RESULTS: Levels of 8 of the 9 phthalate metabolites were above the limit of detection (LOD) in all 56 subjects. Mono (2-ethylhexyl) phthalate (MEHP) was below the LOD in 25/56 samples (14 subjects with precocious puberty and 11 controls). No significant differences between the children with CPP and the controls in either absolute or creatinine-normalized concentrations of any of the 9 phthalate metabolites were measured. CONCLUSIONS: Although phthalates may be associated with certain other toxicities in humans, our study suggests that their exposure is not associated with precocious puberty in female children.
BACKGROUND: Phthalates, ubiquitous environmental pollutants that may disturb the endocrine system, are used primarily as plasticizers of polyvinyl chloride and as additives in consumer and personal care products.Objectives: In this study, we examined the association between urinary concentrations of nine phthalate metabolites and breast cancer (BC) in Mexican women. METHODS: We age-matched 233 BC cases to 221 women residing in northern Mexico. Sociodemographic and reproductive characteristics were obtained by direct interviews. Phthalates were determined in urine samples (collected pretreatment from the cases) by isotope dilution/high-performance liquid chromatography coupled to tandem mass spectrometry. RESULTS: Phthalate metabolites were detected in at least 82% of women. The geometric mean concentrations of monoethyl phthalate (MEP) were higher in cases than in controls (169.58 vs. 106.78 microg/g creatinine). Controls showed significantly higher concentrations of mono-n-butyl phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono(3-carboxypropyl) phthalate (MCPP) than did the cases. After adjusting for risk factors and other phthalates, MEP urinary concentrations were positively associated with BC [odds ratio (OR), highest vs. lowest tertile = 2.20; 95% confidence interval (CI), 1.33-3.63; p for trend < 0.01]. This association became stronger when estimated for premenopausal women (OR, highest vs. lowest tertile = 4.13; 95% CI, 1.60-10.70; p for trend < 0.01). In contrast, we observed significant negative associations for monobenzyl phthalate (MBzP) and MCPP. CONCLUSIONS: We show for the first time that exposure to diethyl phthalate, the parent compound of MEP, may be associated with increased risk of BC, whereas exposure to the parent phthalates of MBzP and MCPP might be negatively associated. These findings require confirmation.
Study Synopsis: Organochlorines are chemicals that were primarily used as pesticides from the 1940s to the 1970s when they were banned due to concerns about their persistence in the environment, bioaccumulation in fat tissues and potential adverse health effects on wildlife and in humans. In this study, researchers measured the levels of the pesticide dichlorodiphenyl trichloroethane (DDT), its breakdown product dichlorodiphenyl dichloroethylene (DDE), beta-hexachlorocyclohexane (HCH), the fungicide hexachlorobenzene and four polychlorinated biphenyls (PCBs) in the cord blood of 453 infants born between 2004 and 2006 in Valencia, Spain. Infants with very high (above the 90th percentile) cord blood beta-HCH levels tended to have higher blood concentration of thyroid-stimulating hormone (TSH). No other chemical was related with TSH levels. These results do not support that prenatal exposure to DDT, DDE or HCB are related with neonatal TSH. Results provide some evidence of a relationship between beta-HCH and TSH in newborns but researchers determined that this result may have been due to chance.
Scientific abstract:
It has been suggested that prenatal exposure to some organochlorine compounds (OCs) may adversely affect thyroid function and may, therefore, impair neurodevelopment. The main aim of this study was to examine the relationship of cord serum levels of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (4,4'-DDT), 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (4,4'-DDE), beta-hexachlorocyclohexane (beta-HCH), hexachlorobenzene (HCB), four individual polychlorobiphenyl (PCB) congeners (118, 138, 153, and 180), and their sum, with neonatal thyroid stimulating hormone (TSH) levels in blood samples in a mother-infant cohort in Valencia, Spain. This study included 453 infants born between 2004 and 2006. We measured OC concentrations in umbilical cord serum and TSH in blood of newborns shortly after birth. Associations between neonatal TSH levels and prenatal OC exposure adjusted for covariates were assessed using multivariate linear regression analyses. Neonatal TSH levels tended to be higher in newborns with beta-HCH levels in umbilical cord above 90th percentile (104 ng/g lipid) than in those with levels below the median (34 ng/g lipid), with an adjusted increment in neonatal TSH levels of 21% (95% confidence interval=-3, 51; P=0.09). No statistically significant association was found between the remaining OCs and TSH at birth. Prenatal exposure to beta-HCH may affect neonatal thyroid hormone status and its function in neurological development.
Study Synopsis: Organochlorines are chemicals that were primarily used as pesticides from the 1940s to the 1970s when they were banned due to concerns about their persistence in the environment, bioaccumulation in fat tissues and potential adverse health effects on wildlife and in humans. In this study, researchers measured the levels of the pesticide dichlorodiphenyl trichloroethane (DDT), its breakdown product dichlorodiphenyl dichloroethylene (DDE), beta-hexachlorocyclohexane (HCH), the fungicide hexachlorobenzene and four polychlorinated biphenyls (PCBs) in the cord blood of 453 infants born between 2004 and 2006 in Valencia, Spain. Infants with very high (above the 90th percentile) cord blood beta-HCH levels tended to have higher blood concentration of thyroid-stimulating hormone (TSH). No other chemical was related with TSH levels. These results do not support that prenatal exposure to DDT, DDE or HCB are related with neonatal TSH. Results provide some evidence of a relationship between beta-HCH and TSH in newborns but researchers determined that this result may have been due to chance.
Scientific abstract:
It has been suggested that prenatal exposure to some organochlorine compounds (OCs) may adversely affect thyroid function and may, therefore, impair neurodevelopment. The main aim of this study was to examine the relationship of cord serum levels of 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (4,4'-DDT), 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (4,4'-DDE), beta-hexachlorocyclohexane (beta-HCH), hexachlorobenzene (HCB), four individual polychlorobiphenyl (PCB) congeners (118, 138, 153, and 180), and their sum, with neonatal thyroid stimulating hormone (TSH) levels in blood samples in a mother-infant cohort in Valencia, Spain. This study included 453 infants born between 2004 and 2006. We measured OC concentrations in umbilical cord serum and TSH in blood of newborns shortly after birth. Associations between neonatal TSH levels and prenatal OC exposure adjusted for covariates were assessed using multivariate linear regression analyses. Neonatal TSH levels tended to be higher in newborns with beta-HCH levels in umbilical cord above 90th percentile (104 ng/g lipid) than in those with levels below the median (34 ng/g lipid), with an adjusted increment in neonatal TSH levels of 21% (95% confidence interval=-3, 51; P=0.09). No statistically significant association was found between the remaining OCs and TSH at birth. Prenatal exposure to beta-HCH may affect neonatal thyroid hormone status and its function in neurological development.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. In this study, researchers measured BPA concentrations in the urine of 190 men recruited through and infertility clinic. They found that men with higher urine levels of BPA had decreased sperm concentration and a trend towards reduced sperm motility. An increase in sperm DNA damage was also detected in relation with higher BPA exposure. These results suggest that BPA may be related with poorer semen quality and sperm DNA damage.
Scientific abstract:
Bisphenol A (BPA) impairs spermatogenesis in animals, but human studies are lacking. We measured urinary BPA concentrations, semen quality, and sperm DNA damage (comet assay) in 190 men recruited through an infertility clinic. BPA was detected in 89% of samples, with a median (interquartile range [IQR]) concentration of 1.3 (0.8-2.5) ng/mL. Urinary BPA concentration was associated with slightly elevated, though not statistically significant, odds for below reference sperm concentration, motility, and morphology. When modeled as continuous dependent variables, an IQR increase in urinary BPA concentration was associated with declines in sperm concentration, motility, and morphology of 23% (95%CI -40%, -0.3%), 7.5% (-17%, +1.5%), and 13% (-26%, -0.1%), respectively, along with a 10% (0.03%, 19%) increase in sperm DNA damage measured as the percentage of DNA in comet tail. In conclusion, urinary BPA may be associated with declined semen quality and increased sperm DNA damage, but confirmatory studies are needed.
BACKGROUND: Organophosphate (OP) compounds, such as tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and triphenyl phosphate (TPP), are commonly used as additive flame retardants and plasticizers in a wide range of materials. Although widespread human exposure to OP flame retardants is likely, there is a lack of human and animal data on potential health effects. OBJECTIVE: We explored relationships of TDCPP and TPP concentrations in house dust with hormone levels and semen quality parameters. METHODS: We analyzed house dust from 50 men recruited through a U.S. infertility clinic for TDCPP and TPP. Relationships with reproductive and thyroid hormone levels, as well as semen quality parameters, were assessed using crude and multivariable linear regression. RESULTS: TDCPP and TPP were detected in 96% and 98% of samples, respectively, with widely varying concentrations up to 1.8 mg/g. In models adjusted for age and body mass index, an interquartile range (IQR) increase in TDCPP was associated with a 3% [95% confidence interval (CI), 5% to 1%) decline in free thyroxine and a 17% (95% CI, 432%) increase in prolactin. There was a suggestive inverse association between TDCPP and free androgen index that became less evident in adjusted models. In the adjusted models, an IQR increase in TPP was associated with a 10% (95% CI, 219%) increase in prolactin and a 19% (95% CI, 30% to 5%) decrease in sperm concentration. CONCLUSION: OP flame retardants may be associated with altered hormone levels and decreased semen quality in men. More research on sources and levels of human exposure to OP flame retardants and associated health outcomes are needed.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. In this study, researchers measured the concentration of BPA in the urine of 2,948 adults aged 18-74 year representative of the U.S. population called the National Health and Nutrition Examination Survey (NHANES). The concentration of BPA was measured participants' urine and questions about diagnosis of heart disease and diabetes were asked as part of NHANES. Researchers found that participants with higher urine levels of BPA had 42% increased odds of suffering from coronary heart disease and 24% elevated odds of being diagnosed with diabetes. Results suggest that higher exposure to BPA may be related with increased odds of coronary heart disease and diabetes.
Scientific abstract:
Background: Bisphenol A (BPA) is a high production volume chemical widely used in food and drinks packaging. Associations have previously been reported between urinary BPA concentrations and heart disease, diabetes and liver enzymes in adult participants of the National Health and Nutrition Examination Survey (NHANES) 2003/04. We aimed to estimate associations between urinary BPA concentrations and health measures in NHANES 2005/06 and in data pooled across collection years. Methodology and Findings: A cross-sectional analysis of NHANES: subjects were 1455 (2003/04) and 1493 (2005/06) adults aged 18-74 years, representative of the general adult population of the United States. Regression models were adjusted for age, sex, race/ethnicity, education, income, smoking, BMI, waist circumference, and urinary creatinine concentration. Main outcomes were reported diagnoses of heart attack, coronary heart disease, angina and diabetes and serum liver enzyme levels. Urinary BPA concentrations in 2005/06 (geometric mean 1.79 ng/ml, 95% CI: 1.64 to 1.96) were lower than in 2003/04 (2.49 ng/ml, CI: 2.20 to 2.83, difference p-value=0.00002). Higher BPA concentrations were associated with coronary heart disease in 2005/06 (OR per z-score increase in BPA=1.33, 95%CI: 1.01 to 1.75, p=0.043) and in pooled data (OR=1.42, CI: 1.17 to 1.72, p=0.001). Associations with diabetes did not reach significance in 2005/06, but pooled estimates remained significant (OR=1.24, CI: 1.10 to 1.40, p=0.001). There was no overall association with gamma glutamyl transferase concentrations, but pooled associations with alkaline phosphatase and lactate dehydrogenase remained significant. Conclusions: Higher BPA exposure, reflected in higher urinary concentrations of BPA, is consistently associated with reported heart disease in the general adult population of the USA. Studies to clarify the mechanisms of these associations are urgently needed.
Mendiola J, Jorgensen N, Andersson AM, Calafat AM, Silva MJ, Redmon JB, Sparks A, Drobnis EZ, Wang C, Liu F, Swan SH. Associations between urinary metabolites of di(2-ethylhexyl) phthalate and reproductive hormones in fertile men. Int J Androl. 2010 Jul;.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers enrolled 425 men who were partners of pregnant women who participated in the Study for Future Families in five US cities and provided urine and serum samples. Eleven phthalate metabolites were measured in urine and serum samples were analysed for reproductive hormones, including follicle-stimulating hormone, luteinizing hormone, testosterone, inhibin B and oestradiol and sex hormone-binding globulin (SHBG). Men with higher urinary concentration of several diethylhexyl phthalate (DEHP) metabolites had a lower free androgen index (an estimate of testosterone unbound to transport proteins and therefore biologically active). Men with higher levels of the metabolite monoethylhexyl phthalate (MEHP), but not other DEHP metabolites, had increased SHBG levels. These results suggest that exposure to DEHP may be related with reduced free testosterone.
Scientific abstract:
Widely used man-made chemicals, including phthalates, can induce hormonal alterations through a variety of cellular and molecular mechanisms. A number of rodent and observational studies have consistently demonstrated the anti-androgenic effect of several phthalates. However, there are only limited data on the relationship between exposure to these chemicals and reproductive hormone levels in men. All men (n = 425) were partners of pregnant women who participated in the Study for Future Families in five US cities and provided urine and serum samples on the same day. Eleven phthalate metabolites were measured in urine and serum samples were analysed for reproductive hormones, including follicle-stimulating hormone, luteinizing hormone, testosterone, inhibin B and oestradiol and sex hormone-binding globulin (SHBG). Pearson correlations and parametric tests were used for unadjusted analyses, and multiple linear regression analysis was performed controlling for appropriate covariates. We observed weak or no associations with urinary phthalates other than di(2-ethylhexyl) phthalate (DEHP). All measures of testosterone [total, calculated free testosterone and the free androgen index (FAI)] were inversely correlated with the urinary concentrations of four DEHP metabolites. After adjustment by appropriate covariates, there was no longer an association between urinary DEHP metabolite concentrations and total testosterone levels; however, FAI was significantly associated with the urinary concentrations of several DEHP metabolites. SHBG was positively related to the urinary concentrations of mono(2-ethylhexyl) phthalate, but not with other DEHP metabolites, an association that was attenuated after adjustment. Our results suggest that DEHP exposure of fertile men is associated with minor alterations of markers of free testosterone.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. In experimental animals, BPA caused oocyte aneuploidy, an error in cell division resulting in an abnormal number of chromosomes in eggs. In this study, researchers measured the level of BPA in 84 women undergoing in vitro fertilization at the Massachusetts General Hospital Fertility Center. They found that a lower number of eggs could be retrieved from women with higher BPA levels in their urine. These results suggest that BPA may be related with egg production in women with fertility issues.
Scientific abstract:
Bisphenol A (BPA) is a synthetic chemical used in the manufacture of materials present in many common consumer products. In experimental animals, BPA caused oocyte aneuploidy and reduced production of oestradiol. In a prospective cohort study, we investigated the association between urinary BPA concentrations and ovarian response among women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital (MGH) Fertility Center. The geometric mean of two specific-gravity (SG) adjusted urinary BPA concentrations collected during each IVF cycle was used as the cycle-specific BPA exposure level. BPA concentrations were measured using online solid phase extraction coupled to isotope dilution-high-performance liquid chromatography-tandem mass spectrometry. Peak serum oestradiol was measured using the Elecsys Estradiol II immunoassay kit. Multivariable mixed effect models and Poisson regression models adjusting for correlation between multiple IVF cycles in the same woman were used to evaluate the association between urinary BPA concentrations and ovarian response, adjusting for age, BMI and day 3 follicle stimulating hormone (FSH) levels, a clinical measure of ovarian reserve. Urinary BPA concentrations were measured in 84 women (mean age 35.6 years) undergoing 112 IVF cycles; 23 women (27%) contributed more than one IVF cycle. BPA concentrations ranged from <0.4 to 25.5 microg/L (geometric mean 2.52 +/- SD 3.2); 15% of urine samples had concentrations <0.4 microg/L. Peak serum oestradiol levels correlated with the total number of oocytes retrieved per cycle (r = 0.65, p < 0.001). For each log unit increase in SG-BPA, there was an average decrease of 12% (95% CI: 4, 23%; p = 0.007) in the number of oocytes retrieved and an average decrease of 213 pg/ml (95% CI: -407, -20; p = 0.03) in peak oestradiol. BPA was detected in the urine of the majority of women undergoing IVF, and was inversely associated with number of oocytes retrieved and peak oestradiol levels.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. In this study, researchers exposed pregnant sheep to BPA at levels that were equivalent to twice the highest levels observed in humans. They found that exposure was related with decreased birth weight. Furthermore the surge in the levels of luteinizing hormone (LH), which triggers ovulation, was dampened by exposure to BPA, suggesting that the chemical may affect reproductive function. Results suggest that high doses of BPA cause lower birth weight and affect LH levels in sheep.
Scientific abstract:
The inappropriate programming of developing organ systems by exposure to excess native or environmental steroids, particularly the contamination of our environment and our food sources with synthetic endocrine disrupting chemicals that can interact with steroid receptors, is a major concern. Studies with native steroids have found that in utero exposure of sheep to excess testosterone, an oestrogen precursor, results in low birth weight offspring and leads to an array of adult reproductive/metabolic deficits manifested as cycle defects, functional hyperandrogenism, neuroendocrine/ovarian defects, insulin resistance and hypertension. Furthermore, the severity of reproductive dysfunction is amplified by excess postnatal weight gain. The constellation of adult reproductive and metabolic dysfunction in prenatal testosterone-treated sheep is similar to features seen in women with polycystic ovary syndrome. Prenatal dihydrotestosterone treatment failed to result in similar phenotype suggesting that many effects of prenatal testosterone excess are likely facilitated via aromatization to oestradiol. Similarly, exposure to environmental steroid imposters such as bisphenol A (BPA) and methoxychlor (MXC) from days 30 to 90 of gestation had long-term but differential effects. Exposure of sheep to BPA, which resulted in maternal levels of 30-50 ng/mL BPA, culminated in low birth weight offspring. These female offspring were hypergonadotropic during early postnatal life and characterized by severely dampened preovulatory LH surges. Prenatal MXC-treated females had normal birth weight and manifested delayed but normal amplitude LH surges. Importantly, the effects of BPA were evident at levels, which approximated twice the highest levels found in human maternal circulation of industrialized nations. These findings provide evidence in support of developmental origin of adult reproductive and metabolic diseases and highlight the risk posed by exposure to environmental endocrine disrupting chemicals.
Study Synopsis: Triclosan is commonly used as an antibacterial and antifungal in a range of household products including soap, mouthwash, toothpaste, deodorants and hand sanitizers. Some studies suggest that triclosan may interfere with hormones. In this study, researchers exposed rats daily to triclosan by oral gavage through pregnancy and lactation. They found that triclosan caused up to a 30% reduction in the thyroid hormone thyroxine (T4) in the pregnant rats and in offspring 4 days after birth. The effect in offspring was however not observed 2 and 3 weeks after birth. These results suggest that exposure to triclosan may reduce T4 in pregnant rats and their newborns. The effect in offspring appeared to be transitory.
Scientific abstract:
Disruption of maternal thyroid hormones during fetal development may result in irreversible neurological consequences in offspring. The present study tested the hypothesis that perinatal triclosan exposure of dams decreases thyroxine in dams and offspring prior to weaning. Pregnant Long-Evans rats received triclosan by oral gavage (0-300 mg/kg/d) in corn oil from gestational day (GD)6 through postnatal day (PND)21. Serum was obtained from pups on PND4, 14, and 21, and from dams on PND22. Serum thyroxine (T4) was reduced 31% in dams on PND22. In pups, a unique pattern of hypothyroxinemia was observed; serum T4 decreased 27% in PND4 pups with no significant reduction observed on PND14 or PND21. Comparable reductions of approximately 30% in serum T4 at 300 mg/kg/d for dams and PND4 neonates and a lack of effect at PND14 and PND21 suggest that toxicokinetic or toxicodynamic factors may have contributed to a reduced exposure or a reduced toxicological response during the lactation period.
Study Synopsis: Triclosan is commonly used as an antibacterial and antifungal in a range of household products including soap, mouthwash, toothpaste, deodorants and hand sanitizers. Some studies suggest that triclosan may interfere with hormones. In this study, researchers exposed rats daily to triclosan by oral gavage through pregnancy and lactation. They found that triclosan caused up to a 30% reduction in the thyroid hormone thyroxine (T4) in the pregnant rats and in offspring 4 days after birth. The effect in offspring was however not observed 2 and 3 weeks after birth. These results suggest that exposure to triclosan may reduce T4 in pregnant rats and their newborns. The effect in offspring appeared to be transitory.
Scientific abstract:
Disruption of maternal thyroid hormones during fetal development may result in irreversible neurological consequences in offspring. The present study tested the hypothesis that perinatal triclosan exposure of dams decreases thyroxine in dams and offspring prior to weaning. Pregnant Long-Evans rats received triclosan by oral gavage (0-300 mg/kg/d) in corn oil from gestational day (GD)6 through postnatal day (PND)21. Serum was obtained from pups on PND4, 14, and 21, and from dams on PND22. Serum thyroxine (T4) was reduced 31% in dams on PND22. In pups, a unique pattern of hypothyroxinemia was observed; serum T4 decreased 27% in PND4 pups with no significant reduction observed on PND14 or PND21. Comparable reductions of approximately 30% in serum T4 at 300 mg/kg/d for dams and PND4 neonates and a lack of effect at PND14 and PND21 suggest that toxicokinetic or toxicodynamic factors may have contributed to a reduced exposure or a reduced toxicological response during the lactation period.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. Animal studies have demonstrate that BPA can mimic the female hormone estrogen. Pregnant rats were gavaged with ethinyl estradiol (an estrogen) or BPA and female offspring were studied. Researchers found that ethinyl estradiol increased anogenital distance, reduced pub body weight, accelerated puberty onset, reduced fertility and induced genital malformations. Offspring who were later also exposed to ethinyl estradiol also showed more male-like behaviors. BPA had no effect on these outcomes. Results suggest that exposure to BPA does not affect anogenital distance, birth weight, puberty onset, fertility, genital development and behavior in female offspring.
Scientific abstract:
Many chemicals released into the environment display estrogenic activity including the oral contraceptive ethinyl estradiol (EE2) and the plastic monomer bisphenol A (BPA). EE2 is present in some aquatic systems at concentrations sufficient to alter reproductive function of fishes. Many concerns have been raised about the potential effects of BPA. The National Toxicology Program rated the potential effects of low doses of BPA on behavior and central nervous system (CNS) as an area of "some concern," whereas most effects were rated as of "negligible" or "minimal" concern. However, the number of robust studies in this area was limited. The current study was designed to determine if maternal exposure to relatively low oral doses of EE2 or BPA in utero and during lactation would alter the expression of well-characterized sexually dimorphic behaviors or alter the age of puberty or reproductive function in the female Long-Evans rat offspring. Pregnant rats were gavaged with vehicle, EE2 (0.05-50 microg/kg/day), or BPA (2, 20, and 200 microg/kg/day) from day 7 of gestation to postnatal day (PND) 18, and the female offspring were studied. EE2 (50 microg/kg/day) increased anogenital distance and reduced pup body weight at PND2, accelerated the age at vaginal opening, reduced F1 fertility and F2 litter sizes, and induced malformations of the external genitalia (5 microg/kg). F1 females exposed to EE2 also displayed a reduced (male-like) saccharin preference (5 microg/kg) and absence of lordosis behavior (15 microg/kg), indications of defeminization of the CNS. BPA had no effect on any of the aforementioned measures. These results demonstrate that developmental exposure to pharmacologically relevant dosage levels of EE2 can permanently disrupt the reproductive morphology and function of the female rat.
Key Words: Animals, Dose-Response Relationship, Drug, Environmental Pollutants/*toxicity, Estrogens, Non-Steroidal/*toxicity, Ethinyl Estradiol/toxicity, Female, Fertility/*drug effects, Genitalia, Female/abnormalities/drug effects, Lactation, Male, *Maternal Exposure, Motor Activity/drug effects, Phenols/*toxicity, Pregnancy, Rats, Rats, Long-Evans, Sex Characteristics, Sexual Behavior, Animal/*drug effects, Sexual Maturation, Toxicity Tests
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. The objective of the present study was to determine whether prenatal and early postnatal exposure to BPA may cause endometriosis. Endometriosis is a chronic gynecological disease characterized by the growth of tissue normally lining the inside of the uterus (the endometrium) outside the uterine cavity. Researchers exposed pregnant mice to different doses of BPA from conception to 7 days after birth. Pups were examined at 3 months of age. Endometriosis-like tissue were found in the female offspring exposed to BPA. In addition, ovarian cysts (fluid-filled sacs) and abnormal endometrial cells were more frequent in BPA-exposed mice. Results of this study suggests that prenatal and early postnatal exposure to BPA may be related with endometriosis in mice.
Scientific abstract:
Endometriosis is a chronic gynecological disease characterized by the growth of endometrial tissue outside the uterine cavity. Exposure to endocrine disruptors during critical period of development causes long-lasting effects, being the genital system one of the targets. This study describes the effects on female genital system caused by developmental exposure to the endocrine-disrupting chemical bisphenol A (BPA) during pre- and peri-natal development in mice. To this end, timed pregnant Balb-C mice were treated from day 1 of gestation to 7 days after delivery with BPA (100, or 1000 microg/kg/day). After delivery, pups were held for 3 months; then, pelvic organs were analyzed in their entirety and livers of both pups and moms were studied for the presence of BPA. We found in the adipose tissue surrounding the genital tracts of a consistent number of treated animals, endometriosis-like structure with the presence of both glands and stroma and expressing both estrogen receptor and HOXA-10. Moreover, cystic ovaries, adenomatous hyperplasia with cystic endometrial hyperplasia and atypical hyperplasia were significantly more frequent in treated animals respect to the controls. Finally, BPA was found in the livers of exposed moms and female offspring. In conclusion, we describe for the first time an endometriosis-like phenotype in mice, elicited by pre-natal exposition to BPA. This observation may induce to thoroughly reconsider the pathogenesis and treatment of endometriosis, considering the high incidence of endometriosis and the problems caused by associated infertility.
Study Synopsis: Triclosan is commonly used as an antibacterial and antifungal in a range of household products including soap, mouthwash, toothpaste, deodorants and hand sanitizers. Some studies suggest that triclosan may interfere with hormones. In this study, researchers exposed female rats daily to different doses of triclosan over 21 days. They found that high doses of triclosan caused earlier vaginal opening, an indicator of puberty onset. Blood levels of the thyroid hormone thyroxine (T4) were also suppressed. Results thus suggest that exposure to high doses of triclosan advances puberty onset and lowers T4 levels.
Scientific abstract:
Triclosan is an antimicrobial found in personal care and sanitizing products, such as soaps, toothpaste, and hair products. There have been recent concerns for the possible effects on human health, as triclosan has been detected in human breast milk, blood, and urine samples. In a previous study, we found that triclosan alters serum thyroid hormone and testosterone concentrations in male rats. In the current study, we evaluated the effects of triclosan in the female Wistar rat following exposure for 21 days in the Endocrine Disruptor Screening Program pubertal protocol and the weanling uterotrophic assay (3-day exposure). In the pubertal study, triclosan advanced the age of onset of vaginal opening and increased uterine weight at 150 mg/kg, indicative of an estrogenic effect. In the uterotrophic assay, rats received oral doses of triclosan (1.18, 2.35, 4.69, 9.37, 18.75, 37.5, 75, 150, and 300 mg/kg) alone, 3 microg/kg ethinyl estradiol (EE), or triclosan (same doses as above) plus 3 microg/kg EE. Uterine weight was increased in the EE group (positive control) as compared with the control but was not affected by triclosan alone. However, there was a significant dose-dependent increase in the group cotreated with EE and triclosan (>or= 4.69 mg/kg) as compared with EE alone, indicating a potentiation of the estrogen response on uterine weight. This result was well correlated with potentiated estrogen-induced changes in uterine histology. Serum thyroid hormone concentrations were also suppressed by triclosan in this study, similar to other studies in the male and female rat. In conclusion, triclosan affected estrogen-mediated responses in the pubertal and weanling female rat and also suppressed thyroid hormone in both studies. The lowest effective concentrations in the rodent model are approximately 10 (for estrogen) and 40 (for thyroid hormone) times higher than the highest concentrations reported in human plasma.
Study Synopsis: This paper reviews the evidence regarding the testicular dysgenesis syndrome (TDS), which posits that common male genital birth defects such as cryptorchidism (undescended testes) and hypospadias (abnormal location of the urethra) as well as testis cancer and poor semen quality have a common origin. Authors argue that environmental exposures play a major role in the TDS and that several persistent chemicals as well as the less persistent phthalates may be related to the TDS.
Scientific abstract:
Cryptorchidism and hypospadias are common genital birth defects that affect 2-9% and 0.2-1% of male newborns, respectively. The incidence of both defects shows large geographic variation, and in several countries increasing trends have been reported. The conditions share many risk factors, and they are also interlinked to the risk of testis cancer and poor semen quality. Testicular Dysgenesis Syndrome (TDS) may underlie many cases of all these male reproductive health problems. Genetic defects in androgen production or action can cause both cryptorchidism and hypospadias, but these are not common. A monogenic reason for cryptorchidism or hypospadias has been identified only in a small proportion of all cases. Environmental effects appear to play a major role in TDS. Exposure to several persistent chemicals has been found to be associated with the risk of cryptorchidism, and exposure to anti-androgenic phthalates has been shown to be associated with hormonal changes predisposing to male reproductive problems. Despite progress in identification of endocrine-disrupting substances, we are still far from knowing all the risk factors for these birth defects, and advice for prevention must be based on precautionary principles.
Study Synopsis: This paper reviews the evidence regarding the testicular dysgenesis syndrome (TDS), which posits that common male genital birth defects such as cryptorchidism (undescended testes) and hypospadias (abnormal location of the urethra) as well as testis cancer and poor semen quality have a common origin. Authors argue that environmental exposures play a major role in the TDS and that several persistent chemicals as well as the less persistent phthalates may be related to the TDS.
Scientific abstract:
Cryptorchidism and hypospadias are common genital birth defects that affect 2-9% and 0.2-1% of male newborns, respectively. The incidence of both defects shows large geographic variation, and in several countries increasing trends have been reported. The conditions share many risk factors, and they are also interlinked to the risk of testis cancer and poor semen quality. Testicular Dysgenesis Syndrome (TDS) may underlie many cases of all these male reproductive health problems. Genetic defects in androgen production or action can cause both cryptorchidism and hypospadias, but these are not common. A monogenic reason for cryptorchidism or hypospadias has been identified only in a small proportion of all cases. Environmental effects appear to play a major role in TDS. Exposure to several persistent chemicals has been found to be associated with the risk of cryptorchidism, and exposure to anti-androgenic phthalates has been shown to be associated with hormonal changes predisposing to male reproductive problems. Despite progress in identification of endocrine-disrupting substances, we are still far from knowing all the risk factors for these birth defects, and advice for prevention must be based on precautionary principles.
Trabert B, De Roos AJ, Schwartz SM, Peters U, Scholes D, Barr DB, Holt VL. Non-dioxin-like polychlorinated biphenyls and risk of endometriosis. Environ Health Perspect. 2010 Sep;118(9):1280-5.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. In this study, researchers measured PCBs in the blood of 251 endometriosis patients and 538 healthy controls living in Western Washington State. No significant differences in PCB blood levels were detected between cases and controls. Results do not support the hypothesis that exposure to PCBs is related with increased risk of endometriosis.
Scientific abstract:
BACKGROUND: Endometriosis, a gynecologic disorder affecting 8-10% of reproductive-age women in the United States, is defined as the presence of endometrial tissue outside the uterus and is linked to pelvic pain and infertility. Environmental contaminants, including polychlorinated biphenyls (PCBs), are hypothesized to contribute to endometriosis risk through effects on steroid hormones. OBJECTIVE: We evaluated serum concentrations of certain noncoplanar PCBs, which have no or only weak dioxin-like properties, as risk factors for endometriosis. METHODS: In a case-control study of Group Health enrollees in western Washington State, 20 PCB congeners were measured in serum from surgically confirmed endometriosis cases that were newly diagnosed between 1996 and 2001 (n = 251) and from female controls matched for age and reference year (n = 538). RESULTS: Summed and estrogenic PCB concentrations were not associated with endometriosis risk [summed: odds ratio (OR) = 1.3; 95% confidence interval (CI), 0.8-2.2; estrogenic: OR = 1.1; 95% CI, 0.8-1.4]. Although several congener-specific ORs were statistically above or below the null (PCB 170: third quartile vs. lowest: OR = 0.5; 95% CI, 0.3-0.9; PCB 196: third quartile vs. lowest: OR = 0.4; 95% CI, 0.2-0.7; PCB 201: second vs. lowest: OR = 0.5; 95% CI, 0.3-0.8; third quartile vs. lowest: OR = 0.4; 95% CI, 0.2-0.7), there were no overall consistent patterns of endometriosis risk. CONCLUSIONS: Taken in context with other North American studies, our findings suggest that noncoplanar PCB concentrations consistent within the range of exposure currently observed in western Washington State do not contribute meaningfully to endometriosis risk.
Weuve J, Hauser R, Calafat AM, Missmer SA, Wise LA. Association of exposure to phthalates with endometriosis and uterine leiomyomata: findings from NHANES, 1999-2004. Environ Health Perspect. 2010 Jun;118(6):825-32.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers used data from 1,227 women aged between 20 and 54 years participating in the National Health and Nutrition Examination Survey (NHANES), a study based on a nationally representative sample. Six phthalate metabolites were measured in participants' urine and information on history of endometriosis and uterine leiomyomata were collected based on questionnaires. Odds of being affected by one of these conditions were 70% higher in women with high urine levels of monobutyl phthalate (MBP) but were 2.4 times lower among women with high levels of monothylhexyl phthalate (MEHP). These results suggest that phthalates may have opposite relationships with endometriosis and uterine leiomyomata. However, it is important to note that phthalates metabolites were measured after the diagnoses. Prospective studies, which measure exposure and then follow individuals to determine their risk of disease, may be needed to evaluate the relationship between exposure to phthalates and endometriosis and uterine leiomyomata,
Scientific abstract:
BACKGROUND: Phthalates are ubiquitous chemicals used in consumer products. Some phthalates are reproductive toxicants in experimental animals, but human data are limited. OBJECTIVE: We conducted a cross-sectional study of urinary phthalate metabolite concentrations in relation to self-reported history of endometriosis and uterine leiomyomata among 1,227 women 20-54 years of age from three cycles of the National Health and Nutrition Examination Survey (NHANES), 1999-2004. METHODS: We examined four phthalate metabolites: mono(2-ethylhexyl) phthalate (MEHP), monobutyl phthalate (MBP), monoethyl phthalate (MEP), and monobenzyl phthalate (MBzP). From the last two NHANES cycles, we also examined mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP). We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: Eighty-seven (7%) and 151 (12%) women reported diagnoses of endometriosis and leiomyomata, respectively. The ORs comparing the highest versus lowest three quartiles of urinary MBP were 1.36 (95% CI, 0.77-2.41) for endometriosis, 1.56 (95% CI, 0.93-2.61) for leiomyomata, and 1.71 (95% CI, 1.07-2.75) for both conditions combined. The corresponding ORs for MEHP were 0.44 (95% CI, 0.19-1.02) for endometriosis, 0.63 (95% CI, 0.35-1.12) for leiomyomata, and 0.59 (95% CI, 0.37-0.95) for both conditions combined. Findings for MEHHP and MEOHP agreed with findings for MEHP with respect to endometriosis only. We observed null associations for MEP and MBzP. Associations were similar when we excluded women diagnosed > 7 years before their NHANES evaluation. CONCLUSION: The positive associations for MBP and inverse associations for MEHP in relation to endometriosis and leiomyomata warrant investigation in prospective studies.
Study Synopsis: This paper reviews the laboratory and human evidence regarding the endocrine disrupting effect of components of personal care products such as phthalates, parabens, ultraviolet filters, polycyclic musks, and antimicrobials. Authors report that studies found that these chemicals had adverse health effects in laboratory animals but that human evidence is lacking.
Scientific abstract:
This article reviews laboratory and epidemiological research into the endocrine disruptive effects of components of personal care products, namely, phthalate esters, parabens, ultraviolet (UV) filters, polycyclic musks, and antimicrobials. High doses of phthalates in utero can produce "phthalate syndrome", demasculinizing effects in male rat offspring due to impaired testosterone production by fetal testes. However, evidence linking phthalate exposure to similar effects in humans appears inconclusive. Furthermore, phthalate exposure derived from personal care products is within safe limits and its principal bioavailable phthalate, diethyl phthalate (DEP), does not produce "phthalate syndrome." Parabens exhibit very weak estrogen activity in vitro and in vivo, but evidence of paraben-induced developmental and reproductive toxicity in vivo lacks consistency and physiological coherence. Evidence attempting to link paraben exposure with human breast cancer is nonexistent. Select UV filters at high doses produce estrogenic, antithyroid, and other effects in rats in vivo. Again, no evidence links UV filter exposure to endocrine disruptive effects in humans. Some polycyclic musks weakly bind to estrogen, androgen, or progestin receptors and exhibit primarily antagonistic activity in vitro, which for the most part, has yet to be confirmed in vivo in mammals. The antimicrobials triclocarban and triclosan evoke weak responses mediated by aryl hydrocarbon, estrogen, and androgen receptors in vitro, which require confirmation in vivo. Preliminary observations suggest a novel interaction between triclocarban and testosterone. In conclusion, although select constituents exhibit interactions with the endocrine system in the laboratory, the evidence linking personal care products to endocrine disruptive effects in humans is for the most part lacking.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured the levels of several phthalate metabolites, phenols and phytoestrogens in urine samples collected from 1,151 girls aged 6 to 8 years and residing in New York City, New York, greater Cincinnati, Ohio, and northern California between 2004 and 2007. Higher urine levels of phthalate metabolites with low molecular weights were weakly associated with accelerated breast and pubic hair development. Elevated concentrations of phthalate metabolites with high molecular weight were weakly associated with delayed pubic hair development and daidzein was related with delayed breast development. Triclosan and phthalates with high molecular weights were related with slower pubic hair development. Results suggest that phthalates, daidzein and triclosan may be related with small alterations in puberty onset.
Scientific abstract:
BACKGROUND: Hormonally active environmental agents may alter the course of pubertal development in girls, which is controlled by steroids and gonadotropins. OBJECTIVES: We investigated associations of concurrent exposures from three chemical classes (phenols, phthalates, and phytoestrogens) with pubertal stages in a multiethnic longitudinal study of 1,151 girls from New York City, New York, greater Cincinnati, Ohio, and northern California who were 6-8 years of age at enrollment (2004-2007). METHODS: We measured urinary exposure biomarkers at visit 1 and examined associations with breast and pubic hair development (present or absent, assessed 1 year later) using multivariate adjusted prevalence ratios (PR) and 95% confidence intervals (CIs). Modification of biomarker associations by age-specific body mass index percentile (BMI%) was investigated, because adipose tissue is a source of peripubertal hormones. RESULTS: Breast development was present in 30% of girls, and 22% had pubic hair. High-molecular-weight phthalate (high MWP) metabolites were weakly associated with pubic hair development [adjusted PR, 0.94 (95% CI, 0.88-1.00), fifth vs. first quintile]. Small inverse associations were seen for daidzein with breast stage and for triclosan and high MWP with pubic hair stage; a positive trend was observed for low-molecular-weight phthalate biomarkers with breast and pubic hair development. Enterolactone attenuated BMI associations with breast development. In the first enterolactone quintile, for the association of high BMI with any development, the PR was 1.34 (95% CI, 1.23-1.45 vs. low BMI). There was no BMI association in the fifth, highest quintile of enterolactone. CONCLUSIONS: Weak hormonally active xenobiotic agents investigated in this study had small associations with pubertal development, mainly among those agents detected at highest concentrations.
Key Words: Body Mass Index, California, Child, Chromatography, High Pressure Liquid, *Environmental Exposure, Female, Humans, Longitudinal Studies, New York City, Ohio, Phenols/*urine, Phthalic Acids/*urine, Phytoestrogens/*urine, Puberty/*drug effects/physiology, Tandem Mass Spectrometry
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers measured the concentration of PBDEs in the cord blood of 102 Chinese women living in an area where an electronic waste recycling plant was located and in 51 women living in a control area. Contrary to most previous studies, BDE-209 (primarily used in electronic products) was the predominant congener. Median levels of PBDEs were higher in women with any adverse pregnancy outcome, including stillbirth, low birth weight, and premature birth, relative to women who delivered term babies with normal birth weights. These results suggest that exposure to PBDEs may be related to adverse pregnancy outcomes. It is however important to note that individuals who live in industrial areas generally have a lower socioeconomic status, which is in turn related with increased risk of adverse pregnancy outcomes. Studies considering socioeconomic status in the analysis are thus needed to confirm this study's findings.
Scientific abstract:
We aimed to evaluate the exposure of neonates to polybrominated diphenyl ethers (PBDEs) from a primitive e-waste (obsolete electrical and electronic devices) recycling area, in Guiyu, China, and a control area, Chaonan, China, through umbilical cord blood (UCB), the health effects, and relevant factors. Questionnaires were addressed, and UCB was collected shortly after birth from 153 pregnant women between May and July 2007. Blood samples were prepared by liquid-liquid extracting methods. PBDE concentration was determined by gas chromatography/mass spectrometry in the electron capture negative ionization mode. The total PBDE concentration was higher in UCB samples from Guiyu than in Chaonan samples (median 13.84, range 1.14-504.97 ng g(-1) lipid, vs 5.23, range 0.29-363.70 ng g(-1) lipid) (p < 0.05). BDE-209 was the dominant PBDE congener, followed by BDE-47, -153, and -99. Residence in Guiyu, which is a site for e-waste recycling, involvement in e-waste recycling, and the residence also being used as a family workshop were significant factors contributing to PBDE exposure. PBDE levels significantly differed in neonates by normal birth and adverse birth outcomes including stillbirth, low birth weight, and premature delivery (p < 0.05). The neonates from Guiyu are exposed to high levels of PBDEs. Prenatal exposure to PBDEs may affect neonates' health in Guiyu, which still needs to be evaluated in larger epidemiological studies.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. The purpose of this study was to evaluate the conditions that influence the contamination of cooking oil and mineral water by phthalates contained in plastic containers. It was found that higher temperatures, longer contact time and dynamic storage states were related with higher contamination. Higher concentrations of phthalates were also found in cooking oil than in mineral water, suggesting that more fatty foods may be more likely contaminated.
Scientific abstract:
The migration of phthalates (PAEs), a class of typical environmental estrogen contaminants in food, from food packaging to packaged food attracts more and more attention worldwide. Many factors will affect the migration processes. The purpose of this study was to evaluate PAE migration from plastic containers to cooking oil and mineral water packed in authentic commercial packaging and stored under various conditions (different storage temperatures, contact times, and storage states (static or dynamic state)) and to identify a potential relationship between the amount and type of PAEs migrated and the lipophilic character of the food matrix. The samples were analyzed by a novel method of liquid chromatography combined with solid-phase extraction by an electrospun nylon 6 nanofibers mat, with PAE detection limits of 0.001 mug/L in mineral water and 0.020 mug/L in cooking oil, respectively. The results demonstrated that the cooking oil was a more suitable medium for the migration of PAEs from packages into foodstuffs than mineral water. Scilicet, the migration potential of the PAEs into foodstuffs, depends on the lipophilic characteristics of the food matrix. The results also demonstrated that migrations were more significant at higher temperature, longer contact time, and higher dynamic frequency; thus, the migration tests should be evaluated with consideration of different storage temperatures and contact times. Mathematical models with good logarithmic relationships were established to demonstrate the relationship between the PAE migration and food/packaging contact time for different storage temperatures. These established mathematical models would be expected to become a set of practical tools for the prediction of PAE migration.
Study Synopsis: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (also called TCDD and, most commonly, dioxin) is the most toxic chemical known to Science. Pre- and postnatal exposure to TCDD causes developmental and reproductive defects that may be mediated by interference with hormones. In this study, male fetuses prenatally exposed to TCDD had reduced testosterone levels in their testicles as well as decreased blood luteinizing hormone (LH) concentration. Exposure to TCDD also tended to reduce the expression of the estrogen and androgen receptors. Estrogen and testosterone must bind to these receptors to exert their effects. These results suggest that exposure to TCDD affects the levels, and possibly the action, of hormones important for sexual development during the fetal period.
Scientific abstract:
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic and widely investigated dioxin congener. In utero and lactational exposure to TCDD results in developmental and reproductive defects that are the most sensitive endpoints for TCDD toxicity. TCDD has a potential to interfere with steroid metabolism, but the mechanisms by which this occurs are not well understood. In this study, we investigated the effects of TCDD on prenatal rat steroidogenesis. Pregnant Sprague2013Dawley female rats were treated once with TCDD (0, 0.3 or 1 03BCg/kg) by gavage on embryonic day (ED) 11 and the expression levels of androgen (AR) and estrogen receptors (ER), steroidogenic enzymes (P450scc and 303B2-HSD) and four regulatory factors (StAR, SF-1, GATA-4 and Insl-3) involved in foetal Leydig cell and adrenal function were analysed on ED 19.5. Hormonal status of male foetuses was determined by measuring testicular testosterone (T) levels, plasma luteinizing hormone (LH) and corticosterone concentrations. In utero exposure to TCDD reduced intratesticular T of foetal males (significant at 0.3 03BCg/kg TCDD) and tended to reduce the protein expression of ER03B1 and AR of foetal male rat testis. Foetal male rat plasma LH levels were significantly reduced at the dose of 1 03BCg/kg TCDD, while corticosterone levels tended to be increased possibly because of the TCDD-induced stress. Only minor alterations in steroidogenesis were observed in rat adrenal. mRNA expression of developmental regulatory factors was not influenced by foetal TCDD exposure, except for significantly reduced adrenal SF-1. The results demonstrate that maternal exposure to TCDD suppressed testicular steroidogenesis of 19.5-day-old foetal male Sprague2013Dawley rat. The highest dose of TCDD (1 03BCg/kg) had also an effect on pituitary LH secretion. Our data implicate that TCDD has direct testicular and pituitary effects on foetal male rat but with different dose2013responses. These changes can lead to impaired steroidogenesis and it may result in the maldevelopment of the testis and weaken masculinization.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. It is also used in carbonless copy paper. BPA has been shown to have the capability to mimic the hormone estrogen. This study showed that young rats exposed to BPA reached puberty earlier and were more likely to have abnormal menstrual cycles.
Scientific abstract:
Developmental exposure to endocrine-disrupting compounds is hypothesized to adversely affect female reproductive physiology by interfering with the organization of the hypothalamic-pituitary-gonadal axis. Here, we compared the effects of neonatal exposure to two environmentally relevant doses of the plastics component bisphenol-A (BPA; 50 Ī¼g/kg and 50 mg/kg) with the ESR1 (formerly known as ERalpha)-selective agonist 4,4,4-(4-propyl-[H]pyrazole-1,3,5-triyl)trisphenol (PPT; 1 mg/kg) on the development of the female rat hypothalamus and ovary. An oil vehicle and estradiol benzoate (EB; 25 Ī¼g) were used as negative and positive controls. Exposure to EB, PPT, or the low dose of BPA advanced pubertal onset. A total of 67% of females exposed to the high BPA dose were acyclic by 15 wk after vaginal opening compared with 14% of those exposed to the low BPA dose, all of the EB- and PPT-treated females, and none of the control animals. Ovaries from the EB-treated females were undersized and showed no evidence of folliculogenesis, whereas ovaries from the PPT-treated females were characterized by large antral-like follicles, which did not appear to support ovulation. Severity of deficits within the BPA-treated groups increased with dose and included large antral-like follicles and lower numbers of corpora lutea. Sexual receptivity, examined after ovariectomy and hormone replacement, was normal in all groups except those neonatally exposed to EB. FOS induction in hypothalamic gonadotropic (GnRH) neurons after hormone priming was impaired in the EB- and PPT-treated groups but neither of the BPA-treated groups. Our data suggest that BPA disrupts ovarian development but not the ability of GnRH neurons to respond to steroid-positive feedback.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to Phthalates is common due to their widespread use. In this study, researchers followed 283 women in 4 U.S. states throughout pregnancy and measured the level of a type of phthalate called diethylhexyl phthalate (DEHP) in their urine. They found that gestation duration was increased by an average of 2 days in women who had high levels of DEHP in their urine. Increased probabilities of cesarean sections and long gestation length (41 weeks or more) as well as reduced risks of preterm deliveries were also observed in women with higher urine DEHP.
Scientific abstract:
Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in consumer and medical products that can cross the placenta, disrupt steroid hormone synthesis, and activate peroxisome proliferator-activated receptor {gamma}. The authors examined DEHP exposure in relation to the timing of labor in a pregnancy cohort study of 283 women recruited in 4 US states (California, Iowa, Minnesota, and Missouri) between 2000 and 2004. The authors estimated associations between concentrations of DEHP metabolites and gestational age at delivery using linear regression models and associations between DEHP metabolites and clinical outcomes using logistic regression models. After covariate adjustment, women at the 75th percentile of DEHP metabolite concentrations had a 2-day-longer mean length of gestation than women at the 25th percentile (95% confidence interval: 1.4, 3.3). Log-unit increases in mono-2-ethylhexyl phthalate and mono-2-ethyl-5-oxohexyl phthalate concentrations were associated with increased odds of cesarean section delivery (30% and 50% increased odds, respectively), increased odds of delivering at 41 weeks or later (100% and 120% increased odds), and reduced odds of preterm delivery (50% and 60% decreased odds). These data suggest that DEHP may interfere with signaling related to the timing of parturition.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to Phthalates is common due to their widespread use. As part of this study, researchers exposed pregnant rats by gavage to two types of phthalates (DEHP and DBP) alone and in combination. They found that exposure to a high dose of DBP (500 mg/kg per day) or to a mixture of DEHP (150 mg/kg per day) and DBP (100 mg/kg per day) caused a decrease in the concentration of the male hormone testosterone in fetal testes. Abnormalities at the cellular level were also observed in the testes of rats whose mother was administered the mixture of DEHP and DBP. No hormone or cell abnormalities were observed in rats exposed to DEHP or DBP alone. In addition, exposure to phthalates did not affect other markers of hormone disruption, reproductive organ weights or the number of sperm per testis. Overall, these results suggest that maternal exposure to high doses of phthalates may affect the development of reproductive organs in male rats. Results also suggest that different phthalates may act in combination.
Scientific abstract:
The reproductive effects of the coadministration of di-2-(ethylhexyl) phthalate (DEHP) and di-butyl phthalate (DBP) were studied in both foetal and adult male rat offspring exposed in utero. Pregnant Wistar rats were treated by oral gavage from gestation day 13 to 21 with vehicle control, 150 mg DEHP/kg body weight (bw)/day, 100 mg DBP/kg bw/ or a combination of the two compounds (DEHP 150 + DBP 100 mg/kg bw/day). An additional group of dams received 500 mg DBP/kg bw/day. A significant decrease in foetal testicular testosterone levels was observed in animals exposed to 500 mg DBP/kg/day or the phthalate mixture. Similarly, histological analysis of the foetal testis revealed that the coadministration of DEHP and DBP was able to increase the diameter of seminiferous cords and induce gonocyte multinucleation at doses that individually had no significant effects on these variables. However, in the phthalate mixture group, no significant changes were observed in anogenital distance and nipple retention, variables that are used to indicate possible anti-androgenic effects. Also, the adult endpoints investigated, that included reproductive organ weights and the number of spermatids per testis, were unaffected by any treatment regimen. Overall, coadministration of DEHP and DBP in utero significantly reduced testicular testosterone levels and resulted in misshapen seminiferous cords and gonocyte multinucleation in rat foetal testis. Our results also confirm that these foetal endpoints seem to be the most sensitive markers of prenatal phthalate exposure.
Study Synopsis: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (also called TCDD and, most commonly, dioxin) is a highly toxic chemicals that persist in the environment, accumulate in human fatty tissue and concentrate up the food chain. Prenatal exposure to TCDD has been associated with a range of adverse health effects, including effects on the male reproductive tract. In this study, researchers injected rhesus monkeys with TCDD during pregnancy and lactation. They found that male offspring whose mother was exposed to a high dose of TCDD (300 ng/kg) had lower sperm concentration, and that sperm viability and activity were reduced in a dose-related fashion. Abnormalities at the tissue level were also observed in the testes of offspring whose mother was exposed to TCDD. These results show that prenatal or lactational exposure to TCDD affects testis development and sperm quality in rhesus monkeys.
Scientific abstract:
A long-term developmental toxicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure was performed in rhesus monkeys and the effect on male reproductive organs was determined in the second generation. Dams received 0, 30 or 300 ng/kg TCDD subcutaneously on Day 20 of gestation, and then 5% of the initial dose was injected every 30 days until Day 90 after delivery. The offspring were maintained until reaching sexual maturity, and evaluated by semen analysis, and histopathology of the testes and epididymides. Ejaculated sperm concentration was severely reduced at 300 ng/kg, and sperm viability and activity were dose-proportionally reduced, although effects on spermatogenesis were slight. Histomorphometry revealed markedly reduced area of the ductus epididymis accompanying decreased reserved sperm in the 30 and 300 ng/kg groups. In conclusion, in utero and lactational exposure to TCDD induced a reduction of sperm quality in rhesus monkeys.
Study Synopsis: Tetrachloroethylene (TCE) is a solvent commonly used for dry cleaning fabrics and degrease metal parts in the automotive and metalworking industries. Most of the TCE evaporates into the air but a small proportion may contaminate drinking water. The health effects of chronic low-level exposure to TCE is not well understood. In this study, researchers estimated exposure to TCE through drinking water in the Cape Cod region of Massachusetts using mathematical models. A total of 959 exposed and 1,087 unexposed women completed a questionnaire regarding residential and pregnancy histories. No associations were found between exposure to TCE and the risk of pregnancy loss. These results thus do not support a relationship between exposure to TCE and an increased risk of pregnancy loss.
Scientific abstract:
There is little information on the impact of solvent-contaminated drinking water on pregnancy outcomes. This retrospective cohort study examined whether maternal exposure to tetrachloroethylene (PCE) - contaminated drinking water in the Cape Cod region of Massachusetts influenced the risk of clinically recognized pregnancy loss. The study identified exposed (n=959) and unexposed (1,087) women who completed a questionnaire on their residential and pregnancy histories, and confounding variables. Exposure was estimated using water distribution system modeling software. No meaningful associations were seen between PCE exposure level and the risk of clinically recognized pregnancy loss at the exposure levels experienced by the study population. Because PCE remains a common water contaminant, it is important to continue monitoring its impact on women and their pregnancies.
BACKGROUND: Prior animal and human studies of prenatal exposure to solvents including tetrachloroethylene (PCE) have shown increases in the risk of certain congenital anomalies among exposed offspring. OBJECTIVES: This retrospective cohort study examined whether PCE contamination of public drinking water supplies in Massachusetts influenced the occurrence of congenital anomalies among children whose mothers were exposed around the time of conception. METHODS: The study included 1,658 children whose mothers were exposed to PCE-contaminated drinking water and a comparable group of 2,999 children of unexposed mothers. Mothers completed a self-administered questionnaire to gather information on all of their prior births, including the presence of anomalies, residential histories and confounding variables. PCE exposure was estimated using EPANET water distribution system modeling software that incorporated a fate and transport model. RESULTS: Children whose mothers had high exposure levels around the time of conception had an increased risk of congenital anomalies. The adjusted odds ratio of all anomalies combined among children with prenatal exposure in the uppermost quartile was 1.5 (95% CI: 0.9, 2.5). No meaningful increases in the risk were seen for lower exposure levels. Increases were also observed in the risk of neural tube defects (OR: 3.5, 95% CI: 0.8, 14.0) and oral clefts (OR 3.2, 95% CI: 0.7, 15.0) among offspring with any prenatal exposure. CONCLUSION: The results of this study suggest that the risk of certain congenital anomalies is increased among the offspring of women who were exposed to PCE-contaminated drinking water around the time of conception. Because these results are limited by the small number of children with congenital anomalies that were based on maternal reports, a follow-up investigation should be conducted with a larger number of affected children who are identified by independent records.
Humans are exposed daily to a great number of xenobiotics and their metabolites present as pollutants. Bisphenol-A (BPA) is extensively used in a broad range of products including baby bottles, food-storage containers, medical equipment, and consumer electronics. Thus, BPA is the most common monomer for polycarbonates intended for food contact. Levels of this industrial product are found in maternal blood, amniotic fluid, follicular fluid, placental tissue, umbilical cord blood, and maternal urine. In this study, we investigated toxic effects of BPA concentrations close to levels found in serum of pregnant women on human cytotrophoblasts (CTB). These cells were isolated from fresh placentas and exposed to BPA for 24 h. Our results showed that very low doses of BPA induce apoptosis (2 to 3 times) as assessed using M30 antibody immunofluorescent detection, and necrosis (1.3 to 1.7 times) as assessed through the cytosolic Adenylate Kinase (AK) activity after cell membrane damage. We also showed that BPA increased significantly the tumor-necrosis factor alpha (TNF-alpha) gene expression and protein excretion as measured by real-time RT-PCR and ELISA luminescent test, respectively. Moreover, we observed that induction of AK activation and TNF-alpha gene expression require lower levels of BPA than apoptosis or TNF-alpha protein excretion. Our findings suggest that exposure of placental cells to low doses of BPA may cause detrimental effects, leading in vivo to adverse pregnancy outcomes such as preeclampsia, intrauterine growth restriction, prematurity and pregnancy loss.
Study Synopsis: Vinclozolin and iprodione are fungicides that have been shown to counteract the effects of androgens, which are hormones that control the development and maintenance of male characteristics. The most well known androgen is testosterone. To exert their effects, androgens must bind to a receptor called the androgen receptor (AR). This study showed that iprodione binds to the AR, prevents androgens from exerting their effect and reduces the weight of tissues that are sensitive to the effects of androgens in male rats. Postnatal exposure to vinclozolin on the other hand delayed puberty (as indicated by the age at preputial separation), reduced the weight of organs sensitive to androgens and increased blood testosterone. Most importantly, this study demonstrated that exposure to both vinclozolin and iprodione delayed puberty to a greater extent than exposure to vinclozolin alone. Iprodione however inhibited the increase in blood testosterone caused by vinclozolin. Taken together, these results suggest that, in rats, the fungicides vinclozolin and iprodione interact by increasing or inhibiting their effects depending on the toxicological outcome.
Scientific abstract:
Vinclozolin and iprodione are dicarboximide fungicides that display antiandrogenic effects in the male rat, which suggests that a mixture would lead to cumulative effects on androgen-sensitive end points. Iprodione is a steroid synthesis inhibitor, but androgen receptor antagonist activity, which is displayed by vinclozolin, has not been fully evaluated. Here, we demonstrate that iprodione binds to the human androgen receptor (IC50 = 86.0{micro}M), reduces androgen-dependent gene expression, and reduces androgen-sensitive tissue weights in castrated male rats (Hershberger assay). Since vinclozolin and iprodione affect common targets in the pubertal male rat, we tested the hypothesis that a mixture would have cumulative antiandrogenic effects. An iprodione dose, that does not significantly affect androgen-dependent morphological end points, was combined with vinclozolin doses (2 x 5 factorial design). Sprague-Dawley rats were dosed by gavage with vinclozolin at 0, 10, 30, 60, and 100 mg/kg/day with and without 50 mg iprodione/kg/day from postnatal day (PND) 23 to 55-57 (n = 8 per group). The age at puberty (preputial separation [PPS]), organ weights, serum hormones, and ex vivo testis steroid hormone production were measured. Vinclozolin delayed PPS, reduced androgen-sensitive organ weights, and increased serum testosterone. The addition of iprodione enhanced the vinclozolin inhibition of PPS (PND 47.5 vs.49.1; two-way ANOVA: iprodione main effect p = 0.0002). The dose response for several reproductive and nonreproductive organ weights was affected in a cumulative manner. In contrast, iprodione antagonized the vinclozolin-induced increase in serum testosterone. These results demonstrate that these fungicides interact on common targets in a tissue-specific manner when coadministered to the pubertal male rat.
Botelho GG, Golin M, Bufalo AC, Morais RN, Dalsenter PR, Martino-Andrade AJ. Reproductive effects of di(2-ethylhexyl)phthalate in immature male rats and its relation to cholesterol, testosterone, and thyroxin levels. Arch Environ Contam Toxicol. 2009 Nov;57(4):777-84.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to Phthalates is common due to their widespread use. In this study, researchers exposed rats daily to different doses of diethylhexyl phthalate (DEHP) for a period of 30 days. They found that exposure to DEHP caused a reduction in the weight of organs usually affected by testosterone, such as the seminal vesicle and prostate. They also found indications of delayed puberty (based on preputial separation) and reduced testosterone blood levels at the highest dose. Although cholesterol blood levels appeared to be affected by DEHP, no effect on the thyroid hormone thyroxine (T4) was observed. These results suggest that DEHP may affect the male reproductive system and puberty onset.
Scientific abstract:
Phthalates are chemicals employed in several industrial products and there is a growing body of evidence demonstrating that they induce numerous adverse effects on the reproductive system. This study was carried out to assess possible alterations induced by the plasticizer di(2-ethylhexyl phthalate (DEHP) on cholesterol, testosterone, and thyroxine (total T4) levels, as well as to discuss the significance of these data in global changes observed in the reproductive tract of pubertal animals. Wistar rats aged 21 days received DEHP orally at 0, 250, 500, and 750 mg/kg/day for 30 days and were examined for different reproductive endpoints. At the end of the treatment, significant decreases in relative weight of testosterone-dependent organs, delayed preputial separation, and low serum testosterone were observed at the highest DEHP dose. The plot of the relationship between DEHP dose and serum cholesterol revealed a biphasic effect. The concentration of cholesterol in serum was significantly reduced at 250 mg/kg/day DEHP but returned to control values at 750 mg/kg/day. Cholesterol levels measured in testicular tissue increased with DEHP treatment. Serum T4 levels were not affected by DEHP at any dose, indicating the absence of a link between total thyroxin concentration and phthalate effects on cholesterol levels. Taken together these results indicate that effects observed in serum and testicular cholesterol levels may reflect distinct effects of DEHP on cholesterol synthesis and usage. These results confirm and extend previously reported findings showing that alterations in cholesterol balance may play a role in the suppression of steroidogenesis induced by DEHP in rats.
Key Words: Animals, Body Weight/drug effects, Cholesterol/ blood/ metabolism, Diethylhexyl Phthalate/ toxicity, Dose-Response Relationship, Drug, Environmental Pollutants/ toxicity, Male, Organ Size/drug effects, Rats, Rats, Wistar, Reproduction/ drug effects, Sexual Maturation/drug effects, Testis/drug effects/metabolism, Testosterone/ blood/metabolism, Thyroxine/ blood
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. PCBs persist in the environment, accumulate in human fatty tissue and are detected in the blood of virtually all human populations. In this study researchers followed 83 women who were planning to become pregnant and measured PCBs in their blood before conception. They found that women with higher blood concentration of PCBs reported to mimic the effects of the hormone estrogen or to inhibit the effects of this hormone were less likely to become pregnant than women with lower blood concentration of these PCBs. These results suggest that PCBs may affect human fertility.
Scientific abstract:
BACKGROUND: Consumption of fish contaminated with polychlorinated biphenyls (PCBs) and prenatal PCB serum concentrations have been associated with a longer time-to-pregnancy (TTP). However, the relationship between preconception serum PCBs concentrations and TTP has not been previously studied. METHODS: Eighty-three women (contributing 442 menstrual cycles) planning pregnancies completed daily diaries regarding menstruation, intercourse, home pregnancy test results, and reported use of alcohol and cigarettes. TTP denoted the number of observed menstrual cycles required for pregnancy. Preconception blood specimens underwent toxicologic analysis for 76 PCB congeners via gas chromatography with electron capture; serum lipids were quantified with enzymatic methods. A priori, PCB congeners were summed into a total and three groupings--estrogenic, anti-estrogenic and other--and entered into discrete analogs of Cox models with time-varying covariates to estimate fecundability odds ratios (FOR) and corresponding 95% confidence intervals (CIs). RESULTS: Estrogenic and anti-estrogenic PCB concentrations (ng/g serum) conferred reduced FORs in fully adjusted models (0.32; 95% CI 0.03, 3.90 and 0.01: 95% CI < 0.00, 1.99, respectively). Reduced FORs (0.96) were observed for alcohol consumption standardized to a 28-day menstrual cycle in the same adjusted model (FOR = 0.96; 95% CI 0.93, 1.00). CONCLUSIONS: These data suggest that environmental exposures including those amenable to change, such as alcohol consumption, may impact female fecundity. The findings are sensitive to model specification and PCB groupings, underscoring the need to further assess the impact of chemical mixtures on sensitive reproductive outcomes, such as TTP, especially in the context of lifestyle factors which are amenable to change, thereby improving reproductive health.
Dallaire R, Dewailly E, Pereg D, Dery S, Ayotte P. Thyroid function and plasma concentrations of polyhalogenated compounds in Inuit adults. Environ Health Perspect. 2009 Sep;117(9):1380-6.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. Polychlorinated biphenyls (PCBs) are closely related chemicals that were formerly used in electrical transformers, inks, plastics and other consumer products whereas perfluorooctanesulfoic acid (PFOS) and are used as stain repellent on fabrics and carpets. In this study, researchers measured PCBs, PBDEs and PFOS in the blood of 623 Inuit adults. They found that participants with higher levels of PCBs and PCB metabolites were related with lower blood levels of total triiodothyronine (T3). In addition, higher levels of hexachlorobenzene were related with lower free thyroxine (T4). BDE-47 blood concentrations were related with increased total T3, whereas PFOS concentrations were associated with reduced thyroid-stimulating hormone (TSH), total T3 and increased free T4 levels. These results suggest that PCBs, hexachlorobenzene, BDE-47 and PFOS are related with changes in thyroid hormones.
Scientific abstract:
BACKGROUND: Several ubiquitous polyhalogenated compounds (PHCs) have been shown to alter thyroid function in animal and in vitro studies. So far, epidemiologic studies have focused on the potential effect of a small number of them, namely, polychlorinated biphenyls (PCBs) and some organochlorines (OCs), without paying attention to other important PHCs. OBJECTIVES: We investigated the relationship between exposure to several PHCs and thyroid hormone homeostasis in Inuit adults from Nunavik. METHODS: We measured thyroid parameters [thyroid-stimulating-hormone (TSH), free thyroxine (fT(4)), total triiodothyronine (tT(3)), and thyroxine-binding globulin (TBG)] and concentrations of 41 contaminants, including PCBs and their metabolites, organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), perfluorooctanesulfonate (PFOS), and a measure of dioxin-like compounds, detected in plasma samples from Inuit adults (n = 623). RESULTS: We found negative associations between tT(3) concentrations and levels of 14 PCBs, 7 hydroxylated PCBs (HO-PCBs), all methylsulfonyl metabolites of PCBs (MeSO(2)-PCBs), and 2 OCPs. Moreover, we found negative associations between fT(4) levels and hexachlorobenzene concentrations. TBG concentrations were inversely related to 8 PCBs, 5 HO-PCBs, and 3 OCPs. Exposure to BDE-47 was positively related to tT (3), whereas PFOS concentrations were negatively associated with TSH, tT(3,) and TBG and positively with fT(4) concentrations. CONCLUSION: Exposure to several PHCs was associated with modifications of the thyroid parameters in adult Inuit, mainly by reducing tT(3) and TBG circulating concentrations. The effects of PFOS and BDE-47 on thyroid homeostasis require further investigation because other human populations display similar or higher concentrations of these chemicals.
Dallaire R, Muckle G, Dewailly E, Jacobson SW, Jacobson JL, Sandanger TM, Sandau CD, Ayotte P. Thyroid hormone levels of pregnant inuit women and their infants exposed to environmental contaminants. Environ Health Perspect. 2009 Jun;117(6):1014-20.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. In this study, researchers measured the concentration of PCBs and some of their metabolites, the fungicide hexachlorobenzene and the wood preservative pentachlorophenol in blood samples collected from 120 mothers after giving birth, 95 umbilical cords and 130 7-month-old children. The levels of thyroid hormones were also measured in these samples. The blood levels of most chemicals were not associated with changes in thyroid hormones. The only findings included higher levels of the thyroid hormone triiodothyronine (T3) among women with higher levels of PCB metabolites and reduced cord free thyroxine (T4) concentrations in mothers with higher pentachlorophenol levels. No association was observed between contaminants and thyroid hormones at 7 months of age. Results provide little evidence in support of the hypothesis that exposure to the chemicals investigated alter thyroid hormone levels.
Scientific abstract:
BACKGROUND: An increasing number of studies have shown that several ubiquitous environmental contaminants possess thyroid hormone-disrupting capacities. Prenatal exposure to some of them, such as polychlorinated biphenyls (PCBs), has also been associated with adverse neurodevelopmental effects in infants. OBJECTIVES: In this study we examined the relationship between exposure to potential thyroid hormone-disrupting toxicants and thyroid hormone status in pregnant Inuit women from Nunavik and their infants within the first year of life. METHODS: We measured thyroid hormone parameters [thyroid stimulating hormone (TSH), free thyroxine (fT(4)), total triiodothyronine (T(3)), thyroxine-binding globulin (TBG)] and concentrations of several contaminants [PCB-153, hydroxylated metabolites of PCBs (HO-PCBs), pentachlorophenol (PCP) and hexachlorobenzene (HCB)] in maternal plasma at delivery (n = 120), in umbilical cord plasma (n = 95), and in infant plasma at 7 months postpartum (n = 130). RESULTS: In pregnant women, we found a positive association between HO-PCBs and T(3) concentrations (beta = 0.57, p = 0.02). In umbilical cord blood, PCB-153 concentrations were negatively associated with TBG levels (beta = -0.26, p = 0.01). In a subsample analysis, a negative relationship was also found between maternal PCP levels and cord fT(4) concentrations in neonates (beta = -0.59, p = 0.02). No association was observed between contaminants and thyroid hormones at 7 months of age. CONCLUSION: Overall, there is little evidence that the environmental contaminants analyzed in this study affect thyroid hormone status in Inuit mothers and their infants. The possibility that PCP may decrease thyroxine levels in neonates requires further investigation.
De Jager C, Aneck-Hahn NH, Bornman MS, Farias P, Leter G, Eleuteri P, Rescia M, Spano M. Sperm chromatin integrity in DDT-exposed young men living in a malaria area in the Limpopo Province, South Africa. Hum Reprod. 2009 Oct;24(10):2429-38.
Study Synopsis: DDT is an insecticide that was banned by the U.S. Environmental Protection Agency (EPA) in the 1970s due to concerns about its persistence in the environment and toxic effects on wildlife and humans. DDT was banned internationally by the Stockholm Convention on Persistent Organic Pollutants, except to control insects that carry diseases such as malaria. In this study, researchers measured the concentration of DDT, and its breakdown product DDE, in the blood of 209 South African men living in an area where DDT is used to control malaria. They found weak relationships between blood levels of DDT and DDE and increased prevalence of sperm DNA abnormalities. These results suggest that exposure to DDT and/or DDE is related with impaired semen quality.
Scientific abstract:
BACKGROUND: There is mounting evidence that deteriorated semen quality may be associated with increased serum concentration of 1,1,1-trichloro-2,2-bis(chlorodiphenyl)ethane (DDT) and its metabolites. The problem is exacerbated in situations where DDT is the only resource available to control malaria mosquitoes and DDT metabolite plasma concentration can reach 1000-fold the level found in other populations. There are limited and contradictory epidemiological data on whether DDT/dichlorodiphenyl-dichloroethylene (DDE) can also damage sperm DNA. Therefore, there is a need to investigate the possible adverse effects on human sperm genetic integrity in a sufficiently large study population with adequate exposure contrasts, especially in the high exposure range. METHODS: We conducted a cross-sectional study, recruiting 209 young males from three communities in an endemic malaria area where DDT is sprayed annually. Blood plasma p,p'-DDT and its metabolite p,p'-DDE levels were measured and expressed as lipid adjusted p,p'-DDT and p,p'-DDE values. The sperm chromatin structure assay and Aniline Blue test were used to assess sperm DNA/chromatin integrity. RESULTS: The lipid adjusted p,p'-DDT mean (+/-SD) and median concentrations were 109.2 (+/-106.6) and 83.9 microg/g, respectively; and the lipid adjusted p,p'-DDE mean (+/-SD) and median concentrations were 246.2 (+/-218.5) and 177.8 microg/g, respectively. The results point to a weak association between DDT/DDE plasma concentration and the incidence of sperm with chromatin defects. CONCLUSIONS: The results suggest that non-occupational environmental DDT exposure may have a negative impact on sperm chromatin integrity in young South African males.
Key Words: Adolescent, Adult, Chromatin/ drug effects, Cross-Sectional Studies, DDT/blood/ toxicity, DNA Damage, DNA Fragmentation, Dichlorodiphenyl Dichloroethylene/blood, Flow Cytometry, Humans, Male, Semen Analysis, South Africa, Spermatozoa/ drug effects
Study Synopsis: This review, by the Endocrine Society, presents the envidence suggesting links between exposure to environmental chemicals and male and female reproduction, breast development, breast cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. These chemicals, which may affect hormone levels or action, are named "Endocrine Disruptors." Authors make a number of recommendations to increase understanding of the effects of Endocrine Disruptors, including enhancing basic and clinical research, and invoking the so called "precautionary principle."
Scientific abstract:
There is growing interest in the possible health threat posed by endocrine-disrupting chemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction. In this first Scientific Statement of The Endocrine Society, we present the evidence that endocrine disruptors have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovascular endocrinology. Results from animal models, human clinical observations, and epidemiological studies converge to implicate EDCs as a significant concern to public health. The mechanisms of EDCs involve divergent pathways including (but not limited to) estrogenic, antiandrogenic, thyroid, peroxisome proliferator-activated receptor {gamma}, retinoid, and actions through other nuclear receptors; steroidogenic enzymes; neurotransmitter receptors and systems; and many other pathways that are highly conserved in wildlife and humans, and which can be modeled in laboratory in vitro and in vivo models. Furthermore, EDCs represent a broad class of molecules such as organochlorinated pesticides and industrial chemicals, plastics and plasticizers, fuels, and many other chemicals that are present in the environment or are in widespread use. We make a number of recommendations to increase understanding of effects of EDCs, including enhancing increased basic and clinical research, invoking the precautionary principle, and advocating involvement of individual and scientific society stakeholders in communicating and implementing changes in public policy and awareness.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers exposed pregnant rats to different doses of a type of phthalate called dibutyl phthalate (DBP) and the synthetic glucocorticoid dexamethasone alone or in combination. They found that prenatal exposure to high doses (500 mg/kg) of DBP reduced testosterone in fetuses testicles, induced hypospadias (abnormal location of the urethra opening) and cryptorchidism (undescended testes) and reduced penile length, testis and prostate weight. While dexamethasone did not affect these outcomes on its own, it exacerbated the effects of DBP on testis weight, hypospadias and cryptorchidism. Glucocorticoids are produced in response to stress. According to authors of this paper, these results thus suggest that exposure to environmental chemicals in combination with maternal stress may increase the risk of male reproductive abnormalities.
Scientific abstract:
Common male reproductive abnormalities including cryptorchidism, hypospadias, and low sperm counts may comprise a testicular dysgenesis syndrome (TDS), resulting from fetal testis dysfunction during a critical developmental period involving reduced androgen production/action. The recent increase in TDS prevalence suggests environmental/lifestyle factors may be etiologically important. The developing fetus is exposed to multimodal challenges, and we hypothesized that exposure to a combination of factors rather than single agents may be important in the pathogenesis of TDS. We experimentally induced fetal testis dysfunction in rats via treatment of pregnant females daily from embryonic day (e) 13.5 to e21.5 with vehicle, 100 or 500 mg/kg {middle dot} d dibutyl phthalate (DBP), 0.1 mg/kg {middle dot} d dexamethasone (Dex), or a combination of DBP + Dex. In adulthood, penile length/normality, testis weight/descent, prostate weight, and plasma testosterone levels were measured plus anogenital distance (AGD) as a measure of androgen action within the masculinization programming window. Intratesticular testosterone and steroidogenic enzyme gene expression were measured in fetal testes at e17.5. High-dose DBP reduced fetal intratesticular testosterone and steroidogenic gene expression; induced mild hypospadias (31%) and cryptorchidism (53%); and reduced penile length, AGD, and testis and prostate weight in adulthood. Dex alone had no effect except to reduce birth weight but amplified the adverse effects of 500 mg/kg {middle dot} d DBP and exacerbated the effects of 100 mg/kg {middle dot} d DBP. All adverse effects were highly correlated to AGD, emphasizing the etiological importance of the masculinization programming window. These findings suggest that exposure to common environmental chemicals in combination with, for example, maternal stress, may increase the risk of common male reproductive abnormalities, with implications for human populations.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured seven phthalate residues in the urine of 295 pregnant women between 25 and 40 weeks' gestation and assessed neurodevelopment in their children within 5 days of delivery using the Brazelton Neonatal Behavioral Assessment Scale. They found that girls with higher levels of phthalate residues with high molecular weight had inhibited responses to visual and auditory stimuli and were less alert. There was also some indication of improved motor performance in boys exposed to higher levels of low molecular weight phthalate residues. These results suggest that exposure to phthalates may modulate neurodevelopment.
Scientific abstract:
We investigated the relationship between prenatal maternal urinary concentrations of phthalate metabolites and neonatal behavior in their 295 children enrolled in a multiethnic birth cohort between 1998 and 2002 at the Mount Sinai School of Medicine in New York City. Trained examiners administered the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) to children within 5 days of delivery. We measured metabolites of 7 phthalate esters in maternal urine that was collected between 25 and 40 weeks' gestation. All but two phthalate metabolites were over 95% detectable. We summed metabolites on a molar basis into low and high molecular weight phthalates. We hypothesized the existence of sex-specific effects from phthalate exposure a priori given the hormonal activity of these chemicals. Overall we found few associations between individual phthalate metabolites or their molar sums and most of the BNBAS domains. However, we observed significant sex-phthalate metabolite interactions (p<0.10) for the Orientation and Motor domains and the overall Quality of Alertness score. Among girls, there was a significant linear decline in adjusted mean Orientation score with increasing urinary concentrations of high molecular weight phthalate metabolites (B=-0.37, p=0.02). Likewise, there was a strong linear decline in their adjusted mean Quality of Alertness score (B=-0.48, p<0.01). In addition, boys and girls demonstrated opposite patterns of association between low and high molecular weight phthalate metabolite concentrations and motor performance, with some indication of improved motor performance with increasing concentration of low molecular weight phthalate metabolites among boys. This is the first study to report an association between prenatal phthalate exposure and neurological effects in humans or animals, and as such requires replication.
Eskenazi B, Chevrier J, Rosas LG, Anderson HA, Bornman MS, Bouwman H, Chen A, Cohn BA, De Jager C, Henshel DS, Leipzig F, Leipzig JS, Lorenz EC, Snedeker SM, Stapleton D. The Pine River statement: human health consequences of DDT use. Environ Health Perspect. 2009 Sep;117(9):1359-67.
Study Synopsis: DDT it an insecticide that was banned by the U.S. Environmental Protection Agency (EPA) in the 1970s due to concerns about its persistence in the environment and toxic effects on wildlife and humans. DDT has now been banned internationally by the Stockholm Convention on Persistent Organic Pollutants, except to control insects that carry diseases such as malaria. This paper reviews the recent evidence concerning the human health effects of exposure to DDT. Authors conclude that the literature suggest associations between exposure to DDT and increased risks of breast cancer, diabetes, spontaneous abortion as well as reduced semen quality and impaired child neurodevelopment.
Scientific abstract:
OBJECTIVES: Dichlorodiphenyltrichloroethane (DDT) was used worldwide until the 1970s, when concerns about its toxic effects, its environmental persistence, and its concentration in the food supply led to use restrictions and prohibitions. In 2001, more than 100 countries signed the Stockholm Convention on Persistent Organic Pollutants (POPs), committing to eliminate the use of 12 POPs of greatest concern. However, DDT use was allowed for disease vector control. In 2006, the World Health Organization and the U.S. Agency for International Development endorsed indoor DDT spraying to control malaria. To better inform current policy, we reviewed epidemiologic studies published from 2003 to 2008 that investigated the human health consequences of DDT and/or DDE (dichlorodiphenyldichloroethylene) exposure. DATA SOURCES AND EXTRACTION: We conducted a PubMed search in October 2008 and retrieved 494 studies. DATA SYNTHESIS: Use restrictions have been successful in lowering human exposure to DDT, but blood concentrations of DDT and DDE are high in countries where DDT is currently being used or was more recently restricted. The recent literature shows a growing body of evidence that exposure to DDT and its breakdown product DDE may be associated with adverse health outcomes such as breast cancer, diabetes, decreased semen quality, spontaneous abortion, and impaired neurodevelopment in children. CONCLUSIONS: Although we provide evidence to suggest that DDT and DDE may pose a risk to human health, we also highlight the lack of knowledge about human exposure and health effects in communities where DDT is currently being sprayed for malaria control. We recommend research to address this gap and to develop safe and effective alternatives to DDT.
Study Synopsis: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA and PFOS. In this study, researchers measured the blood levels of these chemicals in 1,240 pregnant Danish women between 4 and 14 weeks gestation. They found that women with higher blood levels of PFOS and PFOA took longer to become pregnant. Odds of infertility, defined as trying unsuccessfully to become pregnant for more than 12 months or receiving infertility treatment, were increased by 77% and 154% in women with high PFOS and PFOA blood levels, respectively, relative to women with low levels. These findings suggest that exposure to PFOS and PFOA may be associated with reduced fertility in women.
Scientific abstract:
BACKGROUND: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are ubiquitous man-made compounds that are possible hormonal disruptors. We examined whether exposure to these compounds may decrease fecundity in humans. METHODS: Plasma levels of PFOS and PFOA were measured at weeks 4-14 of pregnancy among 1240 women from the Danish National Birth Cohort recruited from 1996 to 2002. For this pregnancy, women reported time to pregnancy (TTP) in five categories (<1, 1-2, 3-5, 6-12 and >12 months). Infertility was defined as having a TTP of >12 months or received infertility treatment to establish this pregnancy. RESULTS: Longer TTP was associated with higher maternal levels of PFOA and PFOS (P < 0.001). Compared with women in the lowest exposure quartile, the adjusted odds of infertility increased by 70-134 and 60-154% among women in the higher three quartiles of PFOS and PFOA, respectively. Fecundity odds ratios (FORs) were also estimated using Cox discrete-time models. The adjusted FORs were virtually identical for women in the three highest exposure groups of PFOS (FOR = 0.70, 0.67 and 0.74, respectively) compared with the lowest quartile. A linear-like trend was observed for PFOA (FOR = 0.72, 0.73 and 0.60 for three highest quartiles versus lowest quartile). When all quartiles were included in a likelihood ratio test, the trends were significant for PFOS and PFOA (P = 0.002 and P < 0.001, respectively). CONCLUSIONS: These findings suggest that PFOA and PFOS exposure at plasma levels seen in the general population may reduce fecundity; such exposure levels are common in developed countries.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, pregnant rats and their male offspring were exposed by gavage to daily doses of 0, 11, 33, 100 or 300 mg/kg of diethylhexyl phthalate (DEHP). Researchers found that exposure to the highest dose of DEHP caused a decreased in sperm count and in the weight of reproductive organs in male offspring. Although blood levels of estradiol (the main estrogen in humans) and of the male hormone testosterone were not affected, reduced anogenital distance, seminal vesicle weight and retained nipples in males exposed to higher doses suggested that DEHP is antiandrogenic. These results suggest that pre- and early postnatal exposure to high doses of DEHP affect the male reproductive system in rats.
Scientific abstract:
In the rat, some phthalates alter sexual differentiation at relatively low dosage levels by altering fetal Leydig cell development and hormone synthesis, thereby inducing abnormalities of the testis, gubernacular ligaments, epididymis, and other androgen-dependent tissues. In order to define the dose-response relationship between di(2-ethylhexyl) phthalate (DEHP) and the Phthalate Syndrome of reproductive alterations in F1 male rats, Sprague-Dawley (SD) rat dams were dosed by gavage from gestational day 8 to day 17 of lactation with 0, 11, 33, 100, or 300 mg/kg/day DEHP (71-93 males per dose from 12 to 14 litters per dose). Some of the male offspring continued to be exposed to DEHP via gavage from 18 days of age to necropsy at 63-65 days of age (PUB cohort; 16-20/dose). Remaining males were not exposed after postnatal day 17 (in utero-lactational [IUL] cohort) and were necropsied after reaching full maturity. Anogenital distance, sperm counts and reproductive organ weights were reduced in F1 males in the 300 mg/kg/day group and they displayed retained nipples. In the IUL cohort, seminal vesicle weight also was reduced at 100 mg/kg/day. In contrast, serum testosterone and estradiol levels were unaffected in either the PUB or IUL cohorts at necropsy. A significant percentage of F1 males displayed one or more Phthalate Syndrome lesions at 11 mg/kg/day DEHP and above. We were able to detect effects in the lower dose groups only because we examined all the males in each litter rather than only one male per litter. Power calculations demonstrate how using multiple males versus one male/litter enhances the detection of the effects of DEHP. The results at 11 mg/kg/day confirm those reported from a National Toxicology Program multigenerational study which reported no observed adverse effect levels-lowest observed adverse effect levels of 5 and 10 mg/kg/day DEHP, respectively, via the diet.
Study Synopsis: This review presents a summary of the biological effects of dioxin and aims to assess the evidence of a relationship with endometriosis, a condition characterized by the growth of tissue normally found in the uterus on other organs or structures. Endometriosis may cause infertility, abdominal pain and abnormal menses. Authors conclude that in vitro and animal studies support that dioxin play a role in the development of endometriosis but that human studies do not clearly establish that link.
Scientific abstract:
A 1993 study reporting the link between exposure to dioxin and the risk of developing endometriosis in rhesus monkeys prompted many investigators to look suspiciously at dioxin. Since 1993, many in vitro, animal and epidemiological studies have been published, but the link between dioxin exposure and endometriosis is still unclear. The aim of our review is to present a summary of the biological effects of dioxin and its aryl hydrocarbon receptor, and to reassess the evidence presented in published, in vitro, preclinical and epidemiological studies regarding the association between dioxins and endometriosis. Although in vitro and animal studies provide results in support for a role of dioxins in the pathogenesis of endometriosis, caution should be exercised since these findings are mostly context dependent and since negative findings from these studies are rarely published. Based on our review of original epidemiological studies, no significant evidence can be found to support a link between dioxins and endometriosis in women. This observation can be explained by positive publication bias and by significant methodological problems associated with these studies, or by the absence of such a link. In conclusion, it seems that there is insufficient evidence at this moment in support of the hypothesis that dioxin exposure may lead to increased risk of developing endometriosis in women.
Han SW, Lee H, Han SY, Lim DS, Jung KK, Kwack SJ, Kim KB, Lee BM. An exposure assessment of di-(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) in human semen. J Toxicol Environ Health A. 2009;72(21-22):1463-9.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers aimed to determine whether phthalates and their residues could be detected in human semen. They enrolled 99 healthy volunteers aged between 20 and 25 years who provided a semen sample. All phthalates measured were detected in at least one sample. These included diethylhexyl phthalate (DEHP), monoethylhexyl phthalate (MEHP, a major metabolite of DEHP), dibutyl phthalate (DBP), monobutyl phthalate (MBP, a major metabolite of DBP), and phthalic acid (P, a common metabolite of some phthalates including DEHP and DBP).
Scientific abstract:
Levels of the phthalates such as di(2-ethylhexyl) phthalate (DEHP), mono(2-ethylhexyl) phthalate (MEHP, a major metabolite of DEHP), di-n-butyl phthalate (DBP), mono-n-butyl phthalate (MBP, a major metabolite of DBP), and phthalic acid (P, (a common metabolite of phthalates, including DEHP and DBP) were determined in the semen samples of 99 healthy volunteers without known prior medicosurgical history. Samples were obtained from young men (age 20-25 yr) who visited a clinic, and the semen concentrations of phthalates were measured using ultra-performance liquid chromatography (UPLC) and tandem mass spectrometry (MS/MS). UPLC/MS/MS showed that mean concentrations in semen samples were 1.07 microg/ml for MEHP, 0.61 microg/ml for DEHP, 0.39 microg/ml for PA, 0.06 microg/ml for MBP, and 0.003 microg/ml for DBP. The concentration of MEHP (the metabolite of DEHP) was highest, and the concentrations of the metabolites including MEHP, MBP, and PA were higher than actual concentrations of parent DEHP and DBP. These findings suggest the detection of phthalates in healthy human semen might require further investigation for effects on human fertility.
Study Synopsis: Researchers measured 22 pesticides in dust samples collected from 197 residences in California's Salinas Valley, an agricultural area with high pesticide use. They found that the concentration of the insecticide chlorpyrifos, the fungicide iprodione and the herbicide tetrachloroterephthalate (DCPA) in house dust was related with agricultural use of these pesticides in the month or season prior to collection of dust samples. Agricultural use of the pesticides diazinon and permethrin were however not related with dust levels. Other variables related with pesticide dust levels included temperature, rainfall, housing density (number of residents per room), home cleanliness, and whether residents owned an air conditioner or had a diazinon product in their homes. Farmworkers who stored their work shoes in their homes tended to have higher house dust pesticide concentrations.
Scientific abstract:
We collected indoor dust samples from homes in the Salinas Valley of California. Of 22 pesticides measured in 504 samples, permethrins and the organophosphate chlorpyrifos were present in highest amounts. In multivariate Tobit regression models among samples from 197 separate residences, reported agricultural uses of chlorpyrifos, a herbicide (2,3,5,6-tetrachloroterephthalate (DCPA)), and a fungicide (iprodione) on agricultural fields were significantly (p < 0.01) associated, with 83%, 19%, and 49% increases, respectively, in dust concentrations for each kg applied per day, near participant homes, in the month or season prior to sample collection. However, agricultural use of diazinon, which was 2.2 times that of chlorpyrifos, and of permethrin were not significantly associated with dust levels. Other variables independently associated with dust levels included temperature and rainfall, farmworkers storing work shoes in the home, storing a diazinon product in the home, housing density, having a home less clean, and having an air conditioner. Permethrins, chlorpyrifos, DCPA, and iprodione have either a log octanolāwater partition coefficient (Kow) greater than 4.0, a very low vapor pressure, or both. Health risk assessments for pesticides that have these properties may need to include evaluation of exposures to house dust.
Herr C, Zur Nieden A, Koch HM, Schuppe HC, Fieber C, Angerer J, Eikmann T, Stilianakis NI. Urinary di(2-ethylhexyl)phthalate (DEHP)--metabolites and male human markers of reproductive function. Int J Hyg Environ Health. 2009 Nov;212(6):648-53.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers recruited 349 men who were part of subfertile couples and were referred for fertility testing between April 2004 and November 2005. Men provided urine and semen samples. The concentration of the breakdown products of one type of phthalate called diethylhexyl phthalate (DEHP) was measured in urine and semen quality parameters were determined based on World Health Organization criteria. No association was found between exposure to DEHP and sperm concentration or motility. These results do not support a relationship between exposure to DEHP and semen quality.
Scientific abstract:
INTRODUCTION: Phthalates are suspected to act as endocrine modulators in humans and exert reproductive toxicity. The general population is exposed to phthalates through nutrition, consumer products, medications and medical devices. The aim of the present study is to explore whether internal phthalate exposure represented by metabolites of di(2-ethylhexyl) phthalate (DEHP) can be related to human markers of reproductive function (i.e. semen concentration, motility and morphology). METHODS: We recruited 349 men who were part of subfertile couples and were referred for fertility work-up between April 2004 and November 2005. Semen analysis was performed according to recommendations of the World Health Organization (WHO). Parameters were dichotomized based on 1999 WHO reference values for sperm concentration (<20million/ml) and motility (<50% sperm with progressive motility), as well as Tygerberg strict criteria for morphology (<4% normal forms). We analyzed internal DEHP exposure in single spot urine samples by determining its secondary metabolites mono(2-ethyl-5-oxo-hexyl)phthalate (5oxo-MEHP), mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP) and 5carboxy-mono(2-ethylhexyl)phthalate (5cx-MEPP) next to the monoester metabolite mono(2-ethylhexyl)phthalate (MEHP). Logistic regression was performed for the three semen parameters (concentration, motility, and normal morphology) to estimate their dependence on the sum of the four DEHP metabolites (DEHP-4) under consideration. Adjustment was performed for age, duration of abstinence, and smoking status. RESULTS: DEHP metabolites of n=349 men (age: median=34ys) were analysed. Median concentrations [microg/l] were MEHP (n=337) 4.35, 5OH-MEHP (n=341) 12.66, 5oxo-MEHP (n=341) 9.02, and 5cx- MEPP (n=292) 14.53. Semen parameters of n=349 men were analysed by logistic regression. Semen concentration (<20mio/ml: 35%) or sperm motility (WHO A+B <50%=20%) were not found to be associated statistically significantly with the sum the DEHP metabolites (DEHP-4). DISCUSSION: Metabolites of DEHP and other phthalates analyzed in urine are very specific for determining recent internal phthalate exposure. According to our evaluation human reproductive parameters from semen analyses do not show significant associations with concentrations of DEHP metabolites determined in spot urine sampled at the day of andrological examination.
Phthalates are developmental and reproductive toxicants for the fetus in pregnant rodents, and the ability of phthalates to penetrate the placenta have been reported. The aims of this study were to evaluate the association between maternal urine excretion, the exposure of fetus to phthalates in amniotic fluid, and the health of newborns. Amniotic fluid and urine samples from pregnant women were collected to measure five phthalate monoesters using liquid chromatography/tandem mass spectrometry (LC/MS-MS) and the newborns' birth weight, gestational age, and anogenital distance (AGD) were collected. The median levels of three phthalate monoesters in urine and amniotic fluid were 78.4 and 85.2 ng/mL monobutyl phthalate (MBP); 24.9 and 22.8 ng/mL mono-(2-ethylhexyl) phthalate (MEHP); 19.8 and Not Detected monoethyl phthalate (MEP). We found a significant positive correlation only between creatinine adjusted urinary MBP and amniotic fluid MBP (R(2)=0.156, p<0.05) in all infants and, only in female infants, a significantly negative correlation between amniotic fluid MBP, AGD (R=-0.31, p<0.06), and the anogenital index adjusted by birth weight (AGI-W) (R=-0.32, p<0.05). Although the influence of prenatal di-n-butyl phthalate (DBP) exposure on the endocrinology and physiology of the fetus is still a puzzle, our data clearly show that in utero exposure to phthalates in general has anti-androgenic effects on the fetus.
Joensen UN, Bossi R, Leffers H, Jensen AA, Skakkebaek NE, Jorgensen N. Do perfluoroalkyl compounds impair human semen quality?. Environ Health Perspect. 2009 Jun;117(6):923-7.
Study Synopsis: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA and PFOS. In this study, researchers measured the blood concentration of these chemicals and obtained a semen sample from 105 Danish men. Men with higher levels of PFOA and PFOS had a 60% reduction in normal sperms relative to those with low levels. Trends towards lower sperm concentration, reduced sperm count and altered reproductive hormones were also observed in relation with higher exposure to PFOA and PFOS but researchers determined that these associations may have been due to chance. Results suggest that high exposure to PFCs may be related with fewer normal sperm.
Scientific abstract:
BACKGROUND: Perfluoroalkyl acids (PFAAs) are found globally in wildlife and humans and are suspected to act as endocrine disruptors. There are no previous reports of PFAA levels in adult men from Denmark or of a possible association between semen quality and PFAA exposure. OBJECTIVES: We investigated possible associations between PFAAs and testicular function. We hypothesized that higher PFAA levels would be associated with lower semen quality and lower testosterone levels. METHODS: We analyzed serum samples for levels of 10 different PFAAs and reproductive hormones and assessed semen quality in 105 Danish men from the general population (median age, 19 years). RESULTS: Considerable levels of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid were found in all young men (medians of 24.5, 4.9, and 6.6 ng/mL, respectively). Men with high combined levels of PFOS and PFOA had a median of 6.2 million normal spermatozoa in their ejaculate in contrast to 15.5 million among men with low PFOS-PFOA (p = 0.030). In addition, we found nonsignificant trends with regard to lower sperm concentration, lower total sperm counts, and altered pituitary-gonadal hormones among men with high PFOS-PFOA levels. CONCLUSION: High PFAA levels were associated with fewer normal sperm. Thus, high levels of PFAAs may contribute to the otherwise unexplained low semen quality often seen in young men. However, our findings need to be corroborated in larger studies.
Key Words: Adult, Alkanesulfonic Acids/blood/toxicity, Chromatography, Liquid, Endocrine Disruptors/blood/toxicity, Fluorocarbons/blood/ toxicity, Humans, Male, Octanoic Acids/blood/toxicity, Spermatozoa/ drug effects/physiology, Tandem Mass Spectrometry, Water Pollutants, Chemical/ toxicity, Young Adult
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers exposed pregnant rats to daily doses of the PBDE congener BDE-209, which is primarily used in electronic products. Offspring of dams exposed to the highest level of BDE-209 had a significant decrease in weight gain relative to controls. An increase in the weight of the thyroid gland as well as a reduction in the blood levels of the thyroid hormone thyroxine (T4) were also observed in offspring prenatally exposed to BDE-209. The lowest dose also reduced the level of estradiol (an estrogen) in female offspring. No effects on testosterone levels were observed. Finally, no effect was found in the development of brain cells. Results suggest that prenatal exposure to BDE-209 alters the blood levels of estradiol in females and of thyroid hormone in both sexes. Body weight gain is also reduced by high prenatal exposure.
Scientific abstract:
Polybrominated diphenyl ethers (PBDE) are a class of brominated flame retardants that are recognized as global environmental contaminants with potential adverse effects on human health. This study examined the effects of prenatal exposure to PBDE on reproductive organs, neuronal development, and levels of thyroid hormones. Pregnant rats were exposed to the vehicle or deca-bromodiphenyl ether (BDE) (BDE-209; 5, 40, or 320 mg/kg body weight/d) during gestation days (GD) 6-18. There was a significant decrease in body weight gain in F1 male offspring exposed to high-dose (320 mg/kg) BDE-209. Significant increases in thyroid weight and a decrease in adrenal weight were observed in high-dose BDE-209. Thyroxine (T4) concentrations were significantly lower in F1 female offspring exposed to BDE-209 at postnatal day (PND) 42. This reduction was more pronounced in the group exposed to higher doses. A low dose (5 mg/kg) of BDE-209 significantly reduced serum estradiol concentration in female offspring but did not affect testosterone levels in males. There was no significant effect on hippocampal neurogenesis in BDE-209 treatment groups. In conclusion, there was no apparent association between thyroid hormone concentrations and low birth weight in F1 rats after gestational exposure to BDE-209.
Study Synopsis: Dioxins are highly toxic chemicals that persist in the environment, accumulate in human fatty tissue and concentrate up the food chain. Furans and polychlorinated biphenyls (PCBs) are closely related chemicals that have toxicological properties that are similar to those of dioxins. In this study, researchers measured the level of 29 congeners of dioxins, furans and PCBs in the blood of 514 pregnant women. They found that blood levels of dioxins and furans were related with lower birth weight, particularly in male infants. Results thus suggest that prenatal exposure to dioxins and/or furants may be related with lower birth weight.
Scientific abstract:
Several human studies have shown that low-level exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs) and organochlorine pesticides, negatively influences birth outcomes. However, the effects of low-level exposure to polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs (DL-PCBs) on birth outcomes have not been clarified in human studies. A prospective cohort study was established to investigate the possible adverse effects of PCDDs/PCDFs and DL-PCBs on fetal growth and neurodevelopment. We recruited 514 pregnant women between July 2002 and October 2005 in Sapporo, Japan. We measured 29 congener levels of PCDDs/PCDFs and DL-PCBs in maternal blood. Using multiple liner regression analysis of the association between birth weight and the levels of PCDDs/PCDFs and DL-PCBs with full adjustments for potential confounders, a significant adverse effect was observed regarding total PCDDs toxic equivalents (TEQ) levels (adjusted [beta]=-231.5 g, 95% CI: -417.4 to -45.6) and total PCDFs TEQ levels (adjusted [beta]=-258.8 g, 95% CI: -445.7 to -71.8). Among male infants, significant adverse associations with birth weight were found for total PCDDs TEQ level, total PCDDs/PCDFs TEQ level, and total TEQ level. However, among female infants, these significant adverse associations were not found. With regard to individual congeners of PCDDs/PCDFs and DL-PCBs, we found significantly negative association with the levels of 2,3,4,7,8-PeCDF (adjusted [beta]=-24.5 g, 95% CI: -387.4 to -61.5). Our findings suggest that prenatal low-level exposure to PCDDs and PCDFs, especially 2,3,4,7,8-PeCDF, may accumulate in the placenta and retard important placental functions, which result in lower birth weight.
Study Synopsis: Triclosan is commonly used as an antibacterial and antifungal in a range of household products including soap, mouthwash, toothpaste, deodorants and hand sanitizers. Some studies suggest that triclosan may interfere with hormones. In this study, researchers exposed rats to triclosan for a period of 60 days. They found that the chemical inhibited a number enzymes involved in androgens synthesis as well as the expression of the androgen receptor (AR). Androgens, such as the male hormone testosterone, must bind to the AR to exert their effects. The levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), cholesterol, pregnenolone and testosterone were also affected by exposure. Finally, malformation in the testis and sex accessory tissues of treated rats were observed. Overall, this study suggests that triclosan has anti-androgenic properties and alters the male reproductive system in rats.
Scientific abstract:
Triclosan (TCS), a chlorophenol, is widely used as a preservative in different types of commercial preparations. The reports on TCS-mediated endocrine disruption are controversial and the present study aimed to elucidate the probable mode of action of TCS as an antiandrogenic compound using a robust study design. Male albino rats, Rattus norvegicus, were treated with three doses of triclosan for a period of 60 days followed by the analysis of various biochemical parameters. RT-PCR analysis demonstrated a significant decrease in mRNA levels for testicular steroidogenic acute regulatory (StAR) protein, cytochrome P450SCC, cytochrome P450C17, 3[beta]-hydroxysteroid dehydrogenase (3[beta]-HSD), 17[beta]-hydroxysteroid dehydrogenase (17[beta]-HSD) and androgen receptor (AR) in TCS treated rats (p < 0.05). TCS also induced a perturbed translation of testicular StAR, and AR proteins as shown by Western blot analysis in treated groups of rats. A reduced level of StAR was further indicated by immunohistochemistry in testicular Leydig cells. Further, there was a significant decrease (p < 0.05) in the level of serum lutenizing hormone (LH), follicle stimulating hormone (FSH), cholesterol, pregnenolone, and testosterone. In vitro assays demonstrated more than 30% decrease in testicular 3[beta]-HSD and 17[beta]-HSD enzyme activities in treated group of animals. Extensive histopathological malformations were observed in the testis and sex accessory tissues of the treated rats. Overall this study showed that TCS decreased the synthesis of androgens followed by reduced sperm production in treated male rats which could be mediated by a decreased synthesis of LH and FSH thus involving hypothalamo-pituitary-gonadal axis.
Study Synopsis: Previous animal studies have shown decreases in the synthesis of androgens, such as the male hormone testosterone, following exposure to DEHP. In this study, researchers proposed to investigate the toxicological mechanism through which this effect occurs. They gavaged pregnant rats with 100 to 950 mg DEHP per kg per day from gestational days 14 to 19 and collected testes from males during gestation and at three time points after birth. Exposure was found to reduce the expression of the mineralocorticoid receptor (MR) in Leydig cells, which are found in the testes. Since MR inhibition is known to repress Leydig cells testosterone synthesis, decreased MR expression may be a mechanism through which phthalates affect testosterone synthesis and male sexual development in rats.
Scientific abstract:
In utero exposure to di-(2-ethylhexyl) phthalate (DEHP) has been shown to result in decreased androgen formation by fetal and adult rat testes. In the fetus, decreased androgen is accompanied by the reduced expression of steroidogenic enzymes. The mechanism by which in utero exposure results in reduced androgen formation in the adult, however, is unknown. We hypothesized that deregulation of the nuclear steroid receptors might explain the effects of in utero DEHP exposure on adult testosterone production. To test this hypothesis, pregnant Sprague Dawley dams were gavaged with 100-950 mg DEHP per kilogram per day from gestational d 14-19, and testes were collected at gestational d 20 and postnatal days (PND) 3, 21, and 60. Among the nuclear receptors studied, the mineralocorticoid receptor (MR) mRNA and protein levels were reduced in PND60 interstitial Leydig cells, accompanied by reduced mRNA expression of MR-regulated genes. Methylation-sensitive PCR showed effects on the nuclear receptor subfamilies NR3A and -3C, but only MR was affected at PND60. Pyrosequencing of two CpG islands within the MR gene promoter revealed a loss of methylation in DEHP-treated animals that was correlated with reduced MR. Because MR activation is known to stimulate Leydig cell testosterone formation, and MR inhibition to be repressive, our results are consistent with the hypothesis that in utero exposure to DEHP leads to MR dysfunction and thus to depressed testosterone production in the adult. We suggest that decreased MR, possibly epigenetically mediated, is a novel mechanism by which phthalates may affect diverse functions later in life.
Mcglynn KA, Guo X, Graubard BI, Brock JW, Klebanoff MA, Longnecker MP. Maternal pregnancy levels of polychlorinated biphenyls and risk of hypospadias and cryptorchidism in male offspring. Environ Health Perspect. 2009 Sep;117(9):1472-6.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. In this study, researchers measured the concentration of PCBs in blood samples collected during pregnancy from mothers of 230 boys with cryptorchidism (undescended testes), 201 boys with hypospadias (abnormal location of the urethra opening) and 593 healthy controls. Data were obtained from the Collaborative Perinatal Project, a study that included pregnant women giving birth at one of 12 U.S. medical centers between 1959 and 1965. No notable associations were found between PCB levels in maternal blood and risks of hypospadias or cryptorchidism. These results do not support the hypothesis that prenatal exposure to PCBs is related to these anomalies.
Scientific abstract:
BACKGROUND: The etiologies of the male urogenital anomalies cryptorchidism and hypospadias are poorly understood. It has been suggested, however, that in utero hormone levels may be related to risk. Endocrine-disrupting chemicals, including polychlorinated biphenyl (PCB) compounds, may alter hormone levels and thereby affect the fetus. OBJECTIVES: To examine whether in utero PCB exposure is related to cryptorchidism and hypospadias, we examined PCB levels among pregnant women enrolled in the Collaborative Perinatal Project (CPP). METHODS: The CPP enrolled pregnant women at 12 U.S. medical centers between 1959 and 1965. For the present research, we analyzed third-trimester serum samples from the mothers of 230 sons with cryptorchidism, 201 sons with hypospadias, and 593 sons with neither condition. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression and examined the associations of each anomaly with individual PCB congener levels, sum of PCBs, and several functional groupings of PCBs. RESULTS: In general, the ORs for cryptorchidism or hypospadias showed no notable associations with individual PCB congener levels or functional groupings of PCBs. However, the ORs and 95% CIs for the sum of PCBs associated with hypospadias were as follows: 0-1.9 microg/L, reference group; 2-2.9 microg/L, OR = 1.57, 95% CI, 1.05-2.34; 3-3.9 microg/L, OR = 1.45, 95% CI, 0.90-2.34; and > or = 4.0 microg/L, OR = 1.69, 95% CI, 1.06-2.68; p-value for trend = 0.08. CONCLUSIONS: Given the large number of associations examined, these findings do not strongly support the hypothesis that PCBs are associated with cryptorchidism or hypospadias. Because population serum PCB levels at the time of sample collection were considerably higher than levels at present, it is unlikely that current PCB exposure is related to the development of either anomaly.
Key Words: Cryptorchidism/ blood, Female, Humans, Hypospadias/ blood, Male, Polychlorinated Biphenyls/ blood, Pregnancy, Risk Factors, United States
Study Synopsis: Pyrethroids are synthetic derivatives of pyrethrins which are naturally occurring insecticides produced from flowers of certain chrysanthemum species. More than 2 million pounds of pyrethroid insecticides are used for agricultural and home pest control each year in the United States. Although pyrethroid use in U.S. homes has substantially increased since the recent residential ban on certain organophosphate pesticide by the U.S. Environmental Protection Agency (EPA), little is known on the human health effects of chronic exposure to these chemicals. In this study, researchers recruited 161 men from an infertility clinic and measured the concentration of pyrethroid residues in their urine. Chemicals measured included 3-phenoxybenzoic acid (3PBA) and cis- and trans-dichlorovinyl dimethylcyclopropane carboxylic acid (CDCCA and TDCCA). Men with higher levels of all pyrethroid residues had higher blood levels of follicle-stimulating hormone (FSH). TDCCA and CDCCA were also related with lower levels of inhibin B. Elevated FSH and depressed inhibin B have been associated with poorer sperm quality in humans. Results suggest that pyrethroid insecticides may be related with altered hormone levels in men.
Scientific abstract:
Experimental studies have reported that pyrethroid insecticides affect male endocrine and reproductive function, but human data are limited. We recruited 161 men from an infertility clinic between years 2000-2003 and measured serum reproductive and thyroid hormone levels, as well as the pyrethroid metabolites 3-phenoxybenzoic acid (3PBA) and cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DCCA and trans-DCCA) in spot urine samples. When adjusting for potential confounders, categories for all three metabolites, as well as their summed values, were positively associated with FSH (all p-values for trend <0.05). Statistically significant or suggestive positive relationships with LH were also found. In addition, cis-DCCA and trans-DCCA were inversely associated with inhibin B (p for trend = 0.03 and 0.02, respectively). Finally, there was evidence that trans-DCCA was inversely associated with testosterone and free androgen index (the ratio of testosterone to sex hormone binding globulin; p for trend = 0.09 and 0.05, respectively). The observed relationships were consistent with previous findings, but further research is needed for a better understanding of the potential association between pyrethroid insecticides and male reproduction.
Experimental animal studies have demonstrated that exposure to some phthalates may be associated with altered endocrine function and adverse effects on male reproductive development and function, but human studies are limited. In the present study, urine and serum samples were collected from 425 men recruited through a US infertility clinic. Urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP), the hydrolytic metabolite of di(2-ethylhexyl) phthalate (DEHP), and other phthalate monoester metabolites were measured, along with serum levels of testosterone, estradiol, sex hormone-binding globulin (SHBG), follicle-stimulating hormone, luteinizing hormone, inhibin B, and prolactin. Two oxidized urinary metabolites of DEHP were also measured in urine from 221 of the men. In multiple regression models adjusted for potential confounders, MEHP was inversely associated with testosterone, estradiol, and free androgen index (FAI). An interquartile range increase in MEHP was associated with 3.7% (95% confidence interval [CI], -6.8% to -0.5%) and 6.8% (95% CI, -11.2% to -2.4%) declines in testosterone and estradiol, respectively, relative to the population median hormone levels. There was limited evidence for effect modification of the inverse association between MEHP and FAI by the proportion of DEHP metabolites in the urine measured as MEHP (MEHP%), which is considered a phenotypic marker of less efficient metabolism of DEHP to its oxidized metabolites. Finally, the ratio of testosterone to estradiol was positively associated with MEHP (P = .07) and MEHP% (P = .007), suggesting potential relationships with aromatase suppression. In conclusion, these results suggest that urinary metabolites of DEHP are inversely associated with circulating steroid hormone levels in adult men. However, additional research is needed to confirm these findings.
Key Words: Adult, Chromatography, High Pressure Liquid, Diethylhexyl Phthalate/*analogs & derivatives/*urine, Enzyme-Linked Immunosorbent Assay, Estradiol/blood, Follicle Stimulating Hormone/blood, Gonadal Steroid Hormones/*blood, Humans, Inhibins/blood, Luteinizing Hormone/blood, Male, Middle Aged, Prolactin/blood, Sex Hormone-Binding Globulin/analysis, Tandem Mass Spectrometry, Testosterone/blood
BACKGROUND: Rates of preterm birth have been rising over the past several decades. Factors contributing to this trend remain largely unclear, and exposure to environmental contaminants may play a role. OBJECTIVE: We investigated the relationship between phthalate exposure and preterm birth. METHODS: Within a large Mexican birth cohort study, we compared third-trimester urinary phthalate metabolite concentrations in 30 women who delivered preterm (< 37 weeks of gestation) with those of 30 controls (> or = 37 weeks of gestation). RESULTS: Concentrations of most of the metabolites were similar to those reported among U.S. females, although in the present study mono-n-butyl phthalate (MBP) concentrations were higher and monobenzyl phthalate (MBzP) concentrations lower. In a crude comparison before correcting for urinary dilution, geometric mean urinary concentrations were higher for the phthalate metabolites MBP, MBzP, mono(3-carboxylpropyl) phthalate, and four metabolites of di(2-ethyl-hexyl) phthalate among women who subsequently delivered preterm. These differences remained, but were somewhat lessened, after correction by specific gravity or creatinine. In multivariate logistic regression analysis adjusted for potential confounders, elevated odds of having phthalate metabolite concentrations above the median level were found. CONCLUSIONS: We found that phthalate exposure is prevalent among this group of pregnant women in Mexico and that some phthalates may be associated with preterm birth.
BACKGROUND: Rates of preterm birth have been rising over the past several decades. Factors contributing to this trend remain largely unclear, and exposure to environmental contaminants may play a role. OBJECTIVE: We investigated the relationship between phthalate exposure and preterm birth. METHODS: Within a large Mexican birth cohort study, we compared third-trimester urinary phthalate metabolite concentrations in 30 women who delivered preterm (< 37 weeks of gestation) with those of 30 controls (> or = 37 weeks of gestation). RESULTS: Concentrations of most of the metabolites were similar to those reported among U.S. females, although in the present study mono-n-butyl phthalate (MBP) concentrations were higher and monobenzyl phthalate (MBzP) concentrations lower. In a crude comparison before correcting for urinary dilution, geometric mean urinary concentrations were higher for the phthalate metabolites MBP, MBzP, mono(3-carboxylpropyl) phthalate, and four metabolites of di(2-ethyl-hexyl) phthalate among women who subsequently delivered preterm. These differences remained, but were somewhat lessened, after correction by specific gravity or creatinine. In multivariate logistic regression analysis adjusted for potential confounders, elevated odds of having phthalate metabolite concentrations above the median level were found. CONCLUSIONS: We found that phthalate exposure is prevalent among this group of pregnant women in Mexico and that some phthalates may be associated with preterm birth.
Meeker JD, Johnson PI, Camann D, Hauser R. Polybrominated diphenyl ether (PBDE) concentrations in house dust are related to hormone levels in men. Sci Total Environ. 2009 May;407(10):3425-9.
Despite documented widespread human exposure to polybrominated diphenyl ethers (PBDEs) through dietary intake and contact with or inhalation of indoor dust, along with growing laboratory evidence for altered endocrine function following exposure, human studies of PBDE exposure and endocrine effects remain limited. We conducted a preliminary study within an ongoing study on the impact of environmental exposures on male reproductive health. We measured serum hormone levels and PBDE concentrations (BDE 47, 99 and 100) in house dust from 24 men recruited through a US infertility clinic. BDE 47 and 99 were detected in 100% of dust samples, and BDE 100 was detected in 67% of dust samples, at concentrations similar to those reported in previous US studies. In multivariable regression models adjusted for age and BMI, there was a statistically significant inverse relationship between dust PBDE concentrations and free androgen index. Dust PBDE concentrations were also strongly and inversely associated with luteinizing hormone (LH) and follicle stimulating hormone (FSH), and positively associated with inhibin B and sex hormone binding globulin (SHBG). Finally, consistent with limited recent human studies of adults, PBDEs were positively associated with free T4. In conclusion, the present study provides compelling evidence of altered hormone levels in relation to PBDE exposures estimated as concentrations in house dust, and that house dust is an important source of human PBDE exposure, but more research is urgently needed.
Messaros BM, Rossano MG, Liu G, Diamond MP, Friderici K, Nummy-Jernigan K, Daly D, Puscheck E, Paneth N, Wirth JJ. Negative effects of serum p,p'-DDE on sperm parameters and modification by genetic polymorphisms. Environ Res. 2009 May;109(4):457-64.
Study Synopsis: DDT was banned by the U.S. Environmental Protection Agency (EPA) in the 1970s and has now been banned internationally except to control insects that carry diseases such as malaria. In this study, researchers measured the concentration of DDE, DDT's main breakdown product, in the blood of 336 men presenting to one of two infertility clinics. Men with higher blood levels of DDE were more likely to have semen with low sperm concentration, reduced sperm motility and abnormal sperm morphology. Susceptibility to the effects of DDE on semen quality was modulated by two genes (GSTT1 and CYP1A1). These results suggest that exposure to DDE may be related to poorer semen quality and that susceptibility to this effect may be affected by genotype.
Scientific abstract:
OBJECTIVE: Effects of ambient exposure to DDT and its metabolites (DDE-DDT) on human sperm parameters and the role of genetic polymorphisms in modifying the association were investigated. METHODS: Demographics, medical history data, blood and semen samples were obtained from the first 336 male partners of couples presenting to 2 infertility clinics. Serum was analyzed for organochlorines (OC) and DNA for polymorphisms in GSTM1, GSTT1, GSTP1 and CYP1A1. Men with each sperm parameter considered low by WHO criteria (concentration <20million/mL, motility <50%, morphology <4%) were compared to men with all normal sperm parameters in logistic regression models, controlling for sum of other OC pesticides. RESULTS: High DDE-DDT level was associated with significantly increased odds for all 3 low sperm parameters. The risk of low motility with high DDE-DDT exposure was increased in men with the GSTT1 null genotype compared to those with GSTT1 intact (odds ratio (OR)=4.19, 95% confidence interval (CI) 1.05-16.78 and OR=3.57, 1.43-8.93, respectively). Risk for low morphology in men with high DDE-DDT and one or both CYP1A1*2A alleles was lower compared to men with the common CYP1A1 alleles (OR=2.18, 0.78-6.07 vs. OR=3.45, 1.32-9.03, respectively). Similar results were obtained for men with low DDE-DDT exposure. Effects of high DDE-DDT on low sperm concentration (OR=2.53, 1.0-6.31) was unaffected by the presence of the polymorphisms. CONCLUSION: High DDE-DDT exposure adversely affected all 3 sperm parameters and its effects were exacerbated by the GSTT1 null polymorphism and by the CYP1A1 common alleles.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. Animal studies have demonstrate that BPA can mimic the female hormone estrogen. The purpose of this study was to determine whether exposure to BPA affects female sexual behavior and to investigate if such an effect may be mediated by altering the expression of receptors to which the female hormone estrogen must bind to exert its effect. Researchers injected rats daily from birth to 85 days of age with either corn oil, as a control, or BPA at one of two doses. They found that the expression one type of estrogen receptor was inhibited in two regions of the brain called the medial preoptic and ventromedial nucleus. BPA exposure also caused lower levels of proceptive behavior (i.e. behavior inciting mounting activity in the male). Results of this study thus indicate that exposure to BPA may alter sexual behavior in female rats and suggests that this effect may be mediated by affecting estrogen action in the brain.
Scientific abstract:
This study examines the effects of neonatal exposure to the endocrine disruptor bisphenol A (BPA) on the hypothalamic circuitry controlling the female sexual behaviors of adult rats. From postnatal day 1 (PND1) to PND7, pups were injected with corn oil (control) or BPA (BPA20: 20 mg/kg-d; BPA.05: 0.05 mg/kg-d) and at PND85 the rats were bilaterally ovariectomized (OVX). At PND100, OVX-rats received estradiol alone or estradiol and progesterone to evaluate estrogen-dependent gene expression in the hypothalamus and sexual behavior. In BPA-exposed females, estrogen receptor alpha (ER[alpha]) expression was down-regulated in both the medial preoptic (MPN) and ventromedial nucleus (VMHvl), while repressor of estrogen receptor activity (REA) expression was up-regulated in the VMHvl. Interestingly, BPA-exposed females displayed significantly lower levels of proceptive behavior. Our results show that BPA permanently alters the hypothalamic estrogen-dependent mechanisms that govern sexual behavior in the adult female rat.
Key Words: Bisphenol A, Sexual behavior, Hypothalamus
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. Animal studies have demonstrate that BPA can mimic the female hormone estrogen. The purpose of this study was to determine whether exposure to BPA affects female sexual behavior and to investigate if such an effect may be mediated by altering the expression of receptors to which the female hormone estrogen must bind to exert its effect. Researchers injected rats daily from birth to 85 days of age with either corn oil, as a control, or BPA at one of two doses. They found that the expression one type of estrogen receptor was inhibited in two regions of the brain called the medial preoptic and ventromedial nucleus. BPA exposure also caused lower levels of proceptive behavior Results of this study thus indicate that exposure to BPA may alter sexual behavior in female rats and suggests that this effect may be mediated by affecting estrogen action in the brain.
Scientific abstract:
This study examines the effects of neonatal exposure to the endocrine disruptor bisphenol A (BPA) on the hypothalamic circuitry controlling the female sexual behaviors of adult rats. From postnatal day 1 (PND1) to PND7, pups were injected with corn oil (control) or BPA (BPA20: 20 mg/kg-d; BPA.05: 0.05 mg/kg-d) and at PND85 the rats were bilaterally ovariectomized (OVX). At PND100, OVX-rats received estradiol alone or estradiol and progesterone to evaluate estrogen-dependent gene expression in the hypothalamus and sexual behavior. In BPA-exposed females, estrogen receptor alpha (ER[alpha]) expression was down-regulated in both the medial preoptic (MPN) and ventromedial nucleus (VMHvl), while repressor of estrogen receptor activity (REA) expression was up-regulated in the VMHvl. Interestingly, BPA-exposed females displayed significantly lower levels of proceptive behavior. Our results show that BPA permanently alters the hypothalamic estrogen-dependent mechanisms that govern sexual behavior in the adult female rat.
Key Words: Bisphenol A, Sexual behavior, Hypothalamus
Niskar AS, Needham LL, Rubin C, Turner WE, Martin CA, Patterson DG, Jr, Hasty L, Wong LY, Marcus M. Serum dioxins, polychlorinated biphenyls, and endometriosis: a case-control study in Atlanta. Chemosphere. 2009 Feb;74(7):944-9.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. Dichlorodiphenyl trichloroethylene (DDE) is the primary residue of the pesticide dichlorodiphenyl trichloroethane (DDT). DDT was banned by the U.S. Environmental Protection Agency (EPA) in the 1970s and has now been banned internationally except to control insects that carry diseases such as malaria. Finally dioxins are highly toxic industrial by-products. These chemicals are persistent and bioaccumulate in humans. In this study, researchers measured the blood concentration of dioxins, PCBs and DDE in 60 cases of endometriosis and 30 controls. No associations were found between the blood level of these chemicals and the risk of endometriosis. These results do not support the hypothesis that exposure to dioxins, PCBs or DDE is related to increased risk of endometriosis.
Scientific abstract:
Endometriosis among women of reproductive age can result in pain and infertility. The objectives of this study were to test if there is a relation between endometriosis and serum dioxin concentrations as expressed by total toxic equivalence and serum total polychlorinated biphenyl concentrations among women patients at one Atlanta reproductive medicine clinic during 1998-1999; a secondary objective was to provide exposure data for individual congeners of these chemicals and 1,1-dichloro-2,2-bis(4-chlorophenyl)ethane (p,p'-DDE) in women in Atlanta. Laparoscopy including biopsy and visualization of the peritoneal cavity, ovaries, outside of the fallopian tubes and uterus confirmed all endometriosis cases (n=60) and confirmed 30 controls without endometriosis. Other controls had an infertile partner (n=27) or ovulation problems (n=7) with no signs or symptoms of endometriosis. All serum samples were analyzed at the U.S. Centers for Disease Control and Prevention in 2003. Statistical analyses included Fisher's exact chi-square tests and logistic regression. Models were presented for the full study sample and for the subset that included all cases (n=60) and only controls (n=30) with surgical confirmation of disease-free status. Serum concentrations (lipid-adjusted and non lipid-adjusted) of analyzed exposure measures were low and similar for cases and controls and did not explain endometriosis in the study population.
Nolan LA, Nolan JM, Shofer FS, Rodway NV, Emmett EA. The relationship between birth weight, gestational age and perfluorooctanoic acid (PFOA)-contaminated public drinking water. Reprod Toxicol. 2009 Jun;27(3-4):231-8.
Study Synopsis: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA and PFOS. Residents drinking PFOA-contaminated water from the Little Hocking Water Association in Washington County, Ohio have serum PFOA levels approximately 80 times those in the general U.S. population. The aim of this study was to evaluate whether maternal exposure to PFOA was related with lower birth weight or increased rates of preterm births. Researchers estimated exposure to PFOA based on data from the Little Hocking Water Association and obtained data on pregnancy outcomes through the Ohio Department of Health. No relationship was found between exposure to PFOA and birth weight, gestational age at birth, low birth weight or preterm birth. These results do not support an association between exposure to PFOA during pregnancy and pregnancy outcomes.
Scientific abstract:
BACKGROUND: Recent studies have examined the associations between perfluorooctanoic acid (PFOA) levels in cord blood and maternal plasma with lowered birth weight and gestational age in humans; however, no study has examined these effects in a population of known high PFOA exposure. Residents drinking PFOA-contaminated water from the Little Hocking Water Association (LHWA) in Washington County, Ohio have serum PFOA levels approximately 80 times those in the general U.S. population. OBJECTIVES: To compare birth weights and gestational ages of neonates born to mothers residing in zip codes with water service provided completely, partially or not at all by the LHWA. METHODS: Multiple logistic and linear regression analyses were performed on singleton neonatal birth weight data supplied by the Ohio Department of Health to examine the associations between LHWA water service category (used as a surrogate for PFOA exposure) with mean birth weight, mean gestational age, the likelihood of low birth weight (<2500 g), and the likelihood of preterm birth (<37 completed weeks of gestation). All models were adjusted for maternal age, gestational age, sex, race and population-level socioeconomic status. RESULTS: The incidence of low birth weight, preterm birth, mean birth weight and mean gestational age of neonates did not significantly differ among water service categories. CONCLUSION: Markedly elevated PFOA exposure, as categorized by water service category, is not associated with increased risk of lowered birth weight or gestational age. This study does not confirm earlier findings of an association between PFOA and lowered birth weight observed at normal population levels.
Key Words: Adult, Birth Weight, Cohort Studies, Cross-Sectional Studies, Female, Fluorocarbons/ blood/pharmacology, Gestational Age, Humans, Infant, Low Birth Weight, Infant, Newborn, Infant, Premature, Linear Models, Male, Octanoic Acids/ blood/pharmacology, Ohio/epidemiology, Pregnancy, Sex Factors, Water Pollutants, Chemical/ toxicity, Water Supply/ analysis, Young Adult
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is commone due to their widespread use. The purpose of this study was to evaluate the hypothesis that exposure to a type of phthalate called diethylexyl pththalate, or DEHP, causes earlier puberty onset at low doses and delayed puberty at high doses. The study also aimed to determine whether exposure to DEHP affects hormones involved in puberty. Researchers thus exposed rats daily to different doses of DEHP (ranging between 0 and 900 mg/kg per day) and found that high exposure caused a delay in puberty onset while exposure at low dose had no effect. Exposure at high dose also affected cells in the testis, reduced the blood level of the male hormone testosterone and increased luteinizing hormone (LH) concentrations. No effects on the testis or hormone levels were observed at low doses. These results suggest that exposure to DEHP delays puberty in rats, possibly by reducing testosterone levels. Results however do not support the hypothesis that exposure to low doses of DEHP has an opposite effect.
Scientific abstract:
Although is clear that exposure to high dosage levels of some phthalates delays the onset of puberty in the male rat, it has been hypothesized that low levels of di(2-ethylhexyl) phthalate (DEHP) accelerate puberty by enhancing testicular androgen synthesis. The current study was designed to determine if the dose response to DEHP was nonmonotonic, as hypothesized. Pubertal administration of DEHP delayed the onset of puberty and reduced androgen-dependent tissue weights in both Long-Evans (LE) and Sprague-Dawley (SD) male rats 300 and 900 mg DEHP/kg/day. These effects were generally of greater magnitude in LE than SD rats. By contrast, alterations in testis histopathology (300 and 900 mg/kg/day) were more severe in SD than in LE rats. Taken together, these results suggest that DEHP may be acting on the pubertal male rat testis via two modes of action; one via the Leydig cells and the other via the Sertoli cells. Treatment with DEHP generally reduced serum testosterone and increased serum luteinizing hormone (LH) levels, demonstrating that the reduction in testosterone was due to the effect of DEHP on the testis and not via an inhibition of LH from hypothalamic-pituitary axis. Testosterone production ex vivo (with and without human chorionic gonadotropin stimulation) was consistently reduced in males at the time of puberty and shortly thereafter. DEHP treatment did not accelerate the age at puberty or enhance testosterone levels at 10 or 100 mg/kg/day in either LE or SD rats, as some have hypothesized. Taken together, these results do not provide any evidence of a nonmonotonic dose response to DEHP during puberty.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. The purpose of this study was to evaluate the hypothesis that exposure to a type of phthalate called diethylexyl phthalate, or DEHP, causes earlier puberty onset at low doses and delayed puberty at high doses. The study also aimed to determine whether exposure to DEHP affects hormones involved in puberty. Researchers thus exposed rats daily to different doses of DEHP (ranging between 0 and 900 mg/kg per day) and found that high exposure caused a delay in puberty onset while exposure at low dose had no effect. Exposure at high dose also affected cells in the testis, reduced the blood level of the male hormone testosterone and increased luteinizing hormone (LH) concentrations. No effects on the testis or hormone levels were observed at low doses. These results suggest that exposure to DEHP delays puberty in rats, possibly by reducing testosterone levels. Results however do not support the hypothesis that exposure to low doses of DEHP has an opposite effect.
Scientific abstract:
Although is clear that exposure to high dosage levels of some phthalates delays the onset of puberty in the male rat, it has been hypothesized that low levels of di(2-ethylhexyl) phthalate (DEHP) accelerate puberty by enhancing testicular androgen synthesis. The current study was designed to determine if the dose response to DEHP was nonmonotonic, as hypothesized. Pubertal administration of DEHP delayed the onset of puberty and reduced androgen-dependent tissue weights in both Long-Evans (LE) and Sprague-Dawley (SD) male rats 300 and 900 mg DEHP/kg/day. These effects were generally of greater magnitude in LE than SD rats. By contrast, alterations in testis histopathology (300 and 900 mg/kg/day) were more severe in SD than in LE rats. Taken together, these results suggest that DEHP may be acting on the pubertal male rat testis via two modes of action; one via the Leydig cells and the other via the Sertoli cells. Treatment with DEHP generally reduced serum testosterone and increased serum luteinizing hormone (LH) levels, demonstrating that the reduction in testosterone was due to the effect of DEHP on the testis and not via an inhibition of LH from hypothalamic-pituitary axis. Testosterone production ex vivo (with and without human chorionic gonadotropin stimulation) was consistently reduced in males at the time of puberty and shortly thereafter. DEHP treatment did not accelerate the age at puberty or enhance testosterone levels at 10 or 100 mg/kg/day in either LE or SD rats, as some have hypothesized. Taken together, these results do not provide any evidence of a nonmonotonic dose response to DEHP during puberty.
Study Synopsis: In this study, researchers injected mice with cadmium chloride and evaluated whether semen quality was affected 24 hours and 35 days later. The short-term effects of cadmium chloride exposure included an increased proportion of sperm with abnormal morphology and with reduced motility. A sharp reduction in the number of sperm cells and sperm motility as well as an increase in DNA fragmentation was observed 35 days after exposure. These results suggest that acute exposure to a high dose of cadmium chloride affects semen quality in mice.
Scientific abstract:
The effects of cadmium chloride exposure on sperm functional parameters were evaluated on eight-week-old ICR-CD1 male mice administered with a single s.c. injection of 1, 2 and 3 mg CdCl2/kg bw. Groups of animals treated with each dose, as well as their respective controls, were sacrificed after 24 h to detect short-term (acute) effects and after 35 days. Sperm cells were collected from the epididymis and several parameters of sperm quality and function were evaluated, namely density, morphology, motility, viability, mitochondrial function, acrosome integrity, together with DNA fragmentation assessed by the TUNEL assay. The short-term effects of cadmium chloride resulted in an increased fraction of sperm with abnormal morphology, premature acrosome reaction and reduced motility. Late term effects (after 35 days) included a drastic reduction of sperm cell numbers and sperm motility. An increase in DNA fragmentation was also detected.
Study Synopsis: Cadmium is a heavy metal widely used in industry in smelting, battery manufacturing, pigment and plastic production. In the general population, tobacco smoke is one of the most common source of exposure. In this study, researchers injected mice with cadmium chloride and evaluated whether semen quality was affected 24 hours and 35 days later. The short-term effects of cadmium chloride exposure included an increased proportion of sperm with abnormal morphology and with reduced motility. A sharp reduction in the number of sperm cells and sperm motility as well as an increase in DNA fragmentation was observed 35 days after exposure. These results suggest that acute exposure to a high dose of cadmium chloride affects semen quality in mice.
Scientific abstract:
The effects of cadmium chloride exposure on sperm functional parameters were evaluated on eight-week-old ICR-CD1 male mice administered with a single s.c. injection of 1, 2 and 3 mg CdCl2/kg bw. Groups of animals treated with each dose, as well as their respective controls, were sacrificed after 24 h to detect short-term (acute) effects and after 35 days. Sperm cells were collected from the epididymis and several parameters of sperm quality and function were evaluated, namely density, morphology, motility, viability, mitochondrial function, acrosome integrity, together with DNA fragmentation assessed by the TUNEL assay. The short-term effects of cadmium chloride resulted in an increased fraction of sperm with abnormal morphology, premature acrosome reaction and reduced motility. Late term effects (after 35 days) included a drastic reduction of sperm cell numbers and sperm motility. An increase in DNA fragmentation was also detected.
Study Synopsis: Hypospadias is a congenital anomaly characterized by the abnormal location of the urethra opening in males. Researchers conducted interviews regarding diet and folate supplementation during pregnancy as well as occupation with the mothers of 471 cases of hypospadias and of 490 healty controls. Occupational exposures were estimated based on published studies. Exposure to hair spray was associated with a doubling of the risk of hypospadias while mothers exposed to phthalates at work had 3 times the risk of giving birth to a boy with hypospadias. Folate supplementation during pregnancy was however related with a 56% reduction in the risk of hypospadias. Vegetarians did not have reduced risks of having a son with hypospadias. Results suggest that maternal exposure to hair spray and phthalates may increase the risk of hypospadias while folate supplementation may be protective. Exposure was however not directly measured. Results must therefore be interpreted with caution.
Scientific abstract:
Background: Hypospadias is one of the most common urogenital congenital anomalies affecting baby boys. Prevalence estimates in Europe range from 4 to 24 per 10,000 births, depending on definition, with higher rates reported from the United States. Relatively little is known about potential risk factors, but a role for endocrine-disrupting chemicals (EDCs) has been proposed. Objective: Our goal was to elucidate the risk of hypospadias associated with occupational exposure of the mother to endocrine-disruptor chemicals, use of folate supplementation during pregnancy, and vegetarianism. Design: We designed a casecontrol study of 471 hypospadias cases referred to surgeons and 490 randomly selected birth controls, born 1 January 199730 September 1998 in southeast England. Telephone interviews of mothers elicited information on folate supplementation during pregnancy and vegetarianism. We used a job exposure matrix to classify occupational exposure. Results: In multiple logistic regression analysis, there were increased risks for self-reported occupational exposure to hair spray [exposed vs. nonexposed, odds ratio (OR) = 2.39 ; 95% confidence interval (CI) , 1.404.17] and phthalate exposure obtained by a job exposure matrix (OR = 3.12 ; 95% CI, 1.0411.46) . There was a significantly reduced risk of hypospadias associated with of folate use during the first 3 months of pregnancy (OR = 0.64 ; 95% CI, 0.440.93) . Vegetarianism was not associated with hypospadias risk. Conclusions: Excess risks of hypospadias associated with occupational exposures to phthalates and hair spray suggest that antiandrogenic EDCs may play a role in hypospadias. Folate supplementation in early pregnancy may be protective.
BACKGROUND: Hypospadias is one of the most common urogenital congenital anomalies affecting baby boys. Prevalence estimates in Europe range from 4 to 24 per 10,000 births, depending on definition, with higher rates reported from the United States. Relatively little is known about potential risk factors, but a role for endocrine-disrupting chemicals (EDCs) has been proposed. OBJECTIVE: Our goal was to elucidate the risk of hypospadias associated with occupational exposure of the mother to endocrine-disruptor chemicals, use of folate supplementation during pregnancy, and vegetarianism. DESIGN: We designed a case-control study of 471 hypospadias cases referred to surgeons and 490 randomly selected birth controls, born 1 January 1997-30 September 1998 in southeast England. Telephone interviews of mothers elicited information on folate supplementation during pregnancy and vegetarianism. We used a job exposure matrix to classify occupational exposure. RESULTS: In multiple logistic regression analysis, there were increased risks for self-reported occupational exposure to hair spray [exposed vs. nonexposed, odds ratio (OR) = 2.39; 95% confidence interval (CI), 1.40-4.17] and phthalate exposure obtained by a job exposure matrix (OR = 3.12; 95% CI, 1.04-11.46). There was a significantly reduced risk of hypospadias associated with of folate use during the first 3 months of pregnancy (OR = 0.64; 95% CI, 0.44-0.93). Vegetarianism was not associated with hypospadias risk. CONCLUSIONS: Excess risks of hypospadias associated with occupational exposures to phthalates and hair spray suggest that antiandrogenic EDCs may play a role in hypospadias. Folate supplementation in early pregnancy may be protective.
BACKGROUND: Hypospadias is one of the most common urogenital congenital anomalies affecting baby boys. Prevalence estimates in Europe range from 4 to 24 per 10,000 births, depending on definition, with higher rates reported from the United States. Relatively little is known about potential risk factors, but a role for endocrine-disrupting chemicals (EDCs) has been proposed. OBJECTIVE: Our goal was to elucidate the risk of hypospadias associated with occupational exposure of the mother to endocrine-disruptor chemicals, use of folate supplementation during pregnancy, and vegetarianism. DESIGN: We designed a case-control study of 471 hypospadias cases referred to surgeons and 490 randomly selected birth controls, born 1 January 1997-30 September 1998 in southeast England. Telephone interviews of mothers elicited information on folate supplementation during pregnancy and vegetarianism. We used a job exposure matrix to classify occupational exposure. RESULTS: In multiple logistic regression analysis, there were increased risks for self-reported occupational exposure to hair spray [exposed vs. nonexposed, odds ratio (OR) = 2.39; 95% confidence interval (CI), 1.40-4.17] and phthalate exposure obtained by a job exposure matrix (OR = 3.12; 95% CI, 1.04-11.46). There was a significantly reduced risk of hypospadias associated with of folate use during the first 3 months of pregnancy (OR = 0.64; 95% CI, 0.44-0.93). Vegetarianism was not associated with hypospadias risk. CONCLUSIONS: Excess risks of hypospadias associated with occupational exposures to phthalates and hair spray suggest that antiandrogenic EDCs may play a role in hypospadias. Folate supplementation in early pregnancy may be protective.
Study Synopsis: Atrazine is a widely used herbicide to control broadleaf and grassy weeds in major crops. In this study, researchers exposed male rats to oral doses of atrazine and examined the expression of several genes involved in the synthesis of the male hormone testosterone and other androgens. They found that exposure caused a significant reduction in androgen synthesis and an inhibition of the expression of the luteinizing hormone receptor (LHR) gene in testis cells. Results suggest that exposure to atrazine affects androgen synthesis by the testis and that this effect may be caused by a reduction in LHR gene expression.
Scientific abstract:
In the present study, we investigated the effects of oral dosing of atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) to peripubertal male rats (50 and 200 mg/kg body weight daily from postnatal days 23-50) on ex vivo Leydig cell steroidogenesis. Leydig cells from treated rats were characterised by significant decline in mRNA transcripts of several genes responsible for steroidogenesis: luteinizing hormone receptor (LHR), scavenger receptor-B1, steroidogenic acute regulatory protein, translocator protein, steroidogenic factor-1, phosphodiesterase 4B, 3{beta}-hydroxysteroid dehydrogenase (HSD), CYP17A1, and 17{beta}HSD. In the presence of human chorion gonadotropin, the dose-dependent decrease in extracellular cAMP level and accordingly strong inhibition of androgenesis were obtained. The transcription of LHR gene in Leydig cells of atrazine-treated rats was downregulated in a dose-dependent manner, which could be the reason for reduction in cAMP level and expression of cAMP-dependent genes. To clarify the activity of the steroidogenic enzymes responsible for androgenesis, purified Leydig cells were challenged with different steroid substrates (22OH-cholesterol, pregnenolone, progesterone, and {Delta}4-androstenedione), and the obtained results indicated inhibition of androgen production in Leydig cells isolated from atrazine-treated animals in the presence of all those substrates. However, when Leydig cells were challenged with 22OH-cholesterol, the progesterone level in the incubation medium was unchanged, indicating that decrease in cholesterol transport and/or CYP17A1 and 17{beta}HSD activity are most probably responsible for inhibition of androgen production after the addition of different substrates. Our results demonstrated that in vivo exposure to atrazine affects Leydig cell steroidogenesis via the inhibition of steroidogenesis gene expression, which is accompanied by decreased androgenesis.
Study Synopsis: Arsenic is a groundwater contaminant that may occur naturally or as the result of agricultural and industrial practices. Human studies suggest that exposure to arsenic may be related with developmental defects. In this study, researchers estimated prenatal exposure by measuring arsenic in urine samples collected from 1,578 pregnant women. They found no associations between exposure to arsenic and weight, length, head circumference or chest circumference at birth over the full range of exposure. However, higher exposure to arsenic was associated with smaller head and chest circumference when analyses were limited to infant with low arsenic exposure. These findings at low but not high exposure to arsenic warrant further investigation.
Scientific abstract:
The authors evaluated the association of prenatal arsenic exposure with size at birth (birth weight, birth length, head and chest circumferences). This prospective cohort study, based on 1,578 mother-infant pairs, was conducted in Matlab, Bangladesh, in 2002-2003. Arsenic exposure was assessed by analysis of arsenic in urine collected at around gestational weeks 8 and 30. The association of arsenic exposure with size at birth was assessed by linear regression analyses. In analysis over the full range of exposure (6-978 {micro}g/L), no dose-effect association was found with birth size. However, significant negative dose effects were found with birth weight and head and chest circumferences at a low level of arsenic exposure (<100 {micro}g/L in urine). In this range of exposure, birth weight decreased by 1.68 (standard error (SE), 0.62) g for each 1-{micro}g/L increase of arsenic in urine. For head and chest circumferences, the corresponding reductions were 0.05 (SE, 0.03) mm and 0.14 (SE, 0.03) mm per 1 {micro}g/L, respectively. No further negative effects were shown at higher levels of arsenic exposure. The indicated negative effect on birth size at a low level of arsenic exposure warrants further investigation.
Study Synopsis: The purpose of this study was to investigate whether exposure to black smoke and sulphur dioxide (SO2) during pregnancy was related to an increased risk of congenital anomalies. Exposure data from cases and controls was obtained from ambient air monitoring stations. Daily readings from all monitors within 10 km of the mothers' residences were averaged to estimate exposure during the first trimester of pregnancy. A small increase in risk of nervous system anomalies was observed in relation with exposure to black smoke. Exposure to SO2 appeared to reduce the risk of congenital heart disease. Other anomalies were not clearly associated with the exposures under study. These results provide little support for associations between maternal exposure to black smoke or SO2 and an increased risk of congenital anomalies.
Scientific abstract:
Studies have suggested an association between maternal exposure to ambient air pollution and risk of congenital anomaly. The aim of this study is to investigate the association between exposure to black smoke (BS; particulate matter with aerodynamic diameter <4 microg/m(3)) and sulphur dioxide (SO(2)) during the first trimester of pregnancy and risk of congenital anomalies. We used a case-control study design among deliveries to mothers resident in the UK Northern health region during 1985-1990. Case data were ascertained from the population-based Northern Congenital Abnormality Survey and control data from national data on all births. Data on BS and SO(2) from ambient air monitoring stations were used to average the total pollutant exposure during the first trimester of pregnancy over the daily readings from all monitors within 10 km of the mother's residence. Logistic regression models estimated the association via odds ratios. A significant but weak positive association was found between nervous system anomalies and BS (OR=1.10 per increase of 1000 microg/m(3) total BS; 95% CI: 1.03, 1.18), but not with other anomaly subtypes. For SO(2), a significant negative association was found with congenital heart disease combined and patent ductus arteriosus: OR significantly <1 for all quartiles relative to the first quartile. The relationship between SO(2) levels and other anomaly subtypes was less clear cut: there were either no significant associations or a suggestion of a U-shaped relationship (OR significantly <1 for moderate compared to lowest levels, but not with high SO(2) levels). Overall, maternal exposure to BS and SO(2) in the Northern region had limited impact on congenital anomaly risk. Studies with detailed exposure assessment are needed to further investigate this relationship.
Study Synopsis: While some metals (such as zinc, copper and molybdenum) are important to human health, others (such as cadmium and lead) are considered nonessential. Too high an intake of most of these metals may adversely affect health. Research suggest that maternal exposure to cadmium may affect birth weight but the mechanism of toxicity is not well defined. The purpose of this study was to test the hypothesis that cadmium may lower birthweight by affecting glucocorticoids, such as corticosterone. Researchers thus exposed pregnant rats to cadmium through drinking water and measured the level of corticosterone and cadmium in maternal and fetal blood as well as in placental tissues at delivery. Exposure resulted in decreased birth weights and increased cadmium levels in maternal blood but not in fetal blood. In addition, blood corticosterone levels were increased both in maternal and fetal blood. Results indicate that exposure to cadmium affects birth weight and offer some support to the hypothesis that this effect may be related to increased fetal and/or maternal corticosterone levels.
Scientific abstract:
Cadmium exposure induces low birth weight through unknown mechanisms. Since low birth weight is associated to foetal exposure to high glucocorticoids (GC) concentrations, we hypothesized that low birth weight induced by prenatal exposure to Cd(2+) is, at least in part, mediated by higher foetal exposure to GC, specifically corticosterone, the main active GC in rodents. Pregnant rats were exposed to different dose of CdCl(2) administered in drinking water during the whole pregnancy period. At term, corticosterone was measured by enzyme immunoassay in maternal and foetal blood and in placental tissues. Cadmium was determined in placentas, maternal tissues (liver and kidney) and foetuses by inductively coupled plasma-mass spectrometry (ICP-MS). Placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity and expression were determined by a radiometric conversion assay and quantitative RT-PCR respectively. Results demonstrated that 50 ppm of Cd(2+), which was accumulated in different maternal tissues but not in the foetus, reduced pup birth weights and increased plasma corticosterone concentrations, both in mother and foetus. Placental 11beta-HSD2 activity and expression did not change by the treatment. We conclude that 50 ppm of Cd(2+) administered during pregnancy, increase foetal corticosterone concentrations due, probably, to alterations of the regulatory mechanisms of placental barrier to GC causing a mild but significant reduced birth weight.
BACKGROUND: Organohalogen compounds (OHCs) are known to have neurotoxic effects on the developing brain. OBJECTIVE: We investigated the influence of prenatal exposure to OHCs, including brominated flame retardants, on motor, cognitive, and behavioral outcome in healthy children of school age. METHODS: This study was part of the prospective Groningen infant COMPARE (Comparison of Exposure-Effect Pathways to Improve the Assessment of Human Health Risks of Complex Environmental Mixtures of Organohalogens) study. It included 62 children in whose mothers the following compounds had been determined in the 35th week of pregnancy: 2,2'-bis-(4 chlorophenyl)-1,1'-dichloroethene, pentachlorophenol (PCP), polychlorinated biphenyl congener 153 (PCB-153), 4-hydroxy-2,3,3',4',5-pentachlorobiphenyl (4OH-CB-107), 4OH-CB-146, 4OH-CB-187, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), BDE-99, BDE-100, BDE-153, BDE-154, and hexabromocyclododecane. Thyroid hormones were determined in umbilical cord blood. When the children were 5-6 years of age, we assessed their neuropsychological functioning: motor performance (coordination, fine motor skills), cognition (intelligence, visual perception, visuomotor integration, inhibitory control, verbal memory, and attention), and behavior. RESULTS: Brominated flame retardants correlated with worse fine manipulative abilities, worse attention, better coordination, better visual perception, and better behavior. Chlorinated OHCs correlated with less choreiform dyskinesia. Hydroxylated polychlorinated biphenyls correlated with worse fine manipulative abilities, better attention, and better visual perception. The wood protective agent (PCP) correlated with worse coordination, less sensory integrity, worse attention, and worse visuomotor integration. CONCLUSIONS: Our results demonstrate for the first time that transplacental transfer of polybrominated flame retardants is associated with the development of children at school age. Because of the widespread use of these compounds, especially in the United States, where concentrations in the environment are four times higher than in Europe, these results cause serious concern.
Study Synopsis: This paper reviews the literature on chemicals formerly or currently used in building materials, furnishing and consumer products found to affect hormone levels or interfere with their action. These include PCBs, chlorinated and brominated flame retardants, pesticides, phthalates, alkylphenols and parabens. Authors summarize reported indoor and outdoor air concentrations, chemical use and sources, and toxicity data for each of these chemical classes.
Scientific abstract:
The past 50 years have seen rapid development of new building materials, furnishings, and consumer products and a corresponding explosion in new chemicals in the built environment. While exposure levels are largely undocumented, they are likely to have increased as a wider variety of chemicals came into use, people began spending more time indoors, and air exchange rates decreased to improve energy efficiency. As a result of weak regulatory requirements for chemical safety testing, only limited toxicity data are available for these chemicals. Over the past 15 years, some chemical classes commonly used in building materials, furnishings, and consumer products have been shown to be endocrine disrupting chemicals - that is they interfere with the action of endogenous hormones. These include PCBs, used in electrical equipment, caulking, paints and surface coatings; chlorinated and brominated flame retardants, used in electronics, furniture, and textiles; pesticides, used to control insects, weeds, and other pests in agriculture, lawn maintenance, and the built environment; phthalates, used in vinyl, plastics, fragrances, and other products; alkylphenols, used in detergents, pesticide formulations, and polystyrene plastics; and parabens, used to preserve products like lotions and sunscreens. This paper summarizes reported indoor and outdoor air concentrations, chemical use and sources, and toxicity data for each of these chemical classes. While industrial and transportation-related pollutants have been shown to migrate indoors from outdoor sources, it is expected that indoor sources predominate for these consumer product chemicals; and some studies have identified indoor sources as the predominant factor influencing outdoor ambient air concentrations in densely populated areas. Mechanisms of action, adverse effects, and dose-response relationships for many of these chemicals are poorly understood and no systematic screening of common chemicals for endocrine disrupting effects is currently underway, so questions remain as to the health impacts of these exposures.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. In this study, researchers gavaged pregnant rats with BPA during pregnancy and lactation and then mated their male offspring with unexposed females. They found that rats prenatally exposed to BPA had more post implantation losses, smaller litter sizes, lower sperm count and altered sperm motility. A reduction in the expression of steroid receptors, essential for the normal activity of reproductive hormones, was also detected in the testicles of both the first, second and third generations. Results suggest that pre- and early postnatal exposure to BPA may affect male fertility in rats and that this effect may extend for multiple generations.
Scientific abstract:
AIMS: The exposure to endocrine disruptor (ED) induces functional and behavioral abnormalities associated with reproduction. Humans are ubiquitously exposed to Bisphenol A (BPA), an ED, as it leaches from polycarbonate plastics into their contents. The aim of the present study was to determine the effect of perinatal exposure of male rats to BPA on fertility parameters and perturbations in the expression of testicular steroid receptors (SRs) in adult F(1) offspring. These effects were studied in adult males of the F(2) and F(3) generations to determine the vertical transmission of BPA exposure. MAIN METHODS: Pregnant female rats (F(0)) were gavaged with either BPA (1.2 and 2.4 microg/kg bw), a vehicle control or positive control with Diethylstilbestrol (10 microg/kg bw) during the perinatal period. Adult F(1) males were subjected to fertility assessment by mating with unexposed females. The reproductive functions of the subsequent F(2) and F(3) litters were investigated in a similar manner. Immunohistochemical localization of SRs was carried out in the testes of F(1), F(2) and F(3) generation adult rats. KEY FINDINGS: A significant increase in post implantation loss and a decrease in litter size and sperm count and motility were observed in the F(1) male offspring. A reduction in the testicular expression profile of SRs was observed. These effects were very prominent in the subsequent F(2) and F(3) generations. SIGNIFICANCE: Perinatal exposure to environmentally relevant doses of BPA affects the male germ line, leading to impairments in the fertility of F(1) male offspring and their subsequent F(2) and F(3) generations.
Study Synopsis: Perfluorooctanoic acid (PFOA) is a highly persistent water and oil repellent used in products such as Teflon, Scotchguard and Gore-Tex. It has been measured in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA. Though a number of studies suggest that exposure to high doses of PFOA affects the male reproductive system in rats, little is known about the health effects of perfluorododecanoic acid (PFDoA), one of PFOA's breakdown product. In this study, researchers exposed male rats daily to PFDoA over a period of 110 days. They found that exposure caused a marked decrease in the blood levels of the male hormone testosterone and a reduction of key proteins, enzymes, growth factors and receptors. Results suggest that chronic exposure to high doses of PFDoA may affect the synthesis of testosterone in male rats.
Scientific abstract:
Perfluorododecanoic acid (PFDoA), a synthetic perfluorinated chemical, has been detected in environmental matrices, wildlife, and human serum. Its potential health risk for humans and animals has raised public concern. However, the effects of chronic PFDoA exposure on male reproduction remain unknown. The aim of this study was to determine the effects of chronic PFDoA exposure (110 days) on testosterone biosynthesis and the expression of genes related to steroidogenesis in male rats. In this study, we examined the serum levels of sex hormones, growth hormone, and insulin in male rats. Testicular morphology and the expression of key genes and proteins in testosterone biosynthesis were also analyzed. Markedly decreased serum testosterone levels were recorded after 110 days of PFDoA exposure at 0.2mg PFDoA/kg/day and 0.5mg PFDoA/kg/day, and cast-off cells were observed in some seminiferous tubules in testes exposed to 0.5mg PFDoA/kg/day. PFDoA exposure resulted in significantly decreased protein levels of steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), along with significantly reduced mRNA levels of insulin-like growth factor I (IGF-I), insulin-like growth factor I receptor (IGF-IR), and interleukin 1alpha (IL-1alpha) in rat testes at 0.2mg/kg/day and 0.5mg/kg/day. In addition, PFDoA exposure also affected the expression of some genes in the hypothalamo-neurohypophyseal system. However, PFDoA did not affect the expression of 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase, or aromatase in testis and liver. These findings demonstrate that chronic PFDoA exposure disrupts testicular steroidogenesis and expression of related genes in male rats. Multiple factors may be involved in the inhibition of testosterone by PFDoA.
BACKGROUND: The upward trend in industrial nations in the incidence of male genitourinary (GU) conditions may be attributed to increased exposure to endocrine disruptors. Polybrominated biphenyl (PBB), a brominated flame retardant, is one such suspected endocrine disruptor. OBJECTIVE: We investigated the relationship between maternal serum levels of PBBs and GU conditions among male offspring exposed in utero. METHODS: In this cohort study of sons born to women accidentally exposed to PBBs during 1973-1974, we examined self-reported data on GU conditions among male offspring in relation to maternal serum PBB levels. We used generalized estimating equations to calculate odds ratios (ORs), controlling for gestational age at birth. RESULTS: Of 464 sons, 33 reported any GU condition (13 hernias, 10 hydroceles, 9 cryptorchidism, 5 hypospadias, and 1 varicocele). Four reported both hernia and hydrocele, and one both hernia and cryptorchidism. After adjustment for gestational age at birth, sons of highly exposed women (> 5 ppb) were twice as likely to report any GU condition compared with sons of the least exposed women [< or =1 ppb; OR = 2.0; 95% confidence interval (CI), 0.8-5.1]. This risk was increased when we excluded sons born after the exposure but before the mother's serum PBB measurement (OR = 3.1; 95% CI, 1.0-9.1). We found evidence of a 3-fold increase in reported hernia or hydrocele among sons with higher PBB exposure (test of trend p-value = 0.04). Neither hypospadias nor cryptorchidism was individually associated with PBB exposure. CONCLUSIONS: Although cryptorchidism and hypospadias were not associated with in utero PBB exposure, this study suggests that other GU conditions may be associated with exposure to endocrine-disrupting chemicals during development.
Stein CR, Savitz DA, Dougan M. Serum levels of perfluorooctanoic acid and perfluorooctane sulfonate and pregnancy outcome. Am J Epidemiol. 2009 Oct;170(7):837-46.
The authors examined the association of serum perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with self-reported pregnancy outcome in Mid-Ohio Valley residents (2000-2006) highly exposed to PFOA. Data on 1,845 pregnancies within the 5 years preceding exposure measurement were analyzed for PFOA, and data on 5,262 pregnancies were analyzed for PFOS. Generalized estimating equations were used to calculate adjusted odds ratios and 95% confidence intervals. Neither PFOA nor PFOS showed any association with miscarriage or preterm birth. Preeclampsia was weakly associated with PFOA (adjusted odds ratio = 1.3, 95% confidence interval: 0.9, 1.9) and PFOS (adjusted odds ratio = 1.3, 95% confidence interval: 1.1, 1.7) exposures above the median. PFOA was not associated with an increase in low birth weight, but PFOS showed an increased risk above the median (adjusted odds ratio = 1.5, 95% confidence interval: 1.1, 1.9) and a dose-response gradient. Birth defects were weakly associated with PFOA exposures above the 90th percentile (adjusted odds ratio = 1.7, 95% confidence interval: 0.8, 3.6). This study identified modest associations of PFOA with preeclampsia and birth defects and of PFOS with preeclampsia and low birth weight, but associations were small, limited in precision, and based solely on self-reported health outcomes.
Van Der Ven LT, Van De Kuil T, Leonards PE, Slob W, Lilienthal H, Litens S, Herlin M, Hakansson H, Canton RF, Van Den Berg M, Visser TJ, Van Loveren H, Vos JG, Piersma AH. Endocrine effects of hexabromocyclododecane (HBCD) in a one-generation reproduction study in Wistar rats. Toxicol Lett. 2009 Feb;185(1):51-62.
Study Synopsis: Hexabromocyclododecane (HBCD) is a flame retardant used in polystyrene insulation and textiles. Although a growing number of studies have examined the potential health effects of other flame retardants, such as polybrominated diphenyl ethers (PBDEs), few studies have examined the effect of exposure to HBCD. In this study, male and female rats were exposed to HBCD through their feed before mating and, for females, during gestation and lactation. Exposure resulted in reduced bone density in female offspring and decreased testis weight in male offspring. The immune system of male offspring also appeared to be affected by exposure to HBCD. Results suggest that prenatal exposure to HBCD may affect bone density, testis weight and the immune system in rats.
Scientific abstract:
The brominated flame retardant (BFR) hexabromocyclododecane was tested in a one-generation reproduction assay in Wistar rats, enhanced for endocrine parameters. A solution of the compound in corn oil was mixed in the feed, targeting at dietary exposure of 0-0.1-0.3-1-3-10-30-100 mg/kg body weight/day (mkd) in parental rats during 10 (males) or 2 (females) weeks premating, during gestation and lactation, and in their F1 offspring from weaning until final necropsy. Effects were assessed in F1 animals. Livers of these animals showed increased HBCD concentrations, in a dose-dependent way. The trabecular bone mineral density of the tibia was dose-dependently decreased in females (BenchMark Dose Lower confidence bound, BMDL=0.056 mkd). The IgG response after immunization with sheep red blood cells (SRBC) was increased in males (BMDL=0.46 mkd). Further sensitive effects were decreased weight of the testis (BMDL=1.5 mkd), increased fraction of neutrophilic granulocytes (BMDL=7.7 mkd), decreased concentration of apolar retinoids in female livers (BMDL=1.3 mkd), and decreased plasma alkaline phosphatase in females (BMDL=8.6 mkd). CYP19/aromatase activity in the ovary was correlated to the concentration of gamma-HBCD in the liver. A developmental origin of these effects is considered, and this is also true for sensitive effects observed in neurobehavioural testing in littermates from the same experiment, i.e. in the brainstem auditory evoked potentials and in a catalepsy test [Lilienthal, H., Van der Ven, L.T.M., Piersma, A.H., Vos, J.G. Neurobehavioral effects of the brominated flame retardant hexabromocyclododecane (HBCD) in rats after pre- and postnatal exposure, in press]. The low BMDLs of these effects may raise concern for human health, particularly when based on body burdens of HBCD, which leads to critical margins of exposure particularly for the occupational setting.
Key Words: Animals, Body Burden, Body Weight/drug effects, Dose-Response Relationship, Drug, Eating/drug effects, Endocrine Disruptors/ toxicity, Female, Fetus/ drug effects, Flame Retardants/ toxicity, Gonadal Steroid Hormones/physiology, Hydrocarbons, Brominated/ toxicity, Immune System/drug effects, Liver/drug effects/metabolism, Male, Organ Size/drug effects, Pregnancy, Rats, Reproduction/ drug effects, Retinoids/metabolism, Spermatozoa/drug effects
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured diethylhexyl phthalate (DEHP) in air samples and four DEHP breakdown products in the urine of 311 pregnant women. Air levels of DEHP were weakly related with shorter gestational duration. Women with higher urine levels of the breakdown product monoethylhexyl phthalate (MEHP) had gestational durations that were 5 days shorter on average. Results were similar for other DEHP breakdown products. Findings suggest that exposure to DEHP is associated with shortened gestation duration.
Scientific abstract:
OBJECTIVE: Our objective was to assess the relationship between di(2-ethylhexyl)phthalate (DEHP) exposure during pregnancy and gestational age at delivery among 311 African American or Dominican women from New York City. METHODS: Forty-eight-hour personal air and/or spot urine samples were collected during the third trimester. DEHP levels were measured in air samples and 4 DEHP metabolite levels were measured in urine. Specific gravity was used to adjust for urinary dilution. Gestational age was abstracted from newborn medical records (n = 289) or calculated from the expected date of delivery (n = 42). Multivariate linear regression models controlled for potential confounders. RESULTS: DEHP was detected in 100% of personal air samples (geometric mean: 0.20 microg/m(3) [95% confidence interval [CI]: 0.18-0.21 microg/m(3)]); natural logarithms of air concentrations were inversely but not significantly associated with gestational age. Two or more of the DEHP metabolites were detected in 100% of urine samples (geometric mean: 4.8-38.9 ng/mL [95% CI: 4.1-44.3 ng/mL]). Controlling for potential confounders, gestational age was shorter by 1.1 days (95% CI: 0.2-1.8 days) for each 1-logarithmic unit increase in specific gravity-adjusted mono(2-ethylhexyl)phthalate concentrations (P = .01) and averaged 5.0 days (95% CI: 2.1-8.0 days) less among subjects with the highest versus lowest quartile concentrations (P = .001). Results were similar and statistically significant for the other DEHP metabolites. CONCLUSIONS: Prenatal DEHP exposure was associated with shorter gestation but, given inconsistencies with previous findings for other study populations, results should be interpreted with caution, and additional research is warranted.
BACKGROUND: Limited studies have suggested that male reproductive function might be associated with exposure to polycyclic aromatic hydrocarbons (PAHs). METHODS: Five hundred and thirteen idiopathic infertile male subjects and 273 fertile males as controls were recruited in this study, through eligibility screening procedures. Individual exposures to PAHs were measured as spot urinary concentrations of four PAH metabolites, including 1-hydroxynaphthalene (1-N), 2-hydroxynaphthalene (2-N), 1-hydroxypyrene (1-OHP) and 2-hydroxyfluorene (2-OHF), which were adjusted by urinary creatinine (CR). Subjects with idiopathic infertility were further divided into 'normal' and 'abnormal' semen quality groups based on their semen volume, sperm concentration, sperm number per ejaculum and sperm motility. RESULTS: The median CR-adjusted urinary concentrations of 1-N, 2-N, 1-OHP, 2-OHF and Sum PAH metabolites (sum of all four metabolites) of control group were lower than those found in case groups. Subjects with higher urinary concentrations of 1-OHP, 2-OHF and Sum PAH metabolites (assessed as tertiles) were more likely to have idiopathic male infertility (P-value for trend = 0.034, 0.022 and 0.022, respectively). Comparing the two groups of idiopathic infertile subjects with different semen quality, a higher idiopathic infertility risk was found in the group with abnormal semen quality. CONCLUSIONS: Increased urinary concentrations of 1-OHP, 2-OHF and Sum PAH metabolites were associated with increased male idiopathic infertility risks, while the idiopathic infertile subjects with abnormal semen might be at higher risk.
Zhang Y, Lin L, Cao Y, Chen B, Zheng L, Ge RS. Phthalate levels and low birth weight: a nested case-control study of Chinese newborns. J Pediatr. 2009 Oct;155(4):500-4.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. High-molecular-weight phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured the levels of several phthalates in maternal blood, cord blood and meconium of 88 low birth weight children and 113 controls residing in Shanghai, China between 2005 and 2006. Higher prenatal exposure to dibutyl phthalate (DBP) was reported in low birth weight infants relative to controls.
Scientific abstract:
OBJECTIVE: To assess maternal-fetal exposure to phthalates and investigate whether in utero phthalate exposure is associated with low birth weight (LBW). STUDY DESIGN: A total of 201 newborn-mother pairs (88 LBW cases and 113 controls) residing in Shanghai were enrolled in this nested case-control study during 2005-2006. Maternal blood, cord blood, and meconium specimens were collected and analyzed for phthalates by high-performance liquid chromatography-mass spectrometry. Nonparametric tests were used to compare demographic characteristics in cases and controls. Conditional logistic regression and Spearman correlation were used to analyze the association between phthalate exposure and LBW. RESULTS: No significant differences in gestational age, prepregnancy body mass index, prenatal care, vitamin supplementation, or socioeconomic levels were found between the LBW and control infants. More than 70% of the biosamples had quantifiable levels of phthalates, with higher levels in the LBW infants compared with the controls. Prenatal di-n-butyl phthalate (DBP) exposure was associated with LBW, and di-2-ethylhexyl phthalate (DEHP) was negatively associated with birth length. After adjusting for the potential confounders, DBP concentrations in the highest quartile were associated with an increased risk of LBW. CONCLUSIONS: Newborns in China are ubiquitously exposed to phthalates; significantly higher phthalate levels were detected in LBW cases compared with controls. In utero DBP and DEHP exposures were associated with LBW in a dose-dependent manner. Prenatal phthalate exposure may be a risk factor for LBW.
Zorrilla LM, Gibson EK, Jeffay SC, Crofton KM, Setzer WR, Cooper RL, Stoker TE. The effects of triclosan on puberty and thyroid hormones in male Wistar rats. Toxicol Sci. 2009 Jan;107(1):56-64.
Study Synopsis: Triclosan is commonly used as an antibacterial and antifungal in a range of household products including soap, mouthwash, toothpaste, deodorants and hand sanitizers. Some studies suggest that triclosan may interfere with hormones. In this study, researchers exposed young male rats to daily doses of triclosan over 30 days. Triclosan did not affect growth or the timing of preputial separation, and indicator of puberty onset. High doses of triclosan however reduced the blood level of the male hormone testosterone and of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Exposure also increased liver weight. Results suggest that exposure to triclosan affects liver weight, as well as the blood levels of testosterone and thyroid hormones.
Scientific abstract:
Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a potent antibacterial and antifungal compound that is widely used in personal care products, plastics, and fabrics. Recently triclosan has been shown to alter endocrine function in a variety of species. The purpose of this study was to determine effects of triclosan on pubertal development and thyroid hormone concentrations in the male rat. Weanling rats were exposed to 0, 3, 30, 100, 200, or 300 mg/kg of triclosan by oral gavage from postnatal day (PND) 23 to 53. Preputial separation (PPS) was examined beginning on PND 33. Rats were killed on PND 53, organ weights were recorded and serum was collected for subsequent analysis. Triclosan did not affect growth or the onset of PPS. Serum testosterone was significantly decreased at 200 mg/kg, however no effects were observed on androgen-dependent reproductive tissue weights. Triclosan significantly decreased total serum thyroxine (T4) in a dose-dependent manner at 30 mg/kg and higher (no observed effect level of 3 mg/kg). Triiodothyronine (T3) was significantly decreased only at 200 mg/kg, but thyroid stimulating hormone was not statistically different at any dose. Liver weights were significantly increased at 100 mg/kg triclosan and above suggesting that the induction of hepatic enzymes may have contributed to the altered T4 and T3 concentrations, but it does not appear to correlate with the T4 dose-response. This study demonstrates that triclosan exposure does not alter androgen-dependent tissue weights or onset of PPS; however, triclosan exposure significantly impacts thyroid hormone concentrations in the male juvenile rat.
Akutsu K, Takatori S, Nozawa S, Yoshiike M, Nakazawa H, Hayakawa K, Makino T, Iwamoto T. Polybrominated diphenyl ethers in human serum and sperm quality. Bull Environ Contam Toxicol. 2008 Apr;80(4):345-50.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. Few human studies have investigated relationships between PBDE exposure and semen quality. In this study, researchers measured the concentration of PBDEs in the blood of 10 men and obtained a semen sample. They found that concentration of one PBDE congeners, namely BDE-153, was very strongly correlated with decreased sperm concentration and reduced testis size. Given the small sample size, however, these results should not be considered conclusive and well-designed, larger studies with data on multiple confounders will be needed to confirm these findings.
Scientific abstract:
Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants; currently, they are identified as ubiquitous environmental contaminants. Several studies indicate that PBDEs might affect male fertility. We present the results of a pilot study on the relationship between human serum PBDEs and sperm quality. The PBDE levels in Japan are comparable to those found in European countries. Strong inverse correlations were observed between the serum concentration of 2,2',4,4',5,5'-hexabromodiphenyl ether and sperm concentration (r = -0.841, p = 0.002) and testis size (r = -0.764, p = 0.01). Extensive studies on the relationship between PBDEs and sperm quality are required.
Key Words: Adult, Flame Retardants/ adverse effects, Gas Chromatography-Mass Spectrometry, Humans, Male, Pilot Projects, Polybrominated Biphenyls/ adverse effects/ blood, Spermatozoa/chemistry/ drug effects, Testis/anatomy & histology/drug effects
Study Synopsis: This study found that the risks of infertility and spontaneous abortion were 30% higher among female hairdressers than in women who had different occupations. Researchers suggest that this finding may be due to occupational exposure to chemicals although other differences between hairdressers and women with other occupations may have played a role.
Scientific abstract:
OBJECTIVES:: The authors investigated the risks of negative reproductive outcome among female hairdressers. METHODS:: A cross-sectional study was conducted in 1997-1999, and 16,907 women in their forties were invited (response 71%). Information on infertility, delayed conception, spontaneous abortions, smoking, education, and occupation was collected. RESULTS:: Infertility and spontaneous abortion were higher among female hairdressers than among women in other occupations (adjusted relative risks = 1.30; 95% confidence intervals = 1.08 to 1.55 and 1.31; 1.07 to 1.60, respectively). There was a significant interaction between work and smoking habits. Smoking increased the risk of infertility among women in other occupations, but this was not found among hairdressers. CONCLUSIONS:: Female hairdressers have an increased risk of infertility and spontaneous abortions that might be due to their occupational chemical exposure. The risk was primarily found among never smokers.
BACKGROUND: Since fetal exposure to anti-androgenic and/or estrogenic compounds has adverse effect on animal reproduction, such exposure could be harmful to human fetus. Data are scarce on cryptorchidism and human exposure to endocrine disruptors. METHODS: We performed a prospective case-control study to assess the incidence of cryptorchidism and fetal exposure to selected chemicals in the Nice area. One hundred and fifty-one cord bloods (67 cryptorchid, 84 tightly matched controls) and 125 colostrums (56 for cryptorchid and 69 for controls) were screened for xenobiotics, including anti-androgenic dichloro-diphenyl-trichloro-ethylene (DDE), polychlorinated biphenyls (PCBs), and dibutylphthalate (and metabolite monobutylphthalate, mBP). RESULTS: Median concentrations in colostrum were higher, although not statistically significantly, in cryptorchid versus controls. Cryptorchid boys were more likely to be classified in the most contaminated groups in colostrum for DDE, Sigma PCBs and the composite score PCB + DDE. The same trend, but again not statistically significantly was observed for mBP. Odds ratio for cryptorchidism was increased for the highest score of Sigma PCB, with a trend only for DDE and Sigma PCB + DDE versus the lowest score of those components. CONCLUSIONS: Our results support an association between congenital cryptorchidism and fetal exposure to PCBs and possibly DDE. Higher concentrations in milk could be a marker of higher exposure or for an impaired detoxification pattern in genetically predisposed individuals.
Key Words: Adolescent, Adult, Africa South of the Sahara/ethnology, Case-Control Studies, Colostrum/*chemistry, Cryptorchidism/*chemically induced, Dichlorodiphenyl Dichloroethylene/*adverse effects, European Continental Ancestry Group, Female, Fetal Blood/chemistry, Humans, Infant, Newborn, Male, Maternal Exposure/*adverse effects, Milk, Human/chemistry, Polychlorinated Biphenyls/*adverse effects, Prospective Studies
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. Dichlorodiphenyl trichloroethylene (DDE) is the primary residue of the pesticide dichlorodiphenyl trichloroethane (DDT). DDT was banned by the U.S. Environmental Protection Agency (EPA) in the 1970s and has now been banned internationally except to control insects that carry diseases such as malaria. In this study, researchers measured the concentration of DDT and PCBs in breastmilk and in the cord blood of 67 children with undescended testes (a condition called cryptorchidism) and 84 healthy controls. Breastmilk concentrations of DDE and PCBs were higher in cases than in controls but this results may have been due to chance. Levels of contaminants in cord blood were similar in cases and controls. These results suggest, though inconclusively, that prenatal exposure to DDE and PCBs may be related with increased risks of cryptorchidism.
Scientific abstract:
BACKGROUND: Since fetal exposure to anti-androgenic and/or estrogenic compounds has adverse effect on animal reproduction, such exposure could be harmful to human fetus. Data are scarce on cryptorchidism and human exposure to endocrine disruptors. METHODS: We performed a prospective case-control study to assess the incidence of cryptorchidism and fetal exposure to selected chemicals in the Nice area. One hundred and fifty-one cord bloods (67 cryptorchid, 84 tightly matched controls) and 125 colostrums (56 for cryptorchid and 69 for controls) were screened for xenobiotics, including anti-androgenic dichloro-diphenyl-trichloro-ethylene (DDE), polychlorinated biphenyls (PCBs), and dibutylphthalate (and metabolite monobutylphthalate, mBP). RESULTS: Median concentrations in colostrum were higher, although not statistically significantly, in cryptorchid versus controls. Cryptorchid boys were more likely to be classified in the most contaminated groups in colostrum for DDE, {Sigma}PCBs and the composite score PCB + DDE. The same trend, but again not statistically significantly was observed for mBP. Odds ratio for cryptorchidism was increased for the highest score of {Sigma}PCB, with a trend only for DDE and {Sigma}PCB + DDE versus the lowest score of those components. CONCLUSIONS: Our results support an association between congenital cryptorchidism and fetal exposure to PCBs and possibly DDE. Higher concentrations in milk could be a marker of higher exposure or for an impaired detoxification pattern in genetically predisposed individuals.
Study Synopsis: Triclocarban (TCC) is an antimicrobial agent commonly used in personal care products. Researchers first exposed cells to TCC and other urea compounds with a similar structure and found that these chemicals enhanced the activity of the male sex hormone testosterone. They also added TCC to the diet of castrated male rats treated with testosterone and found that all male sex accessory organs, such as the ventral prostate, glans penis and seminal vesicles, were increased relative to rats fed a normal diet and also treated with testosterone. TCC exposure without testosterone treatment had little effect on the sex accessory glands of rats. Results suggest that the activity of testosterone may be amplified by oral exposure to sufficient levels of TCC in rats.
Scientific abstract:
Many xenobiotics have been associated with endocrine effects in a wide range of biological systems. These associations are usually between small nonsteroid molecules and steroid receptor signaling systems. In this report, triclocarban (TCC; 3,4,4'-trichlorocarbanilide), a common ingredient in personal care products that is used as an antimicrobial agent was evaluated and found to represent a new category of endocrine-disrupting substance. A cell-based androgen receptor-mediated bioassay was used to demonstrate that TCC and other urea compounds with a similar structure, which have little or no endocrine activity when tested alone, act to enhance testosterone (T)-induced androgen receptor-mediated transcriptional activity in vitro. This amplification effect of TCC was also apparent in vivo when 0.25% TCC was added to the diet of castrated male rats that were supported by exogenous testosterone treatment for 10 d. All male sex accessory organs increased significantly in size after the T+TCC treatment, compared with T or TCC treatments alone. The data presented here suggest that the bioactivity of endogenous hormones may be amplified by exposure to commercial personal care products containing sufficient levels of TCC.
Chevrier J, Eskenazi B, Holland N, Bradman A, Barr DB. Effects of exposure to polychlorinated biphenyls and organochlorine pesticides on thyroid function during pregnancy. Am J Epidemiol. 2008 Aug;168(3):298-310.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. DDT is an insecticide that was banned by the U.S. Environmental Protection Agency (EPA) in the 1970s due to concerns about its persistence in the environment and toxic effects on wildlife and humans. DDT was banned internationally by the Stockholm Convention on Persistent Organic Pollutants, except to control insects that carry diseases such as malaria. In this study, researchers measured the concentration of PCBs, DDT (and its breakdown product DDE) and hexachlorobenzene, a fungicide, in the blood of 334 pregnant women. They found that women with higher concentrations of PCBs and hexachlorobenzene had lower levels of the thyroid hormone free thyroxine. These findings are of particular significance, since thyroid hormones of maternal origin may play an essential role in fetal neurodevelopment.
Scientific abstract:
In this study, the authors' objective was to determine whether serum concentrations of polychlorinated biphenyls (PCBs), hexachlorobenzene, p,p'-dichlorodiphenyl trichloroethane (DDT), o,p'-DDT, and p,p'-dichlorodiphenyl dichloroethylene (DDE) are associated with thyroid function during pregnancy. These compounds, as well as thyroid-stimulating hormone, total thyroxine, and free thyroxine, were measured in serum samples collected between October 1999 and October 2000 from 334 pregnant women living in the Salinas Valley, California. Data were analyzed by multivariate linear regression. After adjustment for covariates, seven of the 19 PCB congeners detected in more than 75% of participants and the sum of those congeners were negatively associated with free thyroxine concentrations. PCBs 44, 52, and 183 remained significant after the exclusion of two outliers. Hexachlorobenzene concentrations were negatively associated with both free thyroxine and total thyroxine. PCB and hexachlorobenzene concentrations were strongly correlated, which hampered the authors' ability to identify their independent associations with thyroid function. None of the exposures under study were associated with thyroid-stimulating hormone. Results suggest that exposure to PCBs and/or hexachlorobenzene at background levels may affect thyroid function during pregnancy. These findings are of particular significance, since thyroid hormones of maternal origin may play an essential role in fetal neurodevelopment.
Study Synopsis: Trihalomethanes (THMs) are synthetic chemicals primarily used in industry as solvents and refrigerants. In this study, researchers collected water samples from 47 locations in Perth, Western Australia and obtained data on birth defects rates in these locations. They found that women living in areas where water was contaminated with high levels of THMs had 22% higher odds of having babies with birth defects relative to women living in areas where water contained low levels of THMs. Associations were strongest for cardiovascular birth defects (62% increased odds). These results suggest that maternal exposure to THMs may be related with increased risks of birth defects. This study however did not directly measured exposure to THM and so other factors related with residence location may explain the findings.
Scientific abstract:
BACKGROUND: By international standards, water supplies in Perth, Western Australia, contain high trihalomethane (THM) levels, particularly the brominated forms. Geographic variability in these levels provided an opportunity to examine cross-city spatial relationships between THM exposure and rates of birth defects (BDs). OBJECTIVES: Our goal was to examine BD rates by exposure to THMs with a highly brominated fraction in metropolitan locations in Perth, Western Australia. METHODS: We collected water samples from 47 separate locations and analyzed them for total and individual THM concentrations (micrograms per liter), including separation into brominated forms. We classified collection areas by total THM (TTHM) concentration: low (< 60 microg/L), medium (> 60 to < 130 microg/L), and high (> or = 130 microg/L). We also obtained deidentified registry-based data on total births and BDs (2000-2004 inclusive) from post codes corresponding to water sample collection sites and used binomial logistic regression to compare the frequency of BDs aggregately and separately for the TTHM exposure groups, adjusting for maternal age and socioeconomic status. RESULTS: Total THMs ranged from 36 to 190 microg/L. A high proportion of the THMs were brominated (on average, 92%). Women living in high-TTHM areas showed an increased risk of any BD [odds ratio (OR) = 1.22; 95% confidence interval (CI), 1.01-1.48] and for the major category of any cardiovascular BD (OR = 1.62; 95% CI, 1.04-2.51), compared with women living in low-TTHM areas. CONCLUSIONS: Brominated forms constituted the significant fraction of THMs in all areas. Small but statistically significant increases in risks of BDs were associated with residence in areas with high THMs.
Study Synopsis: In order to exert their effect, androgens, such as the male sex hormone testosterone, must bind to the androgen receptor (AR). Some chemicals have been found to bind to the AR and prevent androgens from exerting their effect. Such chemicals are called anti-androgens. The fungicides vinclozolin and procymidone, and the pharmaceutical drug flutamide are anti-androgens. In this study, researchers exposed rats during pregnancy and lactation to the above chemicals alone and in combination. They found that although the administration of the chemicals alone had no effects on the development of the male reproductive system, exposure to a mixture of these chemicals increased the occurrence of hypospadias, an anomaly characterized by the abnormal location of the urethra opening. These results suggest that anti-androgens such as vinclozolin, procymidone and flutamide in combination can affect male genital development even when they do not do so on their own.
Scientific abstract:
The incidence of hypospadias is increasing in young boys, but it remains unclear whether human exposure to endocrine disrupting chemicals plays a role. Risk assessment is based on estimation of no-observed-adverse-effect levels for single compounds, although humans are exposed to combinations of several anti-androgenic chemicals. In a mixture (MIX) study with three androgen receptor antagonists, vinclozolin, flutamide and procymidone, rats were gavaged during gestation and lactation with several doses of a MIX of the three chemicals or the chemicals alone. External malformations of the male reproductive organs were assessed on PND 47 using a score from 0 to 3 (normal to marked) for hypospadias. Markedly increased frequencies were observed after exposure to a MIX of the three chemicals compared to administration of the three chemicals alone. Anogenital distance at PND 1, nipple retention at PND 13, and dysgenesis score at PND 16 were highly correlated with the occurrence of hypospadias, and MIX effects were seen at doses where each of the individual chemicals caused no observable effects. Therefore, the results indicate that doses of anti-androgens, which appear to induce no hypospadias when judged on their own, may induce a very high frequency of hypospadias when they interact in concert with other anti-androgens.
Ema M, Fujii S, Hirata-Koizumi M, Matsumoto M. Two-generation reproductive toxicity study of the flame retardant hexabromocyclododecane in rats. Reprod Toxicol. 2008 Apr;25(3):335-51.
Study Synopsis: Hexabromocyclododecane (HBCD) is a flame retardant used in polystyrene insulation and textiles. Although a growing number of studies have examined the potential health effects of other flame retardants, such as polybrominated diphenyl ethers (PBDEs), few studies have examined the effect of exposure to HBCD. In this study, researchers administered HBCD to male and female rats before mating and during gestation and lactation for two generations. They found that high doses of HBCD was related with alteration in the structure of the thyroid gland, reduced levels of the thyroid hormone thyroxine (T4) and/or elevated levels of thyroid-stimulating hormone (TSH) in animals directly exposed as well as in animals exposed through the dam, suggesting that HBCD caused hypothyroidism in animals. Ovarian follicles were also affected in female offspring exposed during pregnancy. The highest dose also caused reduced body weight. These results suggest that exposure to high doses of HBCD affects thyroid hormone and may affect the female reproductive system and impact body weight in rats. Effects were however detected at levels that are substantially higher than those generally measured in humans.
Scientific abstract:
Male and female rats were fed a diet containing flame retardant hexabromocyclododecane (HBCD) at 0, 150, 1500 or 15,000 ppm throughout the study beginning at the onset of a 10-week pre-mating period and continuing through the mating, gestation and lactation periods for two generations. The mean daily intakes of HBCD during the whole period of administration were 10.2, 101 and 1008 mg/kg bw in F0 males, 14.0, 141 and 1363 mg/kg bw in F0 females, 11.4, 115 and 1142 mg/kg bw in F1 males, and 14.3, 138 and 1363 mg/kg bw in F1 females for 150, 1500 and 15,000 ppm, respectively. The incidence of rats with decreased thyroid follicles size was increased in F0 and F1 males and females at 1500 ppm and higher. Serum TSH levels were increased in F0 and F1 females at 1500 ppm and higher, and serum T4 levels were decreased in F0 males and females at 15,000 ppm. The number of the primordial follicles in the ovary of F1 females was reduced at 1500 ppm and higher. There were increases in the absolute and relative weights of the liver in male adults and male and female weanlings at 1500 ppm and higher, and in female adults at 15,000 ppm, and of the thyroid in male and female adults at 15,000 ppm. Decreased body weight and body weight gain associated with reduced food consumption were found in F1 males and females at 15,000 ppm. Decreases were found in the viability index of F2 pups and the body weight of male F1 and F2 pups and female F2 pups at 15,000 ppm. In F2 pups, there were low incidences of the completion of eye opening in males at 15,000 ppm and in females at 1500 ppm and higher, and of completed mid-air righting in females at 15,000 ppm. The data indicate that the NOAEL of HBCD in this study was 150 ppm (10.2mg/kg bw/day). The estimated human intake of HBCD is well below the NOAEL in the present study.
Key Words: Animals, Body Weight/drug effects, Eating/drug effects, Female, Fetus/ drug effects, Flame Retardants/ toxicity, Hydrocarbons, Brominated/ toxicity, Male, Motor Activity/drug effects, No-Observed-Adverse-Effect Level, Organ Size/drug effects, Rats, Rats, Sprague-Dawley, Reproduction/ drug effects, Spermatozoa/drug effects
Study Synopsis: A multidisciplinary expert panel sponsored by the US Environmental Protection Agency, the National Institute of Environmental Health Sciences, and Serono Symposia International was convened to examine the evidence of a secular trend, identify potential environmental factors of concern, and identify research needs regarding environmental factors and puberty timing. The majority of the panelists concluded that the girls' data are sufficient to suggest a secular trend toward earlier breast development onset and menarche from 1940 to 1994 but that the boys' data are insufficient. Panelists also concluded that endocrine-disrupting chemicals, particularly the estrogen mimics and antiandrogens, are important factors associated with puberty timing. A change in the timing of puberty markers was considered adverse from a public health perspective. The panel recommended research areas to further our understanding of the relationships among environmental factors, puberty-timing outcomes, and other reproductive and adult disease.
Scientific abstract:
Puberty-timing measures have historically been used as indicators of adequate nutrition and growth. More recently, these measures have been examined in relation to exposure to estrogenic or antiandrogenic agents, as well as other environmental factors. The scientific community has debated whether puberty timing is occurring earlier today than in the mid-1900s in the United States and, if so, whether environmental factors play a role; however, no one has asked a multidisciplinary panel to resolve this question. Thus, a multidisciplinary expert panel jointly sponsored by the US Environmental Protection Agency, the National Institute of Environmental Health Sciences, and Serono Symposia International was convened to examine the evidence of a secular trend, identify potential environmental factors of concern, and identify research needs regarding environmental factors and puberty timing at "The Role of Environmental Factors on the Timing and Progression of Puberty" workshop. The majority of the panelists concluded that the girls' data are sufficient to suggest a secular trend toward earlier breast development onset and menarche from 1940 to 1994 but that the boys' data are insufficient to suggest a trend during this same period. The weight-of-the-evidence evaluation of human and animal studies suggest that endocrine-disrupting chemicals, particularly the estrogen mimics and antiandrogens, and body fat are important factors associated in altered puberty timing. A change in the timing of puberty markers was considered adverse from a public health perspective. The panel recommended research areas to further our understanding of the relationships among environmental factors, puberty-timing outcomes, and other reproductive and adult disease at the individual and population levels.
Key Words: Age Factors, Body Weight/physiology, Child, Environmental Exposure/*adverse effects/prevention & control, Female, Humans, *Interdisciplinary Communication, Male, Menarche/physiology, Puberty/*physiology, Puberty, Precocious/etiology, United States, United States Environmental Protection Agency/trends
Study Synopsis: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA and PFOS. In this study, researchers measured the blood levels of these chemicals in 1,400 pregnant women participating in the Danish National Birth Cohort. Higher maternal blood PFOA levels were associated with reduced abdominal circumference and birth length. PFOS levels in the blood of pregnant women was not related with fetal growth indicators such as placental weight, birth length, and head and abdominal circumference. Findings suggest that prenatal exposure to PFOA, but not PFOS, may alter fetal growth.
Scientific abstract:
Perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) are widespread persistent organic pollutants that have been associated with reduced birth weight at doses expected in many pregnant populations. The authors randomly selected 1,400 pregnant women and their newborns from the Danish National Birth Cohort (1996-2002) to investigate whether these compounds reduce organ growth. PFOS and PFOA were measured in maternal blood samples taken early in pregnancy. Placental weight, birth length, and head and abdominal circumferences were measured shortly after birth by trained midwives or nurses. Maternal PFOA levels in early pregnancy were associated with smaller abdominal circumference and birth length. For each ng/ml increase in PFOA, birth length decreased by 0.069 cm (95% confidence interval: 0.024, 0.113) and abdominal circumference decreased by 0.059 cm (95% confidence interval: 0.012, 0.106). An inverse association was also observed between PFOA and placental weight and head circumference, and a positive association was observed with newborn ponderal index, but none of these associations was statistically significant. Maternal PFOS levels were not associated with any of the five fetal growth indicators. These findings suggest that fetal exposure to PFOA but not PFOS during organ development may affect the growth of organs and the skeleton.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. Though PCBs were banned in the 1970s, studies show that they are still commonly detected humans' blood. In this study, researchers measured PCB blood levels in 100 Danish women with different intake of fatty fish. They found that women with a high intake of fatty fish (>4 meals per month) had 50% higher PCB concentrations than women who did not eat fatty fish. In addition, women with higher blood PCB levels had babies with a lower birth weight and had reduced placental weight. Results suggest that consumption of fatty fish may increase exposure to PCBs and that PCB blood level may be related with lower birth weight in humans.
Scientific abstract:
In a selected group of women from the Danish National Birth Cohort, the authors investigated the association between intake of fatty fish and plasma concentrations of polychlorinated biphenyls (PCBs) on the one hand and the association between maternal PCB concentrations and fetal growth on the other. Of 70,183 women who filled in a food frequency questionnaire during 1996-2002, 100 nulliparous women aged 25-35 years with normal prepregnancy body mass index were selected according to their intake of fatty fish (low (0 meals/month, n = 34), medium (1-3 meals/month, n = 33), or high (>4 meals/month, n = 33)). Women with a high intake of fatty fish had 50% (95% confidence interval (CI): 31, 72) higher plasma PCB concentrations than women with low intake. Maternal plasma PCB concentrations were inversely associated with birth weight and placental weight. The adjusted mean difference between the 75th and 25th PCB percentiles was -155 g (95% CI: -291, -19) for birth weight and -81 g (95% CI: -135, -26) for placental weight. These results support previous findings from this cohort, where fatty fish intake was inversely associated with fetal growth. Dietary recommendations often encourage weekly consumption of fatty fish. These results suggest that potential exposure to PCBs should be carefully considered before recommending such intakes among women of childbearing age.
Study Synopsis: This paper reviews the literature linking exposure to environmental contaminants with male fertility and reproductive health. Authors point out the need for further research in populations with high exposure to chemicals, including phthalates and bisphenol A. They also mention the need to indentify factors that may render some individuals more susceptible the adverse health effect of chemical exposure and determine whether exposure during certain developmental stages may have more influence on male fertility. Finally, a call to develop methods to study chemical mixtures is made.
Scientific abstract:
In the field of reproductive environmental health there remain many unanswered questions regarding the impact of the environment on male reproductive health. Suggested needs include studies that target populations with high exposure to chemicals, including phthalates and bisphenol A. We also need to identify susceptibility factors and critical exposure windows (life stages) that may increase a man's risk of infertility. Finally, we need to develop methods to better study mixtures of chemicals and develop methods to assess clinical reproductive outcomes of human exposure to the ever-growing list of chemicals.
Herbstman JB, Sjodin A, Apelberg BJ, Witter FR, Halden RU, Patterson DG, Panny SR, Needham LL, Goldman LR. Birth delivery mode modifies the associations between prenatal polychlorinated biphenyl (PCB) and polybrominated diphenyl ether (PBDE) and neonatal thyroid hormone levels. Environ Health Perspect. 2008 Oct;116(10):1376-82.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers measured the concentration of PBDEs in cord blood samples from 297 neonates born at the Johns Hopkins Hospital in 2004 and 2005. No associations were found between cord blood levels of PBDEs and thyroid hormone in infants aged 2 and 18 days but BDE-153 was related with an increased likelihood of low total T4 in 18-day-olds among women who had spontaneous, unassisted, vaginal deliveries. Higher BDE-153 was also related to lower free T4 in cord blood. These results suggest that maternal exposure to PBDEs may be related with alterations in thyroid hormones in cord blood and neonates.
Scientific abstract:
BACKGROUND: Developing infants may be especially sensitive to hormone disruption from chemicals including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). OBJECTIVE: We investigated relationships between cord serum levels of PCBs and PBDEs and thyroid hormones measured in cord blood serum and neonatal blood spots. METHODS: We measured PCBs and PBDEs, thyrotropin (TSH), thyroxine (T4) and free T4 (FT4) in cord blood serum from 297 infants who were delivered at the Johns Hopkins Hospital in 2004-2005. We abstracted results of total T4 (TT4) measured in blood spots collected in the hospital and at neonatal visits. We used delivery mode (augmented vaginal deliveries and nonelective cesarean deliveries) as a surrogate for intrapartum stress, which is known to alter cord blood thyroid hormones. RESULTS: In the full study population, no compounds were associated with a change in average TSH, FT4, or TT4. BDE-100 was associated with increased odds of low cord TT4, BDE-153 with increased odds of low cord TT4 and FT4, and no compounds were associated with increased odds of high TSH. For infants born by spontaneous, vaginal, unassisted deliveries, PCBs were associated with lower cord TT4 and FT4 and lower TT4 measured in neonatal blood spots. PBDEs showed consistent but mainly nonsignificant negative associations with TT4 and FT4 measurements. CONCLUSIONS: Prenatal PCB and PBDE exposures were associated with reduced TT4 and FT4 levels among infants born by spontaneous, unassisted vaginal delivery. Intrapartum stress associated with delivery mode may mask hormonal effects of PCBs and PBDEs.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. PCBs persist in the environment, accumulate in human fatty tissue and are detected in the blood of virtually all human populations. In this study, researchers measured the blood concentration of 11 PCBs in 399 pregnant women participating in the Child Health and Development Study in the San Francisco Bay Area. They found that women with high total PCBs had 33% reduced odds of giving birth to a male baby relative to women with low exposure. Results suggest that high maternal exposure to PCBs may reduce the probability of giving birth to male infants.
Scientific abstract:
BACKGROUND: Polychlorinated biphenyls (PCBs) are ubiquitous industrial chemicals that persist in the environment and in human fatty tissue. PCBs are related to a class of compounds known as dioxins, specifically 2,3,7,8-TCDD (tetrachloro-dibenzodioxin), which has been implicated as a cause of altered sex ratio, especially in relation to paternal exposures. METHODS: In the 1960's, serum specimens were collected from pregnant women participating in the Child Health and Development Study in the San Francisco Bay Area. The women were interviewed and their serum samples stored at -20 degrees C. For this study, samples were thawed and a total of eleven PCBs were determined in 399 specimens. Secondary sex ratio, or sex ratio at birth, was evaluated as a function of maternal serum concentrations using log-binomial and logistic regression, controlling for hormonally active medications taken during pregnancy. RESULTS: The relative risk of a male birth decreased by 33% comparing women at the 90th percentile of total PCBs with women at the 10th percentile (RR = 0.67; 95% CI, 0.48-0.94; p = 0.02), or by approximately 7% for each 1 mug/L increase in total PCB concentration. Although some congener-specific associations with sex ratio were only marginally statistically significant, all nine PCB congeners with < 30% of samples below the LOQ showed the same direction of association, an improbable finding under the null hypothesis. CONCLUSION: Maternal exposure to PCBs may be detrimental to the success of male sperm or to the survival of male embryos. Findings could be due to contaminants, metabolites or PCBs themselves.
Study Synopsis: This review discusses 1) findings regarding the effects of endocrine disrupting chemicals on fish, wildlife and human health, 2) results of representative animal studies on antiandrogens, estrogens and dioxin-like chemicals, and 3) regulatory proposals being considered for screening for endocrine disrupting chemicals.
Scientific abstract:
In 1991 a group of expert scientists at a Wingspread work session on endocrine disrupting chemicals (EDCs) concluded that "Many compounds introduced into the environment by human activity are capable of disrupting the endocrine system of animals, including fish, wildlife, and humans. Endocrine disruption can be profound because of the crucial role hormones play in controlling development." Since that time, there have been numerous documented examples of adverse effects of EDCs in invertebrates, fish, wildlife, domestic animals, and humans. Hormonal systems can be disrupted by numerous different anthropogenic chemicals including anti-androgens, androgens, estrogens, AhR agonists, inhibitors of steroid hormone synthesis, antithyroid substances, and retinoid agonists. In addition, pathways and targets for endocrine disruption extend beyond the traditional estrogen/androgen/thyroid (EAT) receptor-mediated reproductive and developmental systems. For example, scientists have expressed concern about the potential role of EDCs in increasing trends in early puberty in girls, obesity and type II diabetes in the US and other populations. New concerns include complex endocrine alterations induced by mixtures of chemicals, an issue broadened due to the growing awareness that EDCs present in the environment include a variety of potent human and veterinary pharmaceutical products, personal care products, nutraceuticals and phytosterols. In this review we 1) address what have we learned about the effects of EDCs on fish, wildlife, and human health, 2) discuss representative animal studies on (anti)androgens, estrogens and TCDD-like chemicals, and 3) evaluate regulatory proposals being considered for screening and testing these chemicals.
Howdeshell KL, Rider CV, Wilson VS, Gray LE, Jr. Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats. Environ Res. 2008 Oct;108(2):168-76.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this paper, authors review animal studies that evaluated the health effects and toxicological mechanisms of action of exposure to phthalate. They indicate that the fetal rat testes are an important target for phthalates as evidenced by a reduction in testosterone production and insulin-like hormone 3 (insl3) expression, a peptide hormone critical for testis descent. They also mention that mixtures of phthalate with one another and with other anti-androgenic compounds exhibit cumulative effects on male reproductive system development and caution that phthalates may affect human reproductive development since exposure to these chemicals has been reported in pregnant women and fetuses, and androgen-signaling and insl3 are highly conserved among mammals.
Scientific abstract:
Phthalate esters are high production volume chemicals used to impart flexibility to polyvinyl chloride products as well as other applications. In the male laboratory rat, the period of sexual differentiation in utero is particularly sensitive to certain phthalate esters, which induce a suite of reproductive malformations, including epididymal and gubernacular agenesis. The fetal rat testes are a main target for phthalate esters as evidenced by a reduction in testosterone production and insulin-like hormone 3 (insl3) expression, a peptide hormone critical for testis descent. Histopathology of fetal and postnatal testes reveals that in utero exposure to phthalate esters disrupts Leydig and Sertoli cell maturation leading to a reduction in germ cells in the malformed seminiferous tubules in adulthood as well as an increased incidence of multinucleated germ cells. There are some strain-specific differences in the target organs in the male reproductive tract in rats affected by phthalate esters. Mixtures of phthalate esters with one another and with other anti-androgenic compounds exhibit cumulative, largely dose-additive effects on male reproductive tract development when administered during sexual differentiation in utero. Since phthalate ester metabolites are detected in maternal and fetal body fluids, and androgen-signaling and insl3 are highly conserved among mammals, phthalates may potentially affect human reproductive development.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers exposed pregnant rats to six individual phthalates, namely benzylbutyl phthalate (BBP), dibutyl phthalate (DBP), diethylhexyl phthalate (DEHP), diethyl phthalate (DEP), diisobutyl phthalate (DiBP) and dipentyl phthalate (DPP) alone or in combination and determined testicular production of the male hormone testosterone during the fetal stage. Results showed that phthalates acted in an additive fashion to reduce testosterone production in male rat fetuses.
Scientific abstract:
Phthalate diesters are chemicals to which humans are ubiquitously exposed. Exposure to certain phthalates during sexual differentiation causes reproductive tract malformations in male rats. In the fetal rat, exposure to the phthalates benzylbutyl phthalate (BBP), di(n)butyl phthalate (DBP), and diethylhexyl phthalate (DEHP) decreases testicular testosterone production and insulin-like 3 hormone mRNA levels. We characterized the dose-response effects of six individual phthalates (BBP, DBP, DEHP, diethyl phthalate [DEP], diisobutyl phthalate [DiBP], and dipentyl phthalate [DPP]) on gestation day (GD) 18 testicular testosterone production following exposure of Sprague-Dawley rats on GD 8-18. BBP, DBP, DEHP, and DiBP were equipotent (ED50 of 440 {+/-} 16 mg/kg/day), DPP was about threefold more potent (ED50 = 130 mg/kg/day) and DEP had no effect on fetal testosterone production. We hypothesized that coadministration of these five antiandrogenic phthalates would reduce testosterone production in a dose-additive fashion because they act via a common mode of toxicity. In a second study, dams were dosed at 100, 80, 60, 40, 20, 10, 5, or 0% of the mixture. The top dose contained 1300 mg of total phthalates/kg/day including BBP, DBP, DEHP, DiBP (300 mg/kg/day per chemical), and DPP (100 mg DPP/kg/day). This mixture ratio was selected such that each phthalate would contribute equally to the reduction in testosterone. As hypothesized, testosterone production was reduced in a dose-additive manner. Several of the individual phthalates and the mixture also induced fetal mortality, due to pregnancy loss. These data demonstrate that individual phthalates with a similar mechanism of action can elicit cumulative, dose additive effects on fetal testosterone production and pregnancy when administered as a mixture.
Study Synopsis: Motorcycle exhaust (ME) from two-stroke engines contains a large number of toxicants which pose a potential health hazard. In this study, researchers exposed male rats to ME by inhalation 1 hours in the morning and again in the afternoon at different concentrations, Monday through Friday. Exposure was shown to cause a decrease in testicular weight and sperm number in the cauda epididymis, the area of the testicle where sperms are stored, and other structural abnormalities of the male reproductive system which affected fertility. ME also decreased the blood concentration of the male hormone testosterone but this effect was reversed by cotreatment with vitamin E, suggesting the mode of action may involve induction of oxidative stress. Taken together, these results suggest that exposure to ME affects the male reproductive system in rats.
Scientific abstract:
Motorcycle exhaust (ME) from two-stroke engines contains many toxicants and poses a potential health hazard. The major objectives of the present study were to investigate the male reproductive toxicity of ME and the underlying mechanisms of toxicity. Male Wistar rats were exposed to ME by inhalation 1 h each in the morning and afternoon, Monday through Friday. Exposures to 1:50 diluted ME for 4 weeks or to 1:10 diluted ME for 2 and 4 weeks showed concentration- and time-dependent decreases of testicular weight, spermatid number, and cauda epididymal sperm number. Subsequent studies were done using 4-week exposure to 1:10 diluted ME. ME caused histopathological changes including testicular spermatocytic necrosis and seminiferous tubule atrophy and cauda epididymal formation of clusters of pyknotic and necrotic sperm cells. ME-exposed male rats mated with untreated females showed decreases of male mating index and female fertility index and an increase of implantation site loss. ME decreased 7-ethoxycoumarin O-deethylase and superoxide dismutase activities but induced proinflammatory cytokine interleukin-6 (IL-6) messenger RNA (mRNA) in the testis. Male rats were exposed to ME with or without cotreatment with 50 mg/kg vitamin E orally for 4 weeks. ME decreased serum testosterone concentration. This effect was reversed by cotreatment with vitamin E. ME decreased testicular spermatid number and induced IL-6 mRNA and protein. These effects were also reversed by the vitamin E cotreatment. The present findings show that ME causes male reproductive effects and induces testicular IL-6 in rats by mechanisms involving induction of oxidative stress and inhibition of steroidogenesis.
Study Synopsis: A number of studies have shown associations between exposure to heavy metals and altered neurodevelopment. In this study, researchers measured lead, cadmium and mercury in 1,425 premenopausal women who were not pregnant nor breastfeeding. They found a dose-response relationship between blood levels of cadmium and self report of endometriosis. Women in the second and third tertiles of exposure had a 2-fold and 3.4-fold increase in odds of endometriosis, respectively. Blood levels of lead and mercury were not related with endometriosis. None of the heavy metals were related with uterine myomas. Researchers noted that their results should be interpreted with caution because heavy metals and case status were determined at the same time. The possibility that the higher cadmium blood levels in endometriosis cases may be due to different metabolism of the metal in these individuals relative to noncases therefore cannot be entirely ruled out.
Scientific abstract:
BACKGROUND: It has been hypothesized that exposure to exogenous estrogens may be associated with endometriosis and uterine myomas. We sought to investigate the association between heavy metals which have been shown to be hormonally active and these disorders using data from the National Health and Nutrition Examination Survey, 1999-2002. METHODS: Women aged 2049 years who had data on metals and the outcomes of interest, were premenopausal and neither pregnant nor breastfeeding were eligible (n = 1425). Lead, cadmium and mercury were measured in whole blood. Diagnosis of outcomes was based upon self-report. Logistic regression was used to examine the association between tertiles of heavy metals and disease adjusting for age, race/ethnicity, use of birth control pills prior to diagnosis and smoking status at diagnosis. RESULTS: A dose-response association between cadmium and endometriosis was observed [tertile 2 versus 1: adjusted odds ratio (OR) = 1.94, 95% confidence interval (CI): 0.735.18; tertile 3 versus 1: adjusted OR = 3.39, 95% CI 1.378.40]. This association persisted in subanalyses: (i) limiting analysis to women diagnosed in the past 10 years and (ii) limiting analysis to women diagnosed since last pregnancy, although limited by sample size. CONCLUSIONS: These results must be interpreted with caution given the cross-sectional study design. The observed association between cadmium and endometriosis deserves further investigation in properly designed studies.
Study Synopsis: Trihalomethanes (THMs) are synthetic chemicals primarily used in industry as solvents and refrigerants, and form as by-products when chlorine or bromine is used to disinfect drinking water. Nitrates may also contaminate drinking water as microorganisms break down fertilizers and organic matter. In this study, researchers collected water samples in Perth, Western Australia and obtained data on term prelabor rupture of membranes (PROM) among 16,229 women between 2002 and 2004. They found that women living in areas where water was contaminated moderate and high levels of nitrates had 23% and 47% increased odds of PROM relative to women living in areas where water contained low levels of nitrates. Contamination of drinking water with THMs was not related with PROM. These results suggest that maternal exposure to THMs may be related with increased risks of PROM. This study however did not directly measured exposure to nitrates and so other factors related with residence location may explain the findings.
Scientific abstract:
The causes of term prelabor rupture of membranes (term PROM) remain poorly defined. The authors conducted a record-based prevalence study to explore a possible relation between disinfection by-products in drinking water and term PROM in an Australian community with spatially variable trihalomethane and nitrate levels. A multilevel statistical model was used to examine the relation between factors operating at the levels of the individual, district, and water distribution zone and the prevalence of PROM at term among 16,229 women in Perth, Western Australia (2002-2004). Adjusted odds ratios for term PROM increased with increasing tertiles of nitrate exposure (moderate exposure: odds ratio = 1.23, 95% confidence interval: 1.03, 1.52; high exposure: odds ratio = 1.47, 95% confidence interval: 1.20, 1.79), but there was no significant relation with exposure to trihalomethanes. This study raises the possibility that water contaminants may promote the development of PROM at term.
Leijs MM, Koppe JG, Olie K, Van Aalderen WM, Voogt P, Vulsma T, Westra M, Ten Tusscher GW. Delayed initiation of breast development in girls with higher prenatal dioxin exposure; a longitudinal cohort study. Chemosphere. 2008 Oct;73(6):999-1004.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. Dioxins, on the other hand, are highly toxic chemicals which, similarly to PBDEs, persist in the environment, accumulate in human fatty tissue and concentrate up the food chain. In this study, researchers measured PBDEs as well as dioxins and furans in the breastmilk and blood of 33 women three to four weeks after having delivered a baby. The same chemicals were measured at a mean age of 14 years. A delay in breast development was found in girls whose mother had higher levels of dioxins but no associations were found with PBDE levels. No relationship was found with other makers of pubertal development and growth such as pubic and axillary hair growth, genital development, body mass index, testicular volume or onset of menarche. This study does not support a relation between prenatal or postnatal exposure to PBDEs and indicator of pubertal development and growth. Results suggest that prenatal exposure to dioxins, as estimated using maternal blood levels a few weeks after delivery, may be related with delayed breast development.
Scientific abstract:
OBJECTIVES: While many studies have assessed the health impacts of PCDD/Fs and PCBs on animals and humans, long-term consequences for especially adolescents, have not (yet) been well documented. This is certainly also true for the effects of PBDE exposure. As part of a longitudinal cohort study, now well into its second decade, effects of perinatal and current PCDD/F exposure, as well as current dl-PCB and PBDE exposures, on puberty, were assessed. STUDY DESIGN: Prenatal, lactational and current PCDD/F, dl-PCB and PBDE concentrations were determined using GC-MS. Pubertal development and growth were assessed by means of physical examination and the Tanner scale. 33 Children (born between 1986 and 1991) consented to the current follow-up study. Outcomes were evaluated using linear regression or the non parametric Spearman's correlation coefficient. RESULTS: A delay in initiation of breast development was found in girls (n = 18) with higher prenatal (p = 0.023) and lactational PCDD/F exposure (p = 0.048). The males revealed a negative trend with age at first ejaculation. For other endpoints on puberty and growth (pubic hair, axillary hair, genital stage, length, BMI, testicular volume, menarche) no significant relation was found with any of the measured compounds. DISCUSSION AND CONCLUSION: A relation between prenatal PCDD/F exposure and later initiation of breast development was seen. A Belgian study found a delay in breast development with higher current serum concentrations of dioxin-like compounds. The initiation of puberty is a complex process and it is yet not clear how dioxin-like compounds precisely affect this process prenatally. Further follow-up into adulthood is warranted, in order to detect the possibility of developing malignancies and fertility problems.
Study Synopsis: Persistent Organic Pollutants (POPs) are ubiquitous synthetic chemicals that persist in the environment and in humans, accumulate in fat and are generally found at higher concentration in animals situated higher in the food chain. Twelve POPs were banned internationally by the Stockholm Convention on POPs in 2001. In this study, researchers measured the POPs cis-nonachlor, trans-nonachlor, oxychlordane, hexachlorocyclohexane, mirex, p,p'-dichlorodiphenyl trichloroethane (DDT) and DDT's breakdown product p,p'-dichlorodiphenyl dichloroethylene (DDE) in serum samples collected from 754 patients with testicular tumors and 928 healthy controls. Testicular tumors are generally categorized as seminomous or nonseminomous. Individuals with testicular tumors had 70% increased odds of having been exposed to high levels of DDE and about 50% increased odds of having high exposure to cis-nonachlor and trans-nonachlor. Risk of seminoma was about 90% greater in individuals in the highest quartile of exposure to DDE and cis-nonachlor, 70% higher in those with high trans-nonachlor exposure and increased by 60% in individuals with high exposure to oxychlordane. Finally, nonseminoma risk was increased by 60% in those in the highest quartile of DDE exposure. Taken together, these results suggest that exposure to POPs may be related with increased risk of testicular tumors, including seminomous and nonseminomous tumors.
Scientific abstract:
Background: Exposure to endocrine-disrupting chemicals, such as persistent organochlorine pesticides, has been suggested to increase the risk of testicular germ cell tumors (TGCTs). Methods: To study the relationship of POP exposure to TGCT risk, prediagnostic serum samples from 754 case subjects and 928 control subjects enrolled in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study were analyzed for cis-nonachlor, trans-nonachlor, oxychlordane, total chlordanes, -hexachlorocyclohexane, mirex, p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), and p,p'-dichlorodiphenyltrichloroethane. Adjusted odds ratios (ORs) and their associated 95% confidence intervals (CIs) for the risk of TGCT overall and for the histological subgroups, seminoma and nonseminoma, were estimated using multivariable logistic regression. All statistical tests were two-sided. Results: TGCT risk was statistically significantly associated with higher plasma levels of p,p'-DDE (for highest quartile [Q4] vs lowest quartile [Q1], OR = 1.71, 95% CI = 1.23 to 2.38, Ptrend = .0002) and of two chlordane components, cis-nonachlor (Q4 vs Q1, OR = 1.56, 95% CI = 1.11 to 2.18, Ptrend = .009) and trans-nonachlor (Q4 vs Q1, OR = 1.46, 95% CI = 1.07 to 2.00, Ptrend = .026). Seminoma risk was statistically significantly associated with p,p'-DDE (Q4 vs Q1, OR = 1.91, 95% CI = 1.22 to 2.99, Ptrend = .0008), cis-nonachlor (Q4 vs Q1, OR = 1.93, 95% CI = 1.27 to 2.93, Ptrend = .0045), trans-nonachlor (Q4 vs Q1, OR = 1.72, 95% CI = 1.11 to 2.67, P-trend = .033), and a chlordane metabolite, oxychlordane (Q4 vs Q1, OR = 1.64, 95% CI = 1.04 to 2.60, Ptrend = .048), whereas nonseminoma risk showed a statistically significant association with p,p'-DDE only (Q4 vs Q1, OR = 1.63, 95% CI = 1.10 to 2.42, Ptrend = .0044). Conclusions: Increased exposure to p,p'-DDE may be associated with the risk of both seminomatous and nonseminomatous TGCTs, whereas exposure to chlordane compounds and metabolites may be associated with the risk of seminoma. Because evidence suggests that TGCT is initiated in very early life, it is possible that exposure to these persistent organic pesticides during fetal life or via breast feeding may increase the risk of TGCT in young men.
Study Synopsis: Pyrethroids are synthetic derivatives of pyrethrins which are naturally occurring insecticides produced from flowers of certain chrysanthemum species. More than 2 million pounds of pyrethroid insecticides are used for agricultural and home pest control each year in the United States. Although pyrethroid use in U.S. homes has substantially increased since the recent residential ban on certain organophosphate pesticide by the U.S. Environmental Protection Agency (EPA), little is known on the human health effects of chronic exposure to these chemicals. In this study, researchers measured the concentration of pyrethroid residues, including 3-phenoxybenzoic acid (3PBA) and cis- and trans-dichlorovinyl dimethylcyclopropane carboxylic acid (CDCCA and TDCCA), in the urine of 207 men. They found that men with higher urine levels of TDCCA were more likely to have poor semen quality, based on sperm concentration, motility and morphology parameters. Men in the highest quartile of urine TDCCA had a 15.5% decline in sperm motility compared with men in the first quartile. Increased sperm DNA damage was also related with higher urine levels of 3PBA and CDCCA. Results suggest that increased exposure to pyrethroid insecticides may be related to reduced semen quality.
Scientific abstract:
BACKGROUND: Exposure to synthetic pyrethroid insecticides is widespread, and is expected to increase among the general population due to the need to replace other common insecticides following regulatory use restrictions. On the basis of limited studies, there is animal and human evidence for altered reproductive or endocrine function following pyrethroid exposure. METHODS: The present study measured urinary pyrethroid metabolites [3-phenoxybenzoic acid (3PBA) and cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (CDCCA and TDCCA)], semen quality, sperm motion parameters and sperm DNA damage with the neutral comet assay in 207 men recruited from an infertility clinic. RESULTS: In multivariate analysis, the highest 3PBA quartile was associated with a suggestive 20.2 million sperm/ml reduction (95% confidence interval -37.1 to + 2.6) in sperm concentration compared with men below the 3PBA median. There were significant inverse associations between TDCCA and sperm motility and sperm motion parameters when adjusting for CDCCA and other covariates. The highest TDCCA quartile was associated with a 15.5% decline (95% confidence interval -26.2 to -4.8) in sperm motility compared with men below the median. In multiple logistic analyses, there were dose-dependent increased odds for below reference sperm concentration, motility and morphology in relation to TDCCA. Among the comet assay measures, 3PBA and CDCCA were associated with increased sperm DNA damage, measured as percent DNA in the comet tail. CONCLUSIONS: We found evidence for reduced semen quality and increased sperm DNA damage in relation to urinary metabolites of pyrethroid insecticides. These findings may be of concern due to increased pyrethroid use and prevalent human exposure.
Study Synopsis: While some metals (such as zinc, copper and molybdenum) are important to human health, others (such as cadmium and lead) are considered nonessential. Too high an intake of most of these metals may adversely affect health. In this study, researchers measured 10 metals in the blood of 219 men recruited through infertility clinics. Metals included arsenic, cadmium, chromium, copper, lead, manganese, mercury, molybdenum, selenium and zinc. They observed dose-dependent relationships between blood levels of molybdenum and semen quality parameters. For instance, the likelihood of having low sperm concentration and abnormal sperm morphology was 3.5 and 2.6 times higher, respectively, in men with high levels of blood molybdenum relative to those in the with low exposure. Other metals were not associated with sperm parameters. Results suggest that high levels of molybdenum in blood may be related to lower semen quality.
Scientific abstract:
BACKGROUND: Evidence on human semen quality as it relates to exposure to various metals, both essential (e.g., zinc, copper) and nonessential (e.g., cadmium, lead), is inconsistent. Most studies to date used small sample sizes and were unable to account for important covariates. OBJECTIVES: Our goal in this study was to assess relationships between exposure to multiple metals at environmental levels and human semen-quality parameters. METHODS: We measured semen quality and metals in blood (arsenic, Cd, chromium, Cu, Pb, manganese, mercury, molybdenum, selenium, and Zn) among 219 men recruited through two infertility clinics. We used multiple statistical approaches to assess relationships between metals and semen quality while accounting for important covariates and various metals. RESULTS: Among a number of notable findings, the associations involving Mo were the most consistent over the various statistical approaches. We found dose-dependent trends between Mo and declined sperm concentration and normal morphology, even when considering potential confounders and other metals. For example, adjusted odds ratios (ORs) for below-reference semen-quality parameters in the low, medium, and high Mo groups were 1.0 (reference), 1.4 [95% confidence interval (CI), 0.5-3.7], and 3.5 (95% CI, 1.1-11) for sperm concentration and 1.0 (reference), 0.8 (95% CI, 0.3-1.9), and 2.6 (95% CI, 1.0-7.0) for morphology. We also found preliminary evidence for interactions between Mo and low Cu or Zn. In stratified analyses, the adjusted ORs in the high Mo/low Cu group were 14.4 (1.6, 132) and 13.7 (1.6, 114) for below-reference sperm concentration and morphology, respectively. CONCLUSIONS: Our findings represent the first human evidence for an inverse association between Mo and semen quality. These relationships are consistent with animal data, but additional human and mechanistic studies are needed.
Study Synopsis: This paper reviews the literature on links between exposure to environmental chemicals and female reproductive health. Authors reviewed articles indexed in PubMed between 1999 and 2007 regarding environmental exposures and puberty, menstrual and ovarian function, fertility, and menopause. It finds that heavy metals, and particularly lead, has the strongest evidence for altering female reproductive function. Authors determined that effects were primarily observed in unique populations, such as consumers of contaminated fish or in individuals exposed as a result of their occupation and identify some limitations in the literature. They conclude that reproductive function may be affected by exposure to lead, and some pesticides and persistent pollutants.
Scientific abstract:
Study Objective: To broadly review the recent literature linking environmental factors and adult female reproductive health for the UCSF-CHE Summit on Environmental Challenges to Reproductive Health and Fertility. Design: Reviewed articles indexed in PubMed from 1999-2007 addressing environment and puberty, menstrual and ovarian function, fertility, and menopause. Result(s): The strongest evidence of environmental contaminant exposures interfering with healthy reproductive function in adult females is for heavy metals, particularly lead. Compounds that can influence hormone function, including pesticides and persistent pollutants, are also associated with risk. The pattern of effects for these endocrine-active compounds is often complex, with no clear dose response, but alterations in function and poor reproductive health outcomes are observed. From a clinical perspective, most modifiable risk appears to be associated with exposures in unique populations (contaminated fish consumers) or occupational groups (farmworkers). Many compounds have demonstrated increased risks for reproductive health impairment in women, but the literature is largely cross-sectional in nature and too sparse or inconclusive to support causal inference. Conclusion(s): Reproductive function in adult females is impaired by lead exposure. Pesticides and persistent pollutants can alter hormone function resulting in adverse reproductive health effects. Coordinated research is needed to address contaminant effects across the life span.
Study Synopsis: This paper reviews the literature on the effect of exposure to pesticides on human semen quality. Of 20 studies evaluating semen quality, 13 reported associations with pesticide exposure; of 6 studies evaluating DNA damage, 3 found associations with exposure; and of 6 studies assessing sperm aneuploidy or diploidy, 4 reported an association with exposure. Studies varied widely in methods, exposures and outcomes. Although suggestive for semen parameters, authors beleive that the epidemiologic evidence accumulated thus far remains equivocal as to the spermatotoxic and aneugenic potential of pesticides.
Scientific abstract:
Relatively recent discoveries of the hormone disrupting properties of some pesticides have raised interest in how contemporary pesticide exposures, which primarily take the form of low level environmental or occupational exposures, impact spermatogenesis. The objective of the present review was to summarize results to date of studies examining pesticide effects on human sperm. Outcomes evaluated included sperm parameters, DNA damage and numerical chromosome aberrations (aneuploidy (disomy, nullisomy) or diploidy). Studies investigating sperm in men environmentally and/or occupationally exposed to any types of pesticides were included in the review. The targeted literature search over the last 15 years showed a range of pesticide classes have been investigated including pyrethroids, organophosphates, phenoxyacetic acids, carbamates, organochlorines and pesticide mixtures. None of the studies involved acute exposure events such as chemical accidents. There were 20 studies evaluating semen quality, of which 13 studies reported an association between exposure and semen quality; 6 studies evaluating DNA damage, of which 3 reported an association with exposure; and 6 studies assessing sperm aneuploidy or diploidy, of which 4 reported an association with exposure. Studies varied widely in methods, exposures and outcomes. Although suggestive for semen parameters, the epidemiologic evidence accumulated thus far remains equivocal as to the spermatotoxic and aneugenic potential of pesticides given the small number of published studies. This question warrants more investigation and suggestions for future studies are outlined.
Study Synopsis: The aim of this study was to evaluate the association between caffeine consumption by mothers during pregnancy and by their sons later in life. Researchers collected blood and semen samples from 343 Danish men and obtained information on caffeine consumptions based on questionnaires. Men whose mothers drank 4-7 cups of coffee per day had lower testosterone levels on average than those whose mothers drank less than 3 cups per day. On the other hand, men who themselves had higher coffee intake had 14% higher testosterone than men who consumed little. These results suggest that pre and postnatal caffeine consumption may affect testosterone levels in opposite directions.
Scientific abstract:
BACKGROUND: A few studies have investigated the association between male caffeine consumption in adult life and semen quality with conflicting results, but so far no studies have explored the effect of prenatal coffee exposure. We studied the association between prenatal coffee and current caffeine exposure and semen quality and levels of reproductive hormones. METHODS: From a Danish pregnancy cohort established in 1984-1987, 347 sons out of 5109 were selected for a follow-up study conducted 2005-2006. Semen and blood samples were analyzed for conventional semen characteristics and reproductive hormones and were related to information on maternal coffee consumption during pregnancy and present caffeine consumption. Data were available for 343 men. RESULTS: There was a tendency toward decreasing crude median semen volume (P = 0.06) and adjusted mean testosterone (P = 0.06) and inhibin B (P = 0.09) concentrations with increasing maternal coffee consumption during pregnancy. Sons of mothers drinking 4-7 cups/day had lower testosterone levels than sons of mothers drinking 0-3 cups/day (P = 0.04). Current male caffeine intake was associated with increasing testosterone levels (P = 0.007). Men with a high caffeine intake had [~]14% higher concentration of testosterone than those with a low caffeine intake (P = 0.008). CONCLUSIONS: The results observed in this study are only tentative, but they do not exclude a small to moderate effect of prenatal coffee exposure on semen volume and levels of reproductive hormones. Present adult caffeine intake did not show any clear associations with semen quality, but high caffeine intake was associated with a higher testosterone concentration.
Study Synopsis: Regulatory agencies currently consider that chemicals act independently if they affect health through different physiological processes (also called mechanisms of action). This study tested the hypothesis that seven common chemicals known to affect the development of the male reproductive system act in a cumulative manner. Researchers exposed pregnant rats to a mixture of vinclozolin, procymidone, linuron, prochloraz, benzyl butyl phthalate, dibutyl phthalate and diethylhexyl phthalate and examined its effects on markers of hormone disruption. They found that the effects of the mixture was equivalent to the summation of the expected effects of its individual components. These results suggest that some chemicals have a cumulative effect even if they do not that act through the same mechanisms of action. Current regulations, which assume that chemicals that act through different mechanisms of action have independent effects, may thus underestimate the risks of these chemicals.
Scientific abstract:
To date, regulatory agencies have not considered conducting cumulative risk assessments for mixtures of chemicals with diverse mechanisms of toxicity because it is assumed that the chemicals will act independently and the individual chemical doses are not additive. However, this assumption is not supported by new research addressing the joint effects of chemicals that disrupt reproductive tract development in the male rat by disrupting the androgen signalling pathway via diverse mechanisms of toxicity [i.e. androgen receptor (AR) antagonism in the reproductive tract vs. inhibition of androgen synthesis in the foetal testis]. In this study, pregnant rats were exposed to four dilutions of a mixture containing vinclozolin, procymidone, linuron, prochloraz, benzyl butyl phthalate, dibutyl phthalate and diethylhexyl phthalate during the period of sexual differentiation and male offspring were assessed for effects on hormone sensitive endpoints including: anogenital distance, infant areolae retention and reproductive tract tissue weights and malformations. The ratio of the chemicals in the mixture was based upon each chemical's ED(50) for inducing reproductive tract malformations (hypospadias or epididymal agenesis). The observed responses from the mixture were compared with predicted responses generated with a toxic equivalency approach and models of dose addition, response addition or integrated addition. As hypothesized, we found that the mixture of chemicals that alter the androgen signalling pathway via diverse mechanisms disrupted male rat reproductive tract differentiation and induced malformations in a cumulative, dose-additive manner. The toxic equivalency and dose addition models provided the best fit to observed responses even though the chemicals do not act via a common cellular mechanism of action. The current regulatory framework for conducting cumulative risk assessments needs to consider the results, including those presented herein, which indicate that chemicals that disrupt foetal tissues during sexual differentiation act in a cumulative, dose-additive manner irrespective of the specific cellular mechanism of toxicity.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. It is also used in carbonless copy paper. BPA has been shown to have the capability to mimic the hormone estrogen. In this study, researchers exposed rats to high doses of BPA during fetal development and examined them in adulthood. They found that rats exposed to BPA had an increased prevalence of mammary cancer. The observed lesions had an elevated number of estrogen receptors, suggesting that BPA may have caused cancer because of its estrogenic properties. Results suggest that exposure to high doses of BPA causes an increased risk of mammary cancer in rats.
Scientific abstract:
The hypothesis that prenatal exposure to endocrine disruptors might cause cancer arose from challenging two well-accepted notions: (i) mammalian development is merely the unfolding of a genetic programme and (ii) only mutagenic agents can cause cancer. This hypothesis required challenging genetic determinism. The ecological developmental biology (eco-devo) movement revitalized the concept of developmental plasticity through the occurrence of polyphenisms (a single genotype produces diverse phenotypes which are determined by environmental cues). Based on the principles of eco-devo and the tissue organization field theory of carcinogenesis and neoplasia, we tested the hypothesis that exposure to xenoestrogens during foetal development in rats increased the propensity to develop mammary cancer during adulthood. We chose exposure to bisphenol A (BPA) as a model for environmental oestrogen exposure. This endocrine disruptor induced the development of ductal hyperplasias and carcinoma in situ. These highly proliferative lesions contained an increased number of oestrogen receptor alpha-positive cells. Thus, foetal BPA exposure was sufficient to induce the development of oestrogen-sensitive pre-neoplastic and neoplastic lesions in the mammary gland in the absence of any additional treatment aimed at increasing tumour incidence.
Study Synopsis: This paper reviews the literature linking environmental contaminants with adverse pregnancy outcomes in humans. Researchers conclude that occupational exposure to organic solvents is related with increased risks of certain birth defects, that outdoor air pollution is associated with reduced term birth weight and preterm delivery, and that some evidence suggests relations between exposure to pesticides and polychlorinated biphenyls (PCBs) with decreased fetal growth and length of gestation. Relationships between environmental exposures and developmental delays, adult chronic illnesses, and reproductive health are also described.
Scientific abstract:
To better understand the science linking environmental contaminants exposures with adverse pregnancy outcomes, we reviewed the relevant epidemiologic literature. We searched PubMed (primarily 1995-2006) using the key word combinations for select environmental exposures and pregnancy outcomes. Environmental tobacco smoke is a risk factor for reduced birth weight and preterm delivery. Outdoor air pollution is associated with reduced term birth weight and preterm delivery. Suggestive evidence associates pesticides and polychlorinated biphenyls with decreased fetal growth and length of gestation. Stronger evidence, primarily occupational, links certain birth defects with exposure to organic solvents and chlorophenoxy herbicides. Evidence suggests dichlorodiphenyltrichloroethane and bisphenol-A could be associated with pregnancy loss. Exposures in utero can also increase the risk of developmental delays (ie, impaired neurological function), adult chronic illnesses (ie, heart disease, diabetes, cancer), and next generation effects (ie, reduced reproductive capacity). Further research, education, and improved public health policy are needed to reduce potentially adverse exposures.
Turyk ME, Persky VW, Imm P, Knobeloch L, Chatterton R, Anderson HA. Hormone disruption by PBDEs in adult male sport fish consumers. Environ Health Perspect. 2008 Dec;116(12):1635-41.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, funiture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers mesured the concentration of PBDEs, as well as structurally similar polybrominated biphenyls (PCBs), in the blood of 405 adult males. They found that men with higher PBDE levels had higher levels of the thyroid hormone thyroxine (T4) but lower levels of triiodothyronine (T3) and thyroid-stimulating hormone. In addition, blood concentrations of BDE-47, the PBDE congener most commonly detected in humans, were related with higher levels of the male hormone testosterone. Results suggest that exposure to PBDEs may be related with altered levels of thyroid hormone and testosterone in men.
Scientific abstract:
BACKGROUND: Persistent pollutants, such as polychlorinated biphenyls (PCBs), affect endocrine function. Human exposure to polybrominated diphenyl ethers (PBDEs), which are similar in structure to PCBs, has increased recently, but health effects have not been well studied. OBJECTIVES: Our goal in this study was to determine whether PBDE body burdens are related to thyroid and steroid hormone levels, thyroid antibodies, and thyroid disease in a cohort of frequent and infrequent adult male sport fish consumers. METHODS: We tested serum from 405 adult males for PBDE congeners, PCB congeners, testosterone, sex-hormone-binding globulin (SHBG), SHBG-bound testosterone, thyroglobulin antibodies, and the thyroid hormones thyroxine (T(4)), triiodothyronine (T(3)), thyroid-stimulating hormone (TSH), and T(4)-binding globulin (TBG). We collected data on demographics, fish consumption, medical diseases, and medication use. RESULTS: The median sum of PBDEs was 38 ng/g lipid. In 308 men without thyroid disease or diabetes, PBDEs were positively related to measures of T(4) and reverse T(3) and inversely related to total T(3) and TSH. PBDEs were positively related to the percentage of T(4) bound to albumin, and inversely related to the percentage of T(4) bound to TBG. Associations of BDE congeners with hormones varied. BDE-47 was positively associated with testosterone levels. Participants with PBDEs over the 95th percentile were more likely to have thyroglobulin antibodies, although high PBDE exposure was not associated with thyroid disease. PBDE effects were independent of PCB exposure and sport fish consumption. CONCLUSIONS: PBDE exposure, at levels comparable with those of the general U.S. population, was associated with increased thyroglobulin antibodies and increased T(4) in adult males.
Turyk ME, Persky VW, Imm P, Knobeloch L, Chatterton R, Anderson HA. Hormone disruption by PBDEs in adult male sport fish consumers. Environ Health Perspect. 2008 Dec;116(12):1635-41.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. In this study, researchers measured the concentration of PBDE congeners in 308 adult males sport fish consumers. They found elevated levels of thyroxine (T4) and reduced levels of triiodothyronine (T3) and thyroid-stimulating hormone (TSH) among men with higher blood PBDEs. BDE-47 was also associated with elevated testosterone levels. These results suggest that exposure to PBDEs may be related to changes in thyroid hormone and testosterone levels.
Scientific abstract:
BACKGROUND: Persistent pollutants, such as polychlorinated biphenyls (PCBs), affect endocrine function. Human exposure to polybrominated diphenyl ethers (PBDEs), which are similar in structure to PCBs, has increased recently, but health effects have not been well studied. OBJECTIVES: Our goal in this study was to determine whether PBDE body burdens are related to thyroid and steroid hormone levels, thyroid antibodies, and thyroid disease in a cohort of frequent and infrequent adult male sport fish consumers. METHODS: We tested serum from 405 adult males for PBDE congeners, PCB congeners, testosterone, sex-hormone-binding globulin (SHBG), SHBG-bound testosterone, thyroglobulin antibodies, and the thyroid hormones thyroxine (T(4)), triiodothyronine (T(3)), thyroid-stimulating hormone (TSH), and T(4)-binding globulin (TBG). We collected data on demographics, fish consumption, medical diseases, and medication use. RESULTS: The median sum of PBDEs was 38 ng/g lipid. In 308 men without thyroid disease or diabetes, PBDEs were positively related to measures of T(4) and reverse T(3) and inversely related to total T(3) and TSH. PBDEs were positively related to the percentage of T(4) bound to albumin, and inversely related to the percentage of T(4) bound to TBG. Associations of BDE congeners with hormones varied. BDE-47 was positively associated with testosterone levels. Participants with PBDEs over the 95th percentile were more likely to have thyroglobulin antibodies, although high PBDE exposure was not associated with thyroid disease. PBDE effects were independent of PCB exposure and sport fish consumption. CONCLUSIONS: PBDE exposure, at levels comparable with those of the general U.S. population, was associated with increased thyroglobulin antibodies and increased T(4) in adult males.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. In this study, researchers exposed mice to BPA at concentrations ranging from 0 to 600 mg per kg per day. No effects were found on adult mating, fertility, estrous cycle, male:female ratio, sperm parameters, reproductive organ weight and tissue structure. High doses of BPA however caused abnormalities in liver cells, reduced body weight increased kidney and liver weights and abnormalities in kidney structure. Reduced spleen and testis weight, delayed puberty and possibly increases in the rates of undescended testes were also observed in rats exposed to the highest dose of BPA. Given that no effects were observed at low dose, these results suggest that BPA is not a reproductive or developmental toxicant in mice.
Scientific abstract:
Dietary bisphenol A (BPA) was evaluated in a mouse two-generation study at 0, 0.018, 0.18, 1.8, 30, 300, or 3500 ppm (0, 0.003, 0.03, 0.3, 5, 50, or 600 mg BPA/kg/day, 28 per sex per group). A concurrent positive control group of dietary 17beta-estradiol (0.5 ppm; 28 per sex) confirmed the sensitivity of CD-1 mice to an endogenous estrogen. There were no BPA-related effects on adult mating, fertility or gestational indices, ovarian primordial follicle counts, estrous cyclicity, precoital interval, offspring sex ratios or postnatal survival, sperm parameters or reproductive organ weights or histopathology (including the testes and prostate). Adult systemic effects: at 300 ppm, only centrilobular hepatocyte hypertrophy; at 3500 ppm, reduced body weight, increased kidney and liver weights, centrilobular hepatocyte hypertrophy, and renal nephropathy in males. At 3500 ppm, BPA also reduced F1/F2 weanling body weight, reduced weanling spleen and testes weights (with seminiferous tubule hypoplasia), slightly delayed preputial separation (PPS), and apparently increased the incidence of treatment-related, undescended testes only in weanlings, which did not result in adverse effects on adult reproductive structures or functions; this last finding is considered a developmental delay in the normal process of testes descent. It is likely that these transient effects were secondary to (and caused by) systemic toxicity. Gestational length was increased by 0.3 days in F1/F2 generations; the toxicological significance, if any, of this marginal difference is unknown. At lower doses (0.018-30 ppm), there were no treatment-related effects and no evidence of nonmonotonic dose-response curves for any parameter. The systemic no observable effect level (NOEL) was 30 ppm BPA (approximately 5 mg/kg/day); the reproductive/developmental NOEL was 300 ppm (approximately 50 mg/kg/day). Therefore, BPA is not considered a selective reproductive or developmental toxicant in mice.
Van Der Ven LT, Van De Kuil T, Verhoef A, Leonards PE, Slob W, Canton RF, Germer S, Hamers T, Visser TJ, Litens S, Hakansson H, Fery Y, Schrenk D, Van Den Berg M, Piersma AH, Vos JG. A 28-day oral dose toxicity study enhanced to detect endocrine effects of a purified technical pentabromodiphenyl ether (pentaBDE) mixture in Wistar rats. Toxicology. 2008 Mar;245(1-2):109-22.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, rats were dosed with varying doses of the commercial PBDE mixture DE-71. Exposure was shown to result in increased liver weight and alterations in structure of liver tissues. A marked decrease in the blood levels of the thyroid hormone thyroxine (T4) and an increase in blood cholesterol were also observed in exposed animals. In addition, the weight of organs dependent on androgens (such as the seminal vesicles and prostate) was reduced, suggesting that PBDEs antagonize the activity of these hormones. Finally, exposure caused increases in sperm deformities. Results suggest that exposure to DE-71 affects the liver and androgen-dependent organs, the blood levels of thyroid hormone and cholesterol, and semen quality.
Scientific abstract:
A 28-day subacute oral toxicity study was performed in Wistar rats with a purified preparation of the commercial pentabromodiphenyl ether (pentaBDE), DE-71. The applied OECD407 protocol was enhanced for endocrine and immune parameters, and to enable benchmark dose analysis. A vehicle control group and 7 dose groups were included, which received 0.27, 0.82, 2.47, 7.4, 22.2, 66.7 or 200 mg pentaBDE/kg bw/d (mkd). The liver appeared to be a key target organ, showing a marked increase of weight and centrilobular hepatocellular hypertrophy, probably due to the observed induction of P450 enzymes, notably CYP1A and CYP2B. A marked decrease of circulating total thyroxine (TT4) and an increase of plasma cholesterol were probably secondary to the liver effects. Furthermore, dose-dependently decreased weight of epididymis, seminal vesicles, and prostate, as well as sperm head deformities in males, and induction of CYP17 activity in adrenals in females were observed, all possibly related to anti-androgenic activity. Finally, we observed a substantial increase of large unstained cells in the blood and a decrease of apolar retinoids in the liver. All these effects had benchmark doses at the lower confidence bound (BMDL) in the low- or mid-dose range, but particular sensitive, potentially adverse effects were TT4 decrease (BMDLs 1.1 in males and 1.8 mkd in females), and decrease of hepatic apolar retinoids (BMDLs 0.5 mkd in males and 2.3 mkd in females). These results contribute to refinement of the hazard identification of pentaBDE and improved risk assessment of human exposure to this industrial chemical and environmental pollutant.
Van Der Ven LT, Van De Kuil T, Verhoef A, Verwer CM, Lilienthal H, Leonards PE, Schauer UM, Canton RF, Litens S, De Jong FH, Visser TJ, Dekant W, Stern N, Hakansson H, Slob W, Van Den Berg M, Vos JG, Piersma AH. Endocrine effects of tetrabromobisphenol-A (TBBPA) in Wistar rats as tested in a one-generation reproduction study and a subacute toxicity study. Toxicology. 2008 Mar;245(1-2):76-89.
Study Synopsis: Tetrabromobisphenol-A (TBBPA) is a flame retardant primarily used in electronics but also in plastics, paper and textiles. Although a growing number of studies have examined the potential health effects of other flame retardants, such as polybrominated diphenyl ethers (PBDEs), few studies have investigated the effect of exposure to TBBPA. In this study, researchers exposed pregnant rats to different doses of TBBPA and observed potential health effects in offspring. They found that the chemical decreased the blood levels of the thyroid hormone thyroxine (T4) and increased testis weight. The weight of the pituitary gland, which controls a number of hormones, was also increased whereas testis weight and blood testosterone levels were increased in males. In females, TBBPA delayed sexual development and altered the weight of gonads. Postnatal exposure only affected thyroid hormone levels in males, suggesting that most adverse health effects observed may only be caused by exposure during fetal development. Results suggest that prenatal exposure to TBBPA may adversely affect development in rats.
Scientific abstract:
Endocrine effects of the brominated flame retardant tetrabromobisphenol-A (TBBPA) were studied in a one-generation reproduction assay in Wistar rats via repeated dietary exposure, applying eight dose groups at 0-3-10-30-100-300-1,000-3,000 mg/kg body weight/day (mkd). This design enables dose-response analysis and calculation of benchmark doses (BMDL). This reproduction study was preceded by a 28-day repeat dose subacute toxicity study, at 0-30-100-300 mkd. Major effects in the reproduction study included decreased circulating thyroxine (T4) with BMDLs of 31 (m) and 16 (f) mkd, and increased weight of testis and male pituitary (BMDLs of 0.5 and 0.6 mkd). The hypothyroxinemia correlated to a cluster of developmental parameters including delayed sexual development in females, decreased pup mortality, and effects on brainstem auditory evoked potentials [Lilienthal, H., Verwer, C.M., Van der Ven, L.T.M., Piersma, A.H., Vos, J.G., 2008. Neurobehavioral effects of tetrabromobisphenol A (TBBPA) in rats after pre- and postnatal exposure. Toxicology]. A second cluster of parameters in F1 animals was correlated to increased testis weight, and included female gonad weight, endometrium height, CYP19/aromatase activity in the ovary, and plasma testosterone levels in males. These two correlation clusters suggest a dual action of TBBPA. The only effects in the subacute study were decreased circulating T4 and increased T3 levels in males (BMDLs 48 and 124mkd), and non-significant trends for these parameters in females, suggesting that the other effects in the reproduction study were induced during development. Combined with data of human exposure to environmental TBBPA, the margin of exposure for highly exposed populations can be calculated at 2.6, and current use of TBBPA may therefore be a matter of concern for human health.
Key Words: Administration, Oral, Animals, Body Weight/drug effects, Bone Development/drug effects, Bone and Bones/drug effects, Dose-Response Relationship, Drug, Endocrine Disruptors/pharmacokinetics/ toxicity, Female, Male, Organ Size/drug effects, Polybrominated Biphenyls/pharmacokinetics/ toxicity, Rats, Rats, Wistar, Reproduction/ drug effects, Thyroid Hormones/blood, Tissue Distribution, Toxicity Tests/methods
Wirth JJ, Rossano MG, Potter R, Puscheck E, Daly DC, Paneth N, Krawetz SA, Protas BM, Diamond MP. A pilot study associating urinary concentrations of phthalate metabolites and semen quality. Syst Biol Reprod Med. 2008 May-Jun;54(3):143-54.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers obtained semen samples and measured the concentration of several phthalate metabolites in the urine of 45 male partners of subfertile couples presenting to a Michigan infertility clinic. They found that men with high levels of monoethyl phthalate (MEP) had 6.5 times the odds of having low sperm concentration and that those with high levels of monocarboxypropyl phthalate (MCPP) had 7.6 times the odds of having high numbers of abnormal sperms. Men with high levels of diethylhexyl phthalate (DEHP) and MEP also tended to have lower sperm concentration and more sperm with abnormal morphology, respectively. Results suggest that exposure to phthalates may be related to impaired semen quality in male partners of subfertile couples.
Scientific abstract:
Phthalates are ubiquitous industrial chemicals that are reported to adversely affect human reproductive outcomes. Divergent effects on semen quality have been reported in a limited number of studies. To assess the possible contribution of regional differences in phthalate exposure to these results, we wished to determine if ambient phthalate exposure of men from the Great Lakes region was associated with human sperm parameters. Male partners (N=45) of subfertile couples presenting to a Michigan infertility clinic were recruited. Urinary concentrations of several phthalate metabolites were measured in these men. Semen parameters, measured according to the World Health Organization [WHO 1999] protocols, were divided into those at or above WHO cutoffs for motility (50% motile), concentration (20 million/mL) and morphology (4% normal) and those below. Phthalate metabolite concentrations were divided into those concentrations above the median and those at or below the median. Specific gravity was used as a covariate in the regression models to adjust for urine dilution. Low sperm concentration was significantly associated with above median concentrations of monoethyl phthalate (MEP) (OR=6.5, 95% CI: 1.0-43.6) and low morphology with above median concentrations of mono-3-carboxypropyl phthalate (OR=7.6, 95% CI: 1.7-33.3). Increased odds for low concentration and above median concentrations of metabolites of di(2-ethylhexyl) phthalate (DEHP) (OR=5.4, 95% CI: 0.9-30.8) and low morphology and above median concentrations of MEP (OR=3.4, 95% CI: 0.9-13.8) were also found. A significant trend was observed for tertiles of MEP and low sperm concentration (p=0.05). Results suggest that ambient phthalate metabolite concentrations may adversely affect human semen quality.
Key Words: Adult, Diethylhexyl Phthalate/adverse effects, Great Lakes Region, Humans, Infertility, Male/ chemically induced/pathology, Male, Middle Aged, Odds Ratio, Phthalic Acids/ adverse effects/urine, Pilot Projects, Risk Assessment, Semen/ drug effects, Sperm Count, Sperm Motility/drug effects, Spermatozoa/ drug effects/pathology, Water Pollutants, Chemical/ adverse effects/urine
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured the concentration of 10 phthalate metabolites and 5 phenols in urine samples collected from 404 women during their third trimester of pregnancy. They found that phthalates with low molecular weights were associated with longer gestational duration and larger head circumference. Higher levels of 2,5-dichlorophenol (2,5-DCP) was related to lower birth weight in boys and higher maternal benzophenone-3 (BP3) concentrations were associated with lower birth weight among girls but with greater birth weight in boys. Most exposures measured in this study were not associated with gestational duration, head circumference or birth weight. The reported associations may have been due to chance. These results do not support a relationship between prenatal exposure to phthalates or phenols and pregnancy outcomes.
Scientific abstract:
BACKGROUND: Many phthalates and phenols are hormonally active and are suspected to alter the course of development. OBJECTIVE: We investigated prenatal exposures to phthalate and phenol metabolites and their associations with body size measures of the infants at birth. METHODS: We measured 5 phenol and 10 phthalate urinary metabolites in a multiethnic cohort of 404 women in New York City during their third trimester of pregnancy and recorded size of infants at birth. RESULTS: Median urinary concentrations were > 10 microg/L for 2 of 5 phenols and 6 of 10 phthalate monoester metabolites. Concentrations of low-molecular-weight phthalate monoesters (low-MWP) were approximately 5-fold greater than those of high-molecular-weight metabolites. Low-MWP metabolites had a positive association with gestational age [0.97 day gestational age per ln-biomarker; 95% confidence interval (CI), 0.07-1.9 days, multivariate adjusted] and with head circumference. Higher prenatal exposures to 2,5-dichlorophenol (2,5-DCP) predicted lower birth weight in boys (-210 g average birth weight difference between the third tertile and first tertile of 2,5-DCP; 95% CI, 71-348 g). Higher maternal benzophenone-3 (BP3) concentrations were associated with a similar decrease in birth weight among girls but with greater birth weight in boys. CONCLUSIONS: We observed a range of phthalate and phenol exposures during pregnancy in our population, but few were associated with birth size. The association of 2,5-DCP and BP3 with reduced or increased birth weight could be important in very early or small-size births. In addition, positive associations of urinary metabolites with some outcomes may be attributable partly to unresolved confounding with maternal anthropometric factors.
Study Synopsis: Perfluorooctanoic acid (PFOA) is a highly persistent water and oil repellent used in products such as Teflon, Scotchguard and Gore-Tex. It has been measured in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA. In animals, exposure to high doses of PFOA adversely affects offspring development but it is unclear how these chemicals exert their toxic effects. In this study, researchers exposed two group of pregnant mice to PFOA: normal mice as well as mice lacking a receptor (called peroxisome proliferator-activated receptor-alpha, or PPAR-alpha) involved in liver cancer and important for fetal development in rodents. Prenatal exposure to PFOA was related with increased neonatal mortality and delayed eye opening in normal mice but not in mice lacking PPAR-alpha, suggesting that the adverse effect of PFOA on these outcomes is mediated by PPAR-alpha.
Perfluorooctanoic acid (PFOA) is a member of a family of perfluorinated chemicals that have a variety of applications. PFOA persists in the environment and is found in wildlife and humans. In mice, PFOA is developmentally toxic producing mortality, delayed eye opening, growth deficits, and altered pubertal maturation. PFOA activates peroxisome proliferatorsactivated receptor-alpha (PPAR{alpha}), a pathway critical to the mode of induction of liver tumors in rodents. The present study uses 129S1/SvlmJ wild-type (WT) and PPAR{alpha} knockout (KO) mice to determine if PPAR{alpha} mediates PFOA-induced developmental toxicity. Pregnant mice were dosed orally from gestation days 117 with water or 0.1, 0.3, 0.6, 1, 3, 5, 10, or 20 mg PFOA/kg. PFOA did not affect maternal weight, embryonic implantation, number, or weight of pups at birth. At 5 mg/kg, the incidence of full litter resorptions increased in both WT and KO mice. In WT, but not KO, neonatal survival was reduced (0.6 mg/kg) and eye opening was delayed (1 mg/kg). There was a trend across dose for reduced pup weight (WT and KO) on several postnatal days (PND), but only WT exposed to 1 mg/kg were significantly different from control (PND710 and 22). Maternal factors (e.g., background genetics) did not contribute to differences in postnatal mortality, as PFOA induced postnatal mortality in heterozygous pups born to WT or KO dams. In conclusion, early pregnancy loss was independent of PPAR{alpha} expression. Delayed eye opening and deficits in postnatal weight gain appeared to depend on PPAR{alpha} expression, although other mechanisms may contribute. PPAR{alpha} was required for PFOA-induced postnatal lethality and expression of one copy of the gene was sufficient to mediate this effect.
Study Synopsis: Men with diabetes have increased levels of DNA damage in their sperm. Although there were no differences in conventional semen parameters, diabetic men had increased nuclear and mitochondrial DNA damage. Because incidence of diabetes is increasing in men of reproductive age, this study indicates they may have reduced reproductive capability.
Scientific abstract:
BACKGROUND: Diabetes mellitus (DM) is increasing in men of reproductive age. Despite this, the prevalence of diabetes in men attending fertility clinics is largely unknown. Furthermore, studies examining the effects of DM on sperm fertility potential have been limited to conventional semen analysis. METHODS: Conventional semen analysis (semen volume, sperm count, motility and morphology) was performed for 27 diabetic (mean age 34 {+/-} 2 years) and 29 non-diabetic subjects (control group, men undergoing routine infertility investigations, mean age 33 {+/-} 1 years). Nuclear DNA (nDNA) fragmentation was assessed using the alkaline Comet assay and mitochondrial DNA (mtDNA) deletions by Long-PCR. RESULTS: Other than a small, but significant, reduction in semen volume in diabetic men (2.6 versus 3.3 ml; P < 0.05), conventional semen parameters did not differ significantly from control subjects. Diabetic subjects had significantly higher mean nDNA fragmentation (53 versus 32%; P < 0.0001) and median number of mtDNA deletions (4 versus 3; P < 0.05) compared with control subjects. CONCLUSIONS: Diabetes is associated with increased sperm nuclear and mtDNA damage that may impair the reproductive capability of these men.
Key Words: diabetes mellitus, sperm, DNA damage, male infertility, Comet assay
Study Synopsis: Organic solvents are carbon-based substances capable of dissolving other substances. These are used in a wide variety of products including paints, varnishes, lacquers, glues, cleaning agents, and in the production of dyes, plastics, textiles and pharmaceuticals. Millions of U.S. workers are exposed to organic solvents. In this study, researchers asked 1670 Finnish women who delivered singletons about their exposure to solvents at work. They found that women exposed 3 months before or during pregnancy had 67% increased odds of delivering babies that were small-for-gestational-age (also called intrauterine growth restriction), suggesting that maternal exposure to solvents may alter fetal development. Neonates who have a birth weight below the 10th percentile for their gestational age are considered small-for-gestational-age. These neonates have higher risks of mortality and morbidity.
Scientific abstract:
BACKGROUND: Organic solvents are among the most common exposures in the workplace. Our objective was to elaborate the relationship between prenatal occupational solvent exposure and fetal growth as well as duration of pregnancy, and to quantify the impact of occupational organic solvent exposure. METHODS: We conducted a population-based study of 1670 singleton newborns of women who participated in The Finnish Prenatal Environment and Health Study after their delivery (response rate 94%) and who were working during pregnancy (65%). Exposure information was based on questions about exposure to solvents at work before and during pregnancy. The health outcomes, based on information from a questionnaire and the Finnish Medical Birth Registry, were low birth weight (<3000 g), small-for-gestational-age and preterm delivery (<37 weeks). RESULTS: In logistic regression analysis, the risk of the baby being small-for-gestational-age was related to any exposure to solvents 3 months before or during pregnancy with an adjusted odds ratio (OR) of 1.67 [95% confidence interval (CI) = 1.02, 2.73]. Also the adjusted OR for low birth weight was elevated with exposure, although it did not reach statistical significance (1.17; 95% CI = 0.71, 1.93). The population attributable fraction for small-for-gestational-age was 2.3% for all pregnant women. CONCLUSIONS: Work exposure to organic solvents may reduce intrauterine growth by increasing the risk of the baby being small-for-gestational-age.
Study Synopsis: Two components of soy, namely genistein and daidzein, have been shown to have effects that are similar to those of the female hormone estrogen. As part of this study, researchers fed pregnant rats and their male offspring with a diet containing different concentrations of genistein and daidzein. They found that rats fed with the highest dose of the chemicals (1,000 parts per million) had elevated blood levels of the male sex hormones androsterone (at 21 days of age) and testosterone (at 90 days of age). Testosterone secretion by Leydig cells, located in the testes, was however reduced after direct exposure to genistein in petri dishes. These results suggest that high doses of soy or soy products may affect male reproductive tract development.
Scientific abstract:
The use of soy-based products in the diet of infants has raised concerns regarding the reproductive toxicity of genistein and daidzein, the predominant isoflavones in soybeans with estrogenic activity. Time-bred Long-Evans dams were fed diets containing 0, 5, 50, 500, or 1000 ppm of soy isoflavones from gestational d 12 until weaning at d 21 postpartum. Male rats in all groups were fed soy-free diets from postnatal d 21 until 90 d of age. The mean {+/-} SD concentration of unconjugated (i.e. biologically active) genistein and daidzein in serum from the group of dams maintained on the diet containing the highest amount of isoflavones (1000 ppm) were 17 {+/-} 27 and 56 {+/-} 30 nM, respectively, at d 21 postpartum. The concentrations were considerably greater in male offspring (genistein: 73 {+/-} 46 nM; daidzein: 106 {+/-} 53 nM). Although steroidogenesis was decreased in individual Leydig cells, male rats from the highest exposure group (1000 ppm diet) exhibited elevated serum levels of the sex steroid hormones androsterone at 21 d (control: 15 {+/-} 1.5 vs.28 {+/-} 3.5 ng/ml; P < 0.05) and testosterone at 90 d of age (control: 7.5 {+/-} 1 vs.17 {+/-} 2 ng/ml; P < 0.05). Testosterone secretion by immature Leydig cells, isolated from 35-d-old male rats, decreased on exposure to 0.1 nM genistein in vitro (control: 175 {+/-} 5 vs. 117 {+/-} 3 ng/106 cells per 24 h; P < 0.05), indicative of direct phytoestrogen action. Thus, phytoestrogens have the ability to regulate Leydig cells, and additional studies to assess potential adverse effects of dietary soy-based products on reproductive tract development in neonates are warranted.
Aneck-Hahn NH, Schulenburg GW, Bornman MS, Farias P, De Jager C. Impaired semen quality associated with environmental DDT exposure in young men living in a malaria area in the Limpopo Province, South Africa. J Androl. 2007 May-Jun;28(3):423-34.
Study Synopsis: DDT it an insecticide that was banned by the U.S. Environmental Protection Agency (EPA) in the 1970s due to concerns about its persistence in the environment and toxic effects on wildlife and humans. DDT has now been banned internationally by the Stockholm Convention on Persistent Organic Pollutants, except to control insects that carry diseases such as malaria. In this study, researchers measured the levels of DDT in the blood of 311 healthy men living in the Limpopo province of South Africa, where DDT is used to control malaria. They found that men with higher levels of DDE, DDT's breakdown product, had lower ejaculate volume, sperm count and sperm motility. The prevalence of other sperm abnormalities was also related to DDT and DDE blood levels. These results suggest that exposure to DDT and DDE may affect semen quality.
Scientific abstract:
The pesticide DDT [1,1,1-trichloro-2,2-bis(chlorodiphenyl)ethane] is 1 of the 12 persistent organic pollutants (POPs) under negotiation at the Stockholm Convention to restrict or ban their production and use because of their toxicity, resistance to breakdown, bioaccumulation, and potential for being transported over long distances. DDT has estrogenic potential, and the main metabolite, p,p'-dichlorodiphenyl-dichloroethylene (p,p'-DDE), is a potent antiandrogen. In response to mounting evidence on the endocrine-disrupting influence of environmental chemicals on human health, this epidemiological study was initiated to test the hypothesis that nonoccupational exposure to DDT affects male reproductive parameters. In a cross-sectional study, healthy male subjects (n=311) between 18 and 40 years (23+/-5) of age were recruited from 3 communities in an endemic malaria area in which DDT is sprayed annually. A semen analysis according to World Health Organization (WHO) standards was performed. The Hamilton Thorne Computer Assisted Sperm Analysis (CASA) system was simultaneously used to determine additional sperm motility parameters. Blood plasma samples were assayed for p,p'-DDT and metabolites as a measure of exposure. The exposure levels were expressed as lipid-adjusted p,p'-DDT and p,p'-DDE values. The mean p,p'-DDT and p,p'-DDE concentrations were 90.23 microg/g(+/-102.4) and 215.47 microg/g(+/-210.6), respectively. The multivariate linear regression analyses indicated that mean CASA motility was lower with a higher p,p'-DDE concentration (beta=-0.02, P=.001) and the CASA parameter beat cross-frequency (BCF) was higher with a higher p,p'-DDT concentration (beta=0.01, P=.000). There was also a statistically significant positive association between percent sperm with cytoplasmic droplets and p,p'-DDT concentration (beta=0.0014, P=.014). The ejaculate volume (mean 1.9+/-1.33 mL) was lower than the normal range (>or=2.0 mL) according to WHO, and a significant decrease with increasing p,p'-DDE values was seen for both square root-transformed volume (beta=-0.0003; P=.024) and count (beta=-0.003; P=.04). Although there were no associations between either p,p'-DDT or p,p'-DDE concentrations and the rest of the seminal parameters, the incidence of teratozoospermia (99%; normal sperm<15%) was high. Twenty-eight percent of the study group presented with oligozoospermia (<20x10(6) sperm/mL), which had a significant positive association with p,p'-DDE (odds ratio [OR]=1.001, P=.03). There was a significant positive association between participants with asthenozoospermia (32%) and p,p'-DDT (OR 1.003, P=.006) and p,p'-DDE (OR 1.001, P=.02). The results imply that nonoccupational exposure to DDT is associated with impaired seminal parameters in men. The high exposure levels of p,p'-DDT and p,p'-DDE are of concern because these levels could have far-reaching implications for reproductive and general health.
Study Synopsis: Scientists report that almost all babies measured in a large study in Baltimore had been exposed to perfluorinated contaminants -- PFCs -- while in the womb. PFCs are widely used in consumer products like Teflon and Gore-Tex. They are extremely persistent. The levels observed were well beneath those shown in most experiments to be necessary to cause developmental harm in animals.
Polyfluoroalkyl compounds (PFCs), such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), are ubiquitous, man-made chemicals. Human data suggest that in utero exposures to these chemicals occur and some evidence of developmental toxicity in animals exists. To assess the distribution and determinants of fetal exposure to PFCs, we analyzed cord serum samples from 299 singleton newborns delivered between 2004 and 2005 in Baltimore, MD for 10 PFCs by employing on-line solid-phase extraction coupled with reversed-phase high-performance liquid chromatography-tandem mass spectrometry. PFOS and PFOA were detected in 99 and 100% of umbilical cord sera, with geometric mean concentrations of 4.9 and 1.6 ng/mL, respectively. PFOS and PFOA concentrations were highly correlated (Pearson's r = 0.64 after natural log transformation, p < 0.01). Eight other PFCs were detected less frequently and at lower concentrations than PFOS and PFOA. Geometric mean concentrations of PFOS for Asians (6.0 ng/mL) and Blacks (5.1 ng/mL) were higher than those for Whites (4.2 ng/mL), while PFOA levels were more evenly distributed by race. Other maternal demographic and socioeconomic characteristics, including age, education, marital status, and living in the city limits were not significantly associated with cord concentrations. Our findings suggest that in utero exposure to PFOS and PFOA is ubiquitous in a population of babies born in Baltimore, MD.
BACKGROUND: Recent studies have reported developmental toxicity among rodents dosed with perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). OBJECTIVES: We examined the relationship between concentrations of PFOS and PFOA in cord serum (surrogates for in utero exposures) and gestational age, birth weight, and birth size in humans. METHODS: We conducted a hospital-based cross-sectional epidemiologic study of singleton deliveries in Baltimore, Maryland. Cord serum samples (n = 293) were analyzed for PFOS and PFOA by online solid-phase extraction, coupled with reversed-phase high-performance liquid chromatography-isotope dilution tandem mass spectrometry. Maternal characteristics and anthropometric measures were obtained from medical charts. RESULTS: After adjusting for potential confounders, both PFOS and PFOA were negatively associated with birth weight [per ln-unit: beta = -69 g, 95% confidence interval (CI), -149 to 10 for PFOS; beta = -104 g, 95% CI, -213 to 5 for PFOA], ponderal index (per ln-unit: beta = -0.074 g/cm(3) x 100, 95% CI, -0.123 to -0.025 for PFOS; beta = -0.070 g/cm(3) x 100, 95% CI, -0.138 to -0.001 for PFOA), and head circumference (per ln-unit: beta = -0.32 cm, 95% CI, -0.56 to -0.07 for PFOS; beta = -0.41 cm, 95% CI, -0.76 to -0.07 for PFOA). No associations were observed between either PFOS or PFOA concentrations and newborn length or gestational age. All associations were independent of cord serum lipid concentrations. CONCLUSIONS: Despite relatively low cord serum concentrations, we observed small negative associations between both PFOS and PFOA concentrations and birth weight and size. Future studies should attempt to replicate these findings in other populations.
Key Words: Adolescent, Adult, Alkanesulfonic Acids/*blood, *Birth Weight, Body Mass Index, *Body Size, Cephalometry, Chromatography, High Pressure Liquid, Cross-Sectional Studies, Environmental Exposure, Female, Fetal Blood/*chemistry, Fluorocarbons/*blood, *Gestational Age, Humans, Infant, Newborn, Male, Maternal-Fetal Exchange, Octanoic Acids/*blood, Pregnancy, Tandem Mass Spectrometry/methods
Study Synopsis: Danish study finds that fathers of naturally conceived twins have better semen quality than fathers of singletons. Twin fathers had higher percentages of motile sperm and morphologically normal sperm as well as higher sperm concentration and sperm count compared to fathers of singletons. Findings from this study and others support the hypothesis that spontaneous twinning may reflect population trends in male fecundity.
Scientific abstract:
BACKGROUND: Recent studies found an association between a long waiting time to pregnancy (TTP) and reduced probability of twinning and a reduced dizygotic (DZ) twinning rate in subfertile men. However, it remains unsolved whether semen quality is associated with twin offspring. We therefore studied the semen quality in a group of fathers of naturally conceived twins. METHODS: In this study, 37 fathers of DZ twins and 15 fathers of monozygotic (MZ) twins participated, and 349 normal fertile men served as a reference group. All men delivered a semen sample, underwent a physical examination and completed a questionnaire. RESULTS: After adjustment, fathers of DZ and MZ twins had 3.6 (95% CI 1.7; 5.4) and 4.6 (95% CI 2.0; 7.2) percentage points higher percentage of sperm cells with normal morphologic features and percentages of motile sperm cells were 11.5 (95% CI 7.2; 15.9) and 12.5 (95% CI 6.3; 18.6) percentage points higher than the reference group (P < 0.01). Fathers of DZ twins and MZ twins had 24.7 (95% CI; -9.1; 71.3) and 17.0% (-25.2%; 83.0%) higher sperm concentration than the reference group. CONCLUSIONS: Fathers of DZ twins had a better semen quality than the reference group, which supports the assumption that spontaneous DZ twinning rate can be used as a sensor of male fecundity of a population.
Study Synopsis: The placenta is not a barrier that can protect a developing fetus from xenobiotic chemicals. Pharmaceutical drugs, drugs of abuse, tobacco products, and environmental chemicals have been measured in umbilical cord blood, amniotic fluid, and meconium. Some of these chemicals have been associated with adverse birth outcomes, neurological damage and adult-onset disease.
Scientific abstract:
Exposure to a variety of toxic chemicals has been associated with adverse health outcomes. Presumably, the most vulnerable population for these adverse health outcomes are fetuses that are exposed to toxicants in utero. Fetuses have immature organ systems and often their detoxification enzymes or enzymatic processes are not fully developed when exposures occur. Many xenobiotic chemicals have been shown to pass through the placental barrier and into the fetal blood stream. These exposures have been associated with adverse birth outcomes, neurocognitive delays and adult onset disease. Exposures associated with interuterine growth retardation have been linked to a variety of adult onset diseases such as coronary artery disease and diabetes. In this article, we review a variety of chemicals that have been known to enter the fetal environment and their potential to affect both early childhood and subsequently adult health. We restrict our review to chemicals shown to be present in umbilical cord blood, amniotic fluid, or meconium, thus unequivocally demonstrating the chemicals have entered the fetal environment. In some instances where known health outcomes have occurred from these exposures, we note these and any caveats associated with the exposures.
Study Synopsis: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (also called TCDD and, most commonly, dioxin) is a highly toxic chemicals that persist in the environment, accumulate in human fatty tissue and concentrate up the food chain. Prenatal exposure to TCDD has been associated with a range of adverse health effects, including effects on the male reproductive system. In this study, rats were exposed to a single dose of TCDD during pregnancy. TCDD caused a reduction in offspring body weight lasting up to 21 days after birth in the high dose group (1,000 ng/kg body weight) and 7 days in the medium dose group (200 ng/kg body weight). Preputial separation, an indicator of pubertal development, was also delayed in male offspring in the high dose group. An increase in the proportion of abnormal sperm and a slight decrease in testis weight was observed but this did not appear to impair male fertility; sperm count was actually increased in animals prenatally exposed to TCDD. In addition, offspring brain weight was lower in the high dose group. Taken together, these results suggest that prenatal exposure to an acute dose of TCDD affects the development of the male reproductive system, delays puberty onset and affects brain development in rats.
Scientific abstract:
It has been reported that fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes defects in the male reproductive system of the rat. We set out to replicate and extend these effects using a robust experimental design. Groups of 75 (control vehicle) or 55 (50, 200, or 1000 ng of TCDD/kg bodyweight) female Wistar(Han) rats were exposed to TCDD on gestational day (GD)15, then allowed to litter. The high-dose group dams showed no sustained weight loss compared to control, but four animals had total litter loss. Pups in the high-dose group showed reduced body weight up till day 21, and pups in the medium dose group showed reduced body weight in the first week postpartum. Balano-preputial separation was significantly delayed in the high-dose group male offspring. There were no significant effects of treatment when the offspring were subjected to a functional observational battery or mated with females to assess reproductive capability. Twenty-five males per group were killed on postnatal day (PND) 70, and [~]60 animals per group ([~]30 for the high-dose group) on PND120 to assess seminology and other end points. At PND120, the two highest dose groups showed a statistically significant elevation of sperm counts, compared to control; however, this effect was small ([~]30%), within the normal range of sperm counts for this strain of rat, was not reflected in testicular spermatid counts nor PND70 data, and is therefore postulated to have no biological significance. Although there was an increase in the proportion of abnormal sperm at PND70, seminology parameters were otherwise unremarkable. Testis weights in the high-dose group were slightly decreased at PND70 and 120, and at PND120, brain weights were decreased in the high-dose group, liver to body weight ratios were increased for all three dose groups, with an increase in inflammatory cell foci in the epididymis in the high-dose group. These data show that TCDD is a potent developmental toxin after exposure of the developing fetus but that acute developmental exposure to TCDD on GD15 caused no decrease in sperm counts.
Study Synopsis: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (also called TCDD and, most commonly, dioxin) is a highly toxic chemicals that persist in the environment, accumulate in human fatty tissue and concentrate up the food chain. Prenatal exposure to TCDD has been associated with a range of adverse health effects, including effects on the male reproductive system. In this study, researchers fed pregnant rats with feed contaminated with various concentrations of TCDD for a period of 12 weeks. Fetal loss was increased in the high dose group and the number of animals alive 4 days after birth was decreased by about 26% relative to controls. Reduced offspring weight, deficits in motor activity and delayed preputial separation, indicating altered puberty onset, were also observed in animals prenatally exposed to TCDD. Male fertility, sperm parameters, testis weight and prostate weight were generally unaffected by exposure. These results suggest that chronic prenatal exposure to TCDD does not affect fertility or sperm quality but may increase fetal and neonatal mortality, delay puberty onset and affect motor activity in male rats.
Scientific abstract:
We have investigated whether fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes defects in the male reproductive system of the rat using chronically exposed rats to ensure continuous exposure of the fetus. Five- to six-week-old rats were exposed to control diet, or diet containing TCDD, to attain an average dose of 2.4, 8, and 46 ng TCDD/kg/day for 12 weeks, whereupon the rats were mated and allowed to litter; rats were switched to control diet after parturition. Male offsprings were allowed to develop until kills on PND70 (25 per group) or PND120 (all remaining animals). Offspring from the high-dose group showed an increase in total litter loss, and the number of animals alive on postnatal day (PND)4 in the high-dose group was [~]26% less than control. The high and medium dose offsprings showed decreased weights at various ages. Balano-preputial separation (BPS) was significantly delayed in all three dose groups compared to control. There were no significant effects of maternal treatment when the offsprings were subjected to a functional observational battery or learning tests, with the exception that the high-dose group showed a deficit in motor activity. Twenty rats per group were mated to females, and there were no significant effects of maternal treatment on the fertility of these rats or on the F1 or F2 sex ratio. Sperm parameters at PND70 and 120 showed no significant effect of maternal treatment, with the exception that there was an increase in the proportion of abnormal sperm in the high-dose group at PND70; this is associated with the developmental delay in puberty in this dose group. There were no remarkable findings of maternal treatment on organ weights, with the exception that testis weights were reduced by [~]10% at PND70 (but not PND120), and although the experiment was sufficiently powered to detect small changes, ventral prostate weight was not reduced. There were no significant effects of maternal treatment upon histopathological comparison of high-dose and control group organs. These data confirm that developmental exposure to TCDD shows no potent effect on adult sperm parameters or accessory sexual organs, but show that delay in BPS occurs after exposure to low doses of TCDD, and this is dependent upon whether TCDD is administered acutely or chronically.
Study Synopsis: This study investigated the association between maternal exposure to air pollution during pregnancy and birth weight among 358,504 neonates born between 1999 and 2002 in Massachusetts or Connecticut. Researchers found that women who lived in counties with higher air concentrations of nitrogen dioxide (NO2), carbon monoxide (CO) or particulate matter while pregnant delivered children with lower birth weight on average. The association between the air concentration of small particulate matter (< 2.5 microns) and birth weight was stronger for infants of African-American women than those of Caucasian women.
Scientific abstract:
BACKGROUND: Several studies have examined whether air pollution affects birth weight; however results vary and many studies were focused on Southern California or were conducted outside of the United States. OBJECTIVES: We investigated maternal exposure to particulate matter with aerodynamic diameter < 10, < 2.5 microm (PM(10), PM(2.5)), sulfur dioxide, nitrogen dioxide, and carbon monoxide and birth weight for 358,504 births in Massachusetts and Connecticut from 1999 to 2002. METHODS: Analysis included logistic models for low birth weight (< 2,500 g) and linear models with birth weight as a continuous variable. Exposure was assigned as the average county-level concentration over gestation and each trimester based on mother's residence. We adjusted for gestational length, prenatal care, type of delivery, child's sex, birth order, weather, year, and mother's race, education, marital status, age, and tobacco use. RESULTS: An interquartile increase in gestational exposure to NO(2), CO, PM(10), and PM(2.5) lowered birth weight by 8.9 g [95% confidence interval (CI), 7.0-10.8], 16.2 g (95% CI, 12.6-19.7), 8.2 g (95% CI, 5.3-11.1), and 14.7 g (95% CI, 12.3-17.1), respectively. Lower birth weight was associated with exposure in the third trimester for PM(10), the first and third trimesters for CO, the first trimester for NO(2) and SO(2), and the second and third trimesters for PM(2.5). Effect estimates for PM(2.5) were higher for infants of black mothers than those of white mothers. CONCLUSIONS: Results indicate that exposure to air pollution, even at low levels, may increase risk of low birth weight, particularly for some segments of the population.
Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure, combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p'-DDT, vinclozolin (VZ), p,p'-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic 293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was affected in 24 h by all the xenobiotics with a threshold at 50 muM (except for TBTO and DES, 10 muM threshold), and aromatase was inhibited at non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4-10 muM, and aromatase activity by 50% in some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment.
Roundup((R)) is the major herbicide used worldwide, in particular on genetically modified plants that have been designed to tolerate it. We have tested the toxicity and endocrine disruption potential of Roundup (Bioforce(R)) on human embryonic 293 and placental-derived JEG3 cells, but also on normal human placenta and equine testis. The cell lines have proven to be suitable to estimate hormonal activity and toxicity of pollutants. The median lethal dose (LD(50)) of Roundup with embryonic cells is 0.3% within 1 h in serum-free medium, and it decreases to reach 0.06% (containing among other compounds 1.27 mM glyphosate) after 72 h in the presence of serum. In these conditions, the embryonic cells appear to be 2-4 times more sensitive than the placental ones. In all instances, Roundup (generally used in agriculture at 1-2%, i.e., with 21-42 mM glyphosate) is more efficient than its active ingredient, glyphosate, suggesting a synergistic effect provoked by the adjuvants present in Roundup. We demonstrated that serum-free cultures, even on a short-term basis (1 h), reveal the xenobiotic impacts that are visible 1-2 days later in serum. We also document at lower non-overtly toxic doses, from 0.01% (with 210 muM glyphosate) in 24 h, that Roundup is an aromatase disruptor. The direct inhibition is temperature-dependent and is confirmed in different tissues and species (cell lines from placenta or embryonic kidney, equine testicular, or human fresh placental extracts). Furthermore, glyphosate acts directly as a partial inactivator on microsomal aromatase, independently of its acidity, and in a dose-dependent manner. The cytotoxic, and potentially endocrine-disrupting effects of Roundup are thus amplified with time. Taken together, these data suggest that Roundup exposure may affect human reproduction and fetal development in case of contamination. Chemical mixtures in formulations appear to be underestimated regarding their toxic or hormonal impact.
Study Synopsis: A large survey of international infertility rates finds over 70 million women are infertile. Over twelve months, the prevalence ranged from 9-17% in more developed nations and from 7-9% in less developed nations. Worldwide, the average prevalence of infertility was 9%, a rate lower than those that have been previously reported.
Scientific abstract:
INTRODUCTION: The purpose of the present study was to review existing population surveys on the prevalence of infertility and proportion of couples seeking medical help for fertility problems. METHODS: Population surveys, reporting the prevalence of infertility and proportion of couples seeking help in more and less developed countries, were reviewed. RESULTS: Estimates on the prevalence of infertility came from 25 population surveys sampling 172 413 women. The 12-month prevalence rate ranged from 3.5% to 16.7% in more developed nations and from 6.9% to 9.3% in less-developed nations, with an estimated overall median prevalence of 9%. In 17 studies sampling 6410 women, the proportion of couples seeking medial care was, on average, 56.1% (range 42-76.3%) in more developed countries and 51.2% (range 27-74.1%) in less developed countries. The proportion of people actually receiving care was substantially less, 22.4%. Based on these estimates and on the current world population, 72.4 million women are currently infertile; of these, 40.5 million are currently seeking infertility medical care. CONCLUSIONS: The current evidence indicates a 9% prevalence of infertility (of 12 months) with 56% of couples seeking medical care. These estimates are lower than those typically cited and are remarkably similar between more and less developed countries.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers measured the concentration of PBDEs in the breast milk of 20 women from Central Taiwan between December 2000 and November 2001. They found that women with higher breast milk levels of PBDEs delivered babies with decreased birth weight, shorter length, and smaller chest circumference. The Quetelet index, and indicator of body fat. No relationship was found with maternal menstrual cycle length. Results suggest that prenatal exposure to PBDEs may be related with lower birth weight, shorter body length and reduced chest size.
Scientific abstract:
In utero exposure to polybrominated diphenyl ethers (PBDEs) reduces the number of ovarian follicles in rat females and causes permanent effects on rat males. Little data have been gathered on the associations between PBDEs exposure and birth outcome and female menstruation characteristics in both epidemiological and animal studies. The aim of this study was to examine how PBDEs in breast milk are associated with infant birth outcome and maternal menstruation characteristics. Study participants were healthy women recruited from central Taiwan between December 2000 and November 2001. Twelve congener levels of PBDEs (BDE-17, 28, 47, 66, 85, 99, 100, 138, 153, 154, 183, 209) in 20 breast milk samples were measured by gas chromatography with high resolution mass spectrometer. The mean level of PBDEs in breast milk was 3.93+/-1.74 ng/g lipid. The estimated PBDE daily intake for a breastfed infant was 20.6 ng/kg b.w./day after delivery. After maternal age, pre-pregnant BMI, and parity were adjusted, increased PBDEs in breast milk was related with decreased birth outcome, particularly for birth weight and length, chest circumference, and Quetelet's index of infants. No significant differences in PBDEs were found between the two groups of menstrual cycle length higher and lower than 30 days after we adjusted for maternal age, pre-pregnant BMI, and parity. In utero exposure to low doses of PBDEs may result in lower birth weight and short or birth length. Our findings are limited based on the low doses of PBDEs and the small sampling size.
Study Synopsis: Women consuming large amounts of low-fat dairy are at a higher risk for anovulatory infertility. In contrast, women who consumed high fat dairy products everyday had 25% higher fertility rates than women who consumed only one product per week. These fertility rates may reflect the overall amount of body fat in these women rather than a protective effect of consuming high fat dairy.
Scientific abstract:
BACKGROUND: Dairy foods and lactose may impair fertility by affecting ovulatory function. Yet, few studies have been conducted in humans and their results are inconsistent. We evaluated whether intake of dairy foods was associated with anovulatory infertility and whether this association differed according to fat content. METHODS: We prospectively followed 18 555 married, premenopausal women without a history of infertility who attempted a pregnancy or became pregnant during an 8-year period. Diet was assessed twice during the study using food-frequency questionnaires RESULTS: During follow-up, 438 women reported infertility due to an ovulatory disorder. The multivariate-adjusted relative risks (RR) [95% confidence interval (CI); P, trend] of anovulatory infertility comparing women consuming [≥] 2 servings per day to women consuming [≤]1 serving per week was 1.85 (1.24-2.77; 0.002) for low-fat dairy foods. The RR (95% CI; P, trend) comparing women consuming [≥] 1 serving per day of high-fat dairy foods to those consuming [≤]1 serving per week was 0.73 (0.52-1.01; 0.01). There was an inverse association between dairy fat intake and anovulatory infertility (P, trend = 0.05). Intakes of lactose, calcium, phosphorus and vitamin D were unrelated to anovulatory infertility. CONCLUSIONS: High intake of low-fat dairy foods may increase the risk of anovulatory infertility whereas intake of high-fat dairy foods may decrease this risk. Further, lactose (the main carbohydrate in milk and dairy products) may not affect fertility within the usual range of intake levels in humans.
Key Words: dairy, epidemiology, infertility, lactose, ovarian function
Study Synopsis: All teen pregnancies are at risk for adverse birth outcomes. Preterm delivery, low birth weight, and neonatal mortality occur at higher rates in teen pregnancies regardless of socio-economic status, level of pre-natal care and amount of weight gain. This finding challenges commonly accepted assumptions about teen pregnancy outcomes.
Scientific abstract:
Background: Whether the association between teenage pregnancy and adverse birth outcomes could be explained by deleterious social environment, inadequate prenatal care, or biological immaturity remains controversial. The objective of this study was to determine whether teenage pregnancy is associated with increased adverse birth outcomes independent of known confounding factors. Methods: We carried out a retrospective cohort study of 3 886 364 nulliparous pregnant women <25 years of age with a live singleton birth during 1995 and 2000 in the United States. Results: All teenage groups were associated with increased risks for pre-term delivery, low birth weight and neonatal mortality. Infants born to teenage mothers aged 17 or younger had a higher risk for low Apgar score at 5 min. Further adjustment for weight gain during pregnancy did not change the observed association. Restricting the analysis to white married mothers with age-appropriate education level, adequate prenatal care, without smoking and alcohol use during pregnancy yielded similar results. Conclusions: Teenage pregnancy increases the risk of adverse birth outcomes that is independent of important known confounders. This finding challenges the accepted opinion that adverse birth outcome associated with teenage pregnancy is attributable to low socioeconomic status, inadequate prenatal care and inadequate weight gain during pregnancy.
Chevrier J, Eskenazi B, Bradman A, Fenster L, Barr DB. Associations between prenatal exposure to polychlorinated biphenyls and neonatal thyroid-stimulating hormone levels in a Mexican-American population, Salinas Valley, California. Environ Health Perspect. 2007 Oct;115(10):1490-6.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. In this study, researchers measured the concentration of PCBs in the blood of 285 pregnant women. They proposed a new method to group PCB congeners based on their potential to induce an enzyme involved with the elimination of thyroid hormone. They found that women with higher levels of these PCB congeners gave birth to children with elevated levels of thyroid-stimulating hormone (TSH). These results suggest prenatal exposure to PCBs be related with increased TSH. These findings are of particular significance because thyroid hormones play a major role in brain development.
Scientific abstract:
BACKGROUND: Studies have reported that prenatal exposure to polychlorinated biphenyls (PCBs) may alter neurodevelopment in both humans and animals. Furthermore, prenatal exposure to some PCB congeners and commercial mixtures has been shown to decrease free and total thyroxine (T(4)) blood levels in animals. Because thyroid hormones (TH) are essential for normal neurologic development, it has been suggested that the deleterious neurodevelopmental effect of PCBs may occur through TH disruption. PCBs may in turn affect TH levels by inducing the microsomal enzyme uridinediphosphate glucuronosyltransferase (UDP-GT), which is involved in TH elimination. OBJECTIVES: Our goals were to group PCB congeners based on their potential to induce microsomal enzymes in animals, and to examine the relationship between neonatal TSH levels and prenatal exposure to PCB congeners grouped according to their structure and potential mechanisms of action. METHODS: We measured the concentration of 34 PCB congeners in serum samples collected from 285 pregnant women and the thyroid-stimulating hormone (TSH) levels in their children's blood collected shortly after birth. RESULTS: We found no association between the sum of PCB congeners, the toxic equivalents, or structure-based groupings (mono- or di-ortho substituted congeners), and TSH blood concentration. However, we found a positive association between the sum of congeners suspected to be UDP-GT inducers (more specifically cytochrome P450 2B inducers) in animals and neonatal TSH levels. In individual congener analyses, PCBs 99, 138, 153, 180, 183, 187, 194, and 199 were positively associated with neonatal TSH levels after adjustment for covariates. PCBs 194 and 199 remained significant after adjustment for multiple hypothesis testing. CONCLUSIONS: Our results support grouping PCB congeners based on their potential mechanism of action of enzyme induction when investigating associations with TH. Findings also suggest that PCBs affect TH homeostasis even at the low background level of exposure found in the CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas) population.
Study Synopsis: Exposure to endocrine disrupting chemicals affects behavior and mate selection for several generations after exposure. Female rats removed 3 generations from exposure discriminate and prefer males who's grandmothers were not exposed to the pesticide, vinclozolin. These results indicate there is transgenerational inheritance of mate preference that may play a role in evolution.
Scientific abstract:
Environmental contamination by endocrine-disrupting chemicals (EDC) can have epigenetic effects (by DNA methylation) on the germ line and promote disease across subsequent generations. In natural populations, both sexes may encounter affected as well as unaffected individuals during the breeding season, and any diminution in attractiveness could compromise reproductive success. Here we examine mate preference in male and female rats whose progenitors had been treated with the antiandrogenic fungicide vinclozolin. This effect is sex-specific, and we demonstrate that females three generations removed from the exposure discriminate and prefer males who do not have a history of exposure, whereas similarly epigenetically imprinted males do not exhibit such a preference. The observations suggest that the consequences of EDCs are not just transgenerational but can be "transpopulational", because in many mammalian species, males are the dispersing sex. This result indicates that epigenetic transgenerational inheritance of EDC action represents an unappreciated force in sexual selection. Our observations provide direct experimental evidence for a role of epigenetics as a determinant factor in evolution.
Study Synopsis: Regular alcohol intake during pregnancy appears to increase the risk of congenital cryptorchidism in boys. After adjusting for confounders, the odds for cryptorchidism more than tripled in boys born to women who drank at least 5 alcoholic drinks a week during pregnancy.
Scientific abstract:
Background: Prenatal exposure to alcohol can adversely affect the fetus. We investigated the association between maternal alcohol consumption during pregnancy and cryptorchidism (undescended testis) among newborn boys., , Methods: We examined 2,496 boys in a prospective DanishūFinnish birth cohort study for cryptorchidism at birth (cryptorchid/healthy: 128/2,368) and at 3 months of age (33/2,215) . Quantitative information on alcohol consumption (average weekly consumption of wine, beer, and spirits and number of binge episodes) , smoking, and caffeine intake was obtained by questionnaire and/or interview once during the third trimester of pregnancy, before the outcome of the pregnancy was known. For a subgroup (n = 465) , information on alcohol consumption was obtained twice during pregnancy by interviews. Results: We investigated maternal alcohol consumption both as a continuous variable and categorized. The odds for cryptorchidism increased with increasing weekly alcohol consumption. After adjustment for confounders (country, smoking, caffeine intake, binge episodes, social class, maternal age, parity, maturity, and birth weight) the odds remained significant for women with a weekly consumption of five or more alcoholic drinks (odds ratio = 3.10 ; 95% confidence interval, 1.05ū9.10) ., , Conclusions: Regular alcohol intake during pregnancy appears to increase the risk of congenital cryptorchidism in boys. The mechanisms for this association are unknown. Counseling of pregnant women with regard to alcohol consumption should also consider this new finding.
Study Synopsis: Arsenic interferes with the ability of human fat cells to regulate their blood sugar, according to new research. The effect is evident at exposure levels below what is necessary for overt toxicity. This result may help explain how the heavy metal contributes to type II diabetes, a chronic, life-changing disease.
Scientific abstract:
Arsenic (As) contamination of drinking water is considered a serious worldwide environmental health threat that is associated with increased disease risks including skin, lung, bladder and other cancers; type 2 diabetes; vascular and cardiovascular disease; reproductive and developmental effects; and neurological and cognitive effects. Increased health risks may occur at as low as 10-50 ppb, while biological effects have been observed in experimental animal and cell culture systems at much lower levels. We previously reported that As is a potent endocrine disruptor, altering gene regulation by the closely related glucocorticoid, mineralocorticoid, progesterone and androgen steroid receptors at concentrations as low as 0.01 {micro}M ([~] 0.7 ppb). Very low doses enhanced hormone-mediated gene transcription whereas slightly higher but still non-cytotoxic doses were suppressive. We report here that As also disrupts the more distally related estrogen receptor (ER) both in vivo and in cell culture. At non-cytotoxic doses (1-50 {micro}mol/kg arsenite) As strongly suppressed ER-dependent gene transcription of the 17{beta}-estradiol (E2)-inducible vitellogenin II gene in chick embryo liver in vivo. In cell culture, non-cytotoxic levels (0.25-3 {micro}M, [~] 20-225 ppb) of As significantly inhibited E2-mediated gene activation of an ER-regulated reporter gene and the native ER-regulated GREB1 gene in human breast cancer MCF-7 cells. While the effects of As on ER-dependent gene regulation were generally similar to As effects on the other steroid receptors, there were specific differences, particularly the lack of significant enhancement at the lowest doses, that may provide insights into possible mechanisms.
Study Synopsis: Hormonal markers of testicular function may not accurately reflect sperm quality at the population level. Sperm parameters measured in young men from two regions of Flanders were found to be significantly different in sperm count, concentration, and morphology. However, while free testosterone levels were different in the two communities, no differences were detected in total testosterone (T), follicle stimulating hormone (FSH), inhibin B, T/luteinizing hormone ratio, and inhibin B/FSH ratio. Clinically recognized hormonal parameters should not be substituted from semen quality analysis in population-based studies.
Scientific abstract:
Background: Epidemiological studies of sperm quality are hampered by problems such as low participation rates and poor comparability due to methodological differences in semen analysis. More objective sperm quality-related serum markers would facilitate worldwide comparison of male reproductive status. Our objectives were to investigate to what extent a set of hormonal indices of testicular function, previously established in clinical setting, can predict regional variations in seminal parameters in men from the general population. Methods: We recruited 101 men, aged 20-40 years, from two regions in Flanders, and assessed sperm parameters and serum reproductive hormones. Results: In one region compared to the other, participants had a lower sperm concentration (by 34%, p=0.06), total sperm count (by 41%, p=0.02) and sperm morphology (by 32%, p<0.001), which was paralleled by a significantly lower free testosterone (11%, p=0.03), while for total testosterone (T, 10%) and follicle stimulating hormone (FSH, 17%) the differences were non-significant (both p=0.09). There were no differences in inhibin B and the T/luteinizing hormone (LH) ratio, markers of testicular function. Receiver operating characteristic curve analysis demonstrated T/LH, inhibin B, and the inhibin B/FSH ratio to have significant discriminatory power between men with a sperm concentration below or above 13.5x106/mL. Conclusions: Regional variations in semen quality of community-dwelling individuals are not necessarily reflected in altered hormonal indices of testicular function and thus these markers, validated in clinical settings, fail to be substitutes for the traditional semen quality assessment in epidemiological population studies.
Study Synopsis: A growing body of evidence indicates that exposures to environmental chemicals can alter gene expression through epigenetic mechanisms. Epigenetic changes in patterns of DNA methylation and chromatin modification have been observed after exposure to xenobiotic chemicals and low-dose radiation. These changes are transmitted to offspring over several generations and may influence the onset of adult disease.
Scientific abstract:
Traditional studies on the combined effects of genetics and the environment on individual variation in disease susceptibility primarily focus on single nucleotide polymorphisms that influence toxicant uptake and metabolism. A growing body of evidence, however, suggests that epigenetic mechanisms of gene regulation, such as DNA methylation and chromatin modification, are also influenced by the environment, and play an important role in the fetal basis of adult disease susceptibility. Studying the influence of early environmental exposures on metastable epialleles and imprinted genes offers insight into the mechanisms affecting the fetal epigenome and subsequent adult disease susceptibility. In this review, we introduce the reader to the field of environmental epigenomics, provide information on the important epigenetic control mechanisms and epigenetic phenomena in mammals, and summarize the current body of literature on nutritional and environmental influences affecting the epigenome.
Key Words: Developmental origins of adult disease, DNA methylation, Epigenetics, Metastable epialleles, Imprinted genes, Viable yellow agouti (Avy) mouse
Study Synopsis: Prenatal exposure to bisphenol A causes long-lasting changes in female rat breast tissue that increase the risk of cancer and also make the animals more sensitive to cancer-causing chemicals as adults. The study strengthens support for a link between increasing rates of breast cancer in recent decades and increasing exposure to estrogenic chemicals like BPA. It also indicates that human epidemiological studies that fail to incorporate developmental exposures can't be trusted to identify cancer-causing agents.
Scientific abstract:
Background: Humans are routinely exposed to bisphenol A (BPA) , an estrogenic compound that leaches from dental materials, food and beverage containers, and other consumer products. Prenatal exposure to BPA has produced long-lasting and profound effects on rodent hormone-dependent tissues that are manifested 1ū6 months after the end of exposure., , Objective: The aim of the present work was to examine whether in utero exposure to BPA alters mammary gland development and increases its susceptibility to the carcinogen N-nitroso-N-methylurea (NMU) ., , Methods: Pregnant Wistar rats were exposed to BPA (25 _g/kg body weight per day) or to vehicle. Female offspring were sacrificed on postnatal day (PND) 30, 50, 110, or 180. On PND50 a group of rats received a single subcarcinogenic dose of NMU (25 mg/kg) and they were sacrificed on either PND110 or PND180., , Results: At puberty, animals exposed prenatally to BPA showed an increased proliferation/apoptosis ratio in both the epithelial and stromal compartments. During adulthood (PND110 and PND180) , BPA-exposed animals showed an increased number of hyperplastic ducts and augmented stromal nuclear density. Moreover, the stroma associated with hyperplastic ducts showed signs of desmoplasia and contained an increased number of mast cells, suggesting a heightened risk of neoplastic transformation. Administration of a subcarcinogenic dose of NMU to animals exposed prenatally to BPA increased the percentage of hyperplastic ducts and induced the development of neoplastic lesions., , Conclusions: Our results demonstrate that the prenatal exposure to low doses of BPA perturbs mammary gland histoarchitecture and increases the carcinogenic susceptibility to a chemical challenge administered 50 days after the end of BPA exposure.
Study Synopsis: Women exposed to high levels of dioxin have a lower risk of uterine fibroids. Women were studied 20 years after an industrial accident in Seveso, Italy resulted in widespread contamination with the dioxin, TCDD. Women with the highest levels of exposure had the 38% decreased risk of uterine fibroids suggesting that TCDD has anti-estrogenic effects on the uterus.
Scientific abstract:
Uterine leiomyomata (fibroids), benign neoplasms of the smooth muscle, are a major cause of hysterectomy. Exposure to hormonally active chemicals may play an etiologic role. The authors investigated the risk of uterine leiomyoma associated with exposure to 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) for women who resided near Seveso, Italy, in 1976 at the time of a chemical explosion. Twenty years later, women enrolled in the Seveso Women's Health Study were asked about history of fibroids, medical records were obtained, and vaginal ultrasonography was performed for a subset. Serum collected soon after the explosion was analyzed for TCDD. A likelihood-based method that combines both historical and current status (ultrasound) data was adapted to estimate the hazard ratio. Of 956 eligible women, 251 (26.3%) had fibroids. Compared with that for women with TCDD levels of [≤]20 parts per trillion, the age-adjusted hazard ratios were 0.58 (95% confidence interval: 0.41, 0.81) for women with levels of 20.1-75.0 parts per trillion and 0.62 (95% confidence interval: 0.44, 0.89) for women with levels of >75.0 parts per trillion. This finding suggests that TCDD may have antiestrogenic effects in the uterine myometrium, in contrast to apparently estrogenic effects previously found in the breast of Seveso Women's Health Study women.
Fei C, McLaughlin JK, Tarone RE, Olsen J. Perfluorinated chemicals and fetal growth: a study within the Danish National Birth Cohort. Environ Health Perspect. 2007 Nov;115(11):1677-82.
Study Synopsis: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA and PFOS. In this study, researchers measured the blood levels of these chemicals in 1,400 pregnant women participating in the Danish National Birth Cohort. They found that women with higher PFOA delivered babies with lower birth weight. There were no relationship with preterm birth or birth weight for gestational age, an indicator of abnormally slow growth. Results suggest that maternal blood levels of PFOA is associated with reduced birth weight.
Scientific abstract:
BACKGROUND: Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) are man-made, persistent organic pollutants widely spread throughout the environment and human populations. They have been found to interfere with fetal growth in some animal models, but whether a similar effect is seen in humans is uncertain. OBJECTIVES: We investigated the association between plasma levels of PFOS and PFOA in pregnant women and their infants' birth weight and length of gestation. METHODS: We randomly selected 1,400 women and their infants from the Danish National Birth Cohort among those who completed all four computer-assisted telephone interviews, provided the first blood samples between gestational weeks 4 and 14, and who gave birth to a single live-born child without congenital malformation. PFOS and PFOA were measured by high performance liquid chromatography-tandem mass spectrometer. RESULTS: PFOS and PFOA levels in maternal plasma were on average 35.3 and 5.6 ng/mL, respectively. Only PFOA levels were inversely associated with birth weight (adjusted beta = -10.63 g; 95% confidence interval, -20.79 to -0.47 g). Neither maternal PFOS nor PFOA levels were consistently associated with the risk for preterm birth or low birth weight. We observed no adverse effects for maternal PFOS or PFOA levels on small for gestational age. CONCLUSION: Our nationwide cohort data suggest an inverse association between maternal plasma PFOA levels and birth weight. Because of widespread exposure to these chemicals, our findings may be of potential public health concern.
Study Synopsis: Mothers of naturally-occurring multiples are found to be have a shorter time to pregnancy than mothers of singletons. From data collected from 1955-66, the US Collaborative Perinatal Project found women who became pregnant within the first six months of trying to conceive were nearly two times more likely to have a multiple birth than mothers who took longer than 6 months to conceive., Reasons for the heightened fecundity among mothers of multiples is largely unknown, but monitoring naturally-occurring multiple births could help track trends of reproductive health in the general population.
Scientific abstract:
BACKGROUND: Mothers of multiples are alleged to be more fecund than mothers of singletons. Some authors have suggested monitoring twinning rates for assessing temporal changes in a population's reproductive health. METHODS: Using a nested case-control design, we estimated the odds of a multiple birth in relation to fecundity in the US Collaborative Perinatal Project inclusive of 8546 pregnant women who reported a known time-to-pregnancy (TTP) upon enrolment in the cohort, 1959-1966. Case mothers comprised 81 women giving birth to twins/triplets; control mothers comprised 243 women giving birth to singletons matched to case mothers on maternal age at a ratio of 3:1. The odds ratio (OR) for a multiple birth within 6 months of trying adjusting for maternal age and prior pregnancies was estimated using logistic regression. Discrete time Cox regression analysis was also utilized to estimate the fecundability OR. RESULTS: Women with a TTP of 6 months [OR = 1.95; 95% confidence interval (95% CI) = 1.09-3.51]. Excluding pregnancies after 13+ months resulted in a loss of precision (OR = 2.14; 95% CI = 0.90-5.04). CONCLUSIONS: These data support higher fecundity among mothers of multiples than mothers of singletons.
Study Synopsis: Dieldrin is a synthetic organochlorine insecticide developed in the 1940s and banned internationally by the Stockholm Convention on Persistent Organic Pollutants. In order to evaluate whether dieldrin could disrupt the function of the human fetal testis, researchers collected 10 fetal testes during the second trimester of pregnancy and exposed cells to the chemical. They found that dieldrin reduced the secretion of the male hormone testosterone by testes and that the cell concentration of luteinizing hormone (LH) receptors was reduced. LH must bind to these receptors to exert its effect. Consequently, the amount of proteins whose synthesis is regulated by LH was reduced. These results show that human testis cells exposed to dieldrin results in reduced testosterone secretion and protein expression, which may affect reproductive development.
Scientific abstract:
BACKGROUND: Declining human reproductive health over the last 60 years has been proposed to be due to effects of environmental chemicals, especially endocrine disrupting compounds, on fetal development. We investigated whether a model pesticide, dieldrin, at concentrations within both maternal circulation and environmental ranges (1 pmol/l = 0.0004 p.p.b. = 380.9 pg/l), could disrupt the human fetal testis. METHODS: Human fetal testes were collected during the second trimester, a critical period of male sexual differentiation (development and masculinization). Testis explants were cultured for 24 h in the presence and absence of LH (10-1000 IU LH/l) and dieldrin (1 pmol and 1 nmol/l). Endocrine, immunohistological and proteome characteristics of the tissues were investigated. RESULTS: Exposure to dieldrin reduced LH-induced testosterone secretion (P < 0.05) and tissue protein concentrations of LH receptor and steroid acute regulatory protein (P < 0.05). Dieldrin altered proteins associated with cancer, apoptosis, transcription and development. Wnt-2b was reduced 3-fold and immunolocalized to Leydig and Sertoli cells. Dieldrin also reversed some LH-induced changes in protein expression, supporting the conclusion that Leydig cell function is at risk from environmental chemicals. CONCLUSIONS: Our findings indicate that exposure to very low, biologically relevant, concentrations of environmental chemicals could affect the fetal human Leydig cell, reducing testosterone secretion and potentially leading to subtle dysregulation of reproductive development and adult fecundity.
Study Synopsis: Prenatal exposure to common plasticizer chemicals, phthalates, results in features consistent with testicular dysgenesis syndrome. Genital malformations, sperm abnormalities, and testicular tumors are found in testicular dysgenesis syndrome (TDS) and are reportedly increasing in humans. TDS has been observed in rodents after exposure to phthalates and human studies have found similar outcomes in humans exposed to phthalates prenatally.
Scientific abstract:
Humans have significant exposures to phthalates, as these chemical plasticizers are ubiquitously present in flexible plastics. Recent epidemiological evidence indicates that boys born to women exposed to phthalates during pregnancy have an increased incidence of congenital genital malformations and spermatogenic dysfunction, signs of a condition referred to as testicular dysgenesis syndrome (TDS). TDS is thought to develop as a result of environmental factors that cause a testicular disturbance at an early fetal stage with a resultant spectrum of clinical testicular dysfunction, ranging from impaired spermatogenesis and genital malformations to increased risk for development of testicular cancer. Proposed environmental factors in the etiology of TDS include endocrine disrupting compounds such as the phthalates. Leydig cells have been classified as one of the main targets for phthalate ester toxicity in the body based on studies in rodents. In support of this hypothesis, two Leydig cell products - insulin-like growth factor 3 (INSL3) and testosterone (T) - are both suppressed after phthalate exposures. Both fetal and adult generations of Leydig cells are affected by phthalate esters, although their sensitivities may differ. In rodent models, when pregnant dams are exposed to phthalate esters, fetal Leydig cells form enlarged clusters that are retained in the testis even after birth, in contrast to untreated controls. Despite the retention of fetal Leydig cells, however, their numbers and average cell volume of total in exposed males are reduced, as are INSL3 production and steroidogenic competence. These alterations are directly associated with clinical features of TDS, including cryptorchidism and impaired spermatogenesis.
Study Synopsis: Polybrominated biphenyls (PBBs) are synthetic chemicals formerly used as flame retardants. In 1973, the Michigan food supply was contaminated with PBBs when the cattle feed supplement NutriMaster was accidently replaced with the flame retardant FireMaster. More than 4,000 individuals were exposed to PBBs, 444 of which were exposed during pregnancy and were enrolled in the current study. Mothers gave birth to 899 infants between 1975 and 1997. Researchers estimated maternal exposure to PBBs and to closely related chemicals named polychlorinated biphenyls (PCBs) during pregnancy based on blood measurements collected at the time of enrollment in the study. PCBs were formerly used in electrical transformers, inks, plastics and other consumer products. Results suggested that women with higher PBB serum levels at the time of enrollment were related with lower birth weight. No association was however found between estimated maternal pregnancy PBB or measured PCB serum levels and gestational duration or birth weight. These results provide some support for the hypothesis that maternal exposure to PBBs may be related with lower birth weight.
Scientific abstract:
Understanding the influence of maternal exposures on gestational age and birth weight is essential given that pre-term and/or low birth weight infants are at risk for increased mortality and morbidity. We performed a retrospective analysis of a cohort exposed to polybrominated biphenyls (PBB) through accidental contamination of cattle feed and polychlorinated biphenyls (PCB) through residual contamination in the geographic region. Our study population consisted of 444 mothers and their 899 infants born between 1975 and 1997. Using restricted maximum likelihood estimation, no significant association was found between estimated maternal serum PBB at conception or enrollment PCB levels and gestational age or infant birth weight in unadjusted models or in models that adjusted for maternal age, smoking, parity, infant gender, and decade of birth. For enrollment maternal serum PBB, no association was observed for gestational age. However, a negative association with high levels of enrollment maternal serum PBB and birth weight was suggested. We also examined the birth weight and gestational age among offspring of women with the highest (10%) PBB or PCB exposure, and observed no significant association. Because brominated compounds are currently used in consumer products and therefore, are increasingly prevalent in the environment, additional research is needed to better understand the potential relationship between in utero exposure to brominated compounds and adverse health outcomes.
Givens ML, Small CM, Terrell ML, Cameron LL, Michels Blanck H, Tolbert PE, Rubin C, Henderson AK, Marcus M. Maternal exposure to polybrominated and polychlorinated biphenyls: infant birth weight and gestational age. Chemosphere. 2007 Oct;69(8):1295-304.
Study Synopsis: Polybrominated biphenyls (PBBs) are synthetic chemicals formerly used as flame retardants. In 1973, the Michigan food supply was contaminated with PBBs when the cattle feed supplement NutriMaster was accidently replaced with the flame retardant FireMaster. More than 4,000 individuals were exposed to PBBs, 444 of which were exposed during pregnancy and were enrolled in the current study. Women gave birth to a total of 899 children between 1975 and 1997. Researchers estimated maternal exposure to PBBs and to closely related chemicals named polychlorinated biphenyls (PCBs) during pregnancy based on blood measurements. They found no associations between PBB or PCB exposure and gestational duration or birth weight. These results do not support relationships between prenatal exposure to PBBs or PCBs and the birth outcomes examined.
Scientific abstract:
Understanding the influence of maternal exposures on gestational age and birth weight is essential given that pre-term and/or low birth weight infants are at risk for increased mortality and morbidity. We performed a retrospective analysis of a cohort exposed to polybrominated biphenyls (PBB) through accidental contamination of cattle feed and polychlorinated biphenyls (PCB) through residual contamination in the geographic region. Our study population consisted of 444 mothers and their 899 infants born between 1975 and 1997. Using restricted maximum likelihood estimation, no significant association was found between estimated maternal serum PBB at conception or enrollment PCB levels and gestational age or infant birth weight in unadjusted models or in models that adjusted for maternal age, smoking, parity, infant gender, and decade of birth. For enrollment maternal serum PBB, no association was observed for gestational age. However, a negative association with high levels of enrollment maternal serum PBB and birth weight was suggested. We also examined the birth weight and gestational age among offspring of women with the highest (10%) PBB or PCB exposure, and observed no significant association. Because brominated compounds are currently used in consumer products and therefore, are increasingly prevalent in the environment, additional research is needed to better understand the potential relationship between in utero exposure to brominated compounds and adverse health outcomes.
Study Synopsis: There is a non-monotonic relationship between birth weight and risk of Type II diabetes later in life. In this synthesis or meta-analysis of scientific studies, both low (<2,500g) was associated with a 32% increased risk and high (>4,000 g) birthweight was associated with a 27% increased risk of diabetes later in life. This is yet another study suggesting that fetal programming play an important role in adult-onset disease.
Scientific abstract:
The "small baby syndrome hypothesis" suggests that an inverse linear relation exists between birth weight and risk of type 2 diabetes. The authors conducted a meta-analysis to examine this association. They included studies that reported odds ratios and 95% confidence intervals (or data with which to calculate them) for the association of type 2 diabetes with birth weight. Fourteen studies involving a total of 132,180 persons were identified. Low birth weight (<2,500 g), as compared with a birth weight of [≥]2,500 g, was associated with increased risk of type 2 diabetes (odds ratio (OR) = 1.32, 95% confidence interval (CI): 1.06, 1.64). High birth weight (>4,000 g), as compared with a birth weight of [≤]4,000 g, was associated with increased risk to the same extent (OR = 1.27, 95% CI: 1.01, 1.59). Pooled estimates increased further when normal birth weight (2,500-4,000 g) was used as the reference category (low birth weight: OR = 1.47, 95% CI: 1.26, 1.72; high birth weight: OR = 1.36, 95% CI: 1.07, 1.73). Meta-regression and categorical analyses showed a U-shaped relation between birth weight and diabetes risk. These findings indicate that there exists a relation between birth weight and later-life risk of type 2 diabetes which is not linearly inverse but U-shaped.
Key Words: birth weight; diabetes mellitus, type 2; meta-analysis
Hauser R, Meeker JD, Singh NP, Silva MJ, Ryan L, Duty S, Calafat AM. DNA damage in human sperm is related to urinary levels of phthalate monoester and oxidative metabolites. Hum Reprod. 2007 Mar;22(3):688-95.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers obtained semen samples from 379 male partners of subfertile couples who presented for semen analysis to the Massachusetts General Hospital between January 2000 and May 2004. The concentration of phthalate residues was measured in men's urine. Higher urine concentration of residues called monobutyl phthalate (MBP) and monoethylhexyl phthalate (MEHP), was associated with increases in sperm DNA damage. These results suggest that higher exposure to some phthalates may be associated with sperm DNA damage.
Scientific abstract:
BACKGROUND: The ubiquitous use of phthalate esters in plastics, personal care products and food packaging materials results in widespread general population exposure. In this report, we extend our preliminary study on the relationship between urinary concentrations of phthalate metabolites and sperm DNA damage among a larger sample of men and include measurements of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), two oxidative metabolites of di-(2-ethylhexyl) phthalate (DEHP). METHODS: Among 379 men from an infertility clinic, urinary concentrations of phthalate metabolites were measured using isotope-dilution high-performance liquid chromatography-tandem mass spectrometry. Sperm DNA damage measurements, assessed with the neutral comet assay, included comet extent (CE), percentage of DNA in tail (Tail%) and tail distributed moment (TDM). RESULTS: Monoethyl phthalate (MEP), a metabolite of diethyl phthalate, was associated with increased DNA damage, confirming our previous findings. Mono-(2-ethylhexyl) phthalate (MEHP), a metabolite of DEHP, was associated with DNA damage after adjustment for the oxidative DEHP metabolites. After adjustment for MEHHP, for an interquartile range increase in urinary MEHP, CE increased 17.3% [95% confidence interval (CI) = 8.7-25.7%], TDM increased 14.3% (95% CI = 6.8-21.7%) and Tail% increased 17.5% (95% CI = 3.5-31.5%). CONCLUSIONS: Sperm DNA damage was associated with MEP and with MEHP after adjusting for DEHP oxidative metabolites, which may serve as phenotypic markers of DEHP metabolism to 'less toxic' metabolites. The urinary levels of phthalate metabolites among these men were similar to those reported for the US general population, suggesting that exposure to some phthalates may affect the population distribution of sperm DNA damage.
Study Synopsis: Arsenic is a groundwater contaminant that may occur naturally or as the result of agricultural and industrial practices. Human studies suggest that exposure to arsenic may be related with developmental defects and miscarriage. In this study, researchers exposed pregnant mice to different doses of sodium arsenite through drinking water from conception to weaning. Results show decreased fecundity at doses of 20 ppm or more. Exposure was also related with an abnormal development of blood vessels in the placenta. This may result in an insufficient supply of oxygen and nutrients to the developing fetus (called placental insufficiency), which may cause miscarriage. Authors thus conclude that arsenic may cause miscarriage through placental insufficiency.
Scientific abstract:
Arsenic is an abundant toxicant in ground water and soil around areas with extractive industries. Human epidemiological studies have shown that arsenic exposure is linked to developmental defects and miscarriage. The placenta is known to utilize vasculogenesis to develop its circulation. The hypothesis tested here states the following: arsenic exposure causes placental dysmorphogenesis and defective placental vasculogenesis resulting in placental insufficiency and subsequent spontaneous abortion. To test this hypothesis, pregnant mice were exposed to sodium arsenite (AsIII) through drinking water from conception through weanling stages. Neonatal assessment of birth rates, pup weights, and litter sizes in arsenic exposed and control mothers revealed that AsIII-exposed mothers had only 40% the fecundity of controls. Preterm analysis at E12.5 revealed a loss of fecundity at E12.5 from either 20 ppm or greater exposures to AsIII. There was no loss of fecundity at E7.5 suggesting that spontaneous abortion occurs during placentation. Histomorphometry on E12.5 placentae from arsenic-exposed mice revealed placental dysplasia especially in the vasculature. These results suggest that arsenic toxicity is causative for mammalian spontaneous abortion by virtue of aberrant placental vasculogenesis and placental insufficiency.
Study Synopsis: Leading scientists who study the fetal basis of adult disease review major findings in an issue of Reproductive Toxicology that focuses on this subject. This shifting paradigm in science suggests that susceptibility to disease is set in utero or neonatally. Exposures to environmental toxicants during this time and/or altered nutrition may result in irreversible changes that are manifest in adulthood as obesity, reproductive disorders, cardiovascular, respiratory or neurological disease.
Hoffman CS, Small CM, Blanck HM, Tolbert P, Rubin C, Marcus M. Endometriosis among women exposed to polybrominated biphenyls. Ann Epidemiol. 2007 Jul;17(7):503-10.
Study Synopsis: Polybrominated biphenyls (PBBs) are synthetic chemicals formerly used as flame retardants. In 1973, the Michigan food supply was contaminated with PBBs when the cattle feed supplement NutriMaster was accidently replaced with the flame retardant FireMaster. More than 4,000 individuals were exposed to PBBs; 308 women were included in the current study. Researchers estimated maternal exposure to PBBs and to closely related chemicals named polychlorinated biphenyls (PCBs) based on blood measurements (PCBs were formerly used in electrical transformers, inks, plastics and other consumer products). They also determined whether women suffered from endometriosis based on interviews. Although no association was found between exposure to PBBs and the risk of endometriosis, a women exposed to moderate and high levels of PCBs had 70% increased risk of endometriosis. Results do not support an association between exposure to PBB and endometriosis but do suggest that exposure to PCBs may be related to this condition.
Scientific abstract:
PURPOSE: We examined the association between endometriosis and exposure to polybrominated biphenyls (PBBs) and polychlorinated biphenyls (PCBs) among women inadvertently exposed to PBBs in 1973. METHODS: Serum PBBs and PCBs were measured in the late 1970s. Women self-reported endometriosis at interview in 1997. We constructed Cox models to estimate the relative incidence of endometriosis in relation to PBB and PCB levels. RESULTS: Seventy-nine of 943 women (9%) reported endometriosis. Compared with women with low PBB exposure (or=4 ppb) (HR = 0.90; 95% CI, 0.51-1.59) exposure did not have increased incidence of endometriosis. Increased incidence of endometriosis was suggested among women exposed to moderate PCB (5-8 ppb) (HR = 1.67; 95% CI, 0.91-3.10) and high PCB (>or=8 ppb) (HR = 1.68; 95% CI, 0.95-2.98) levels compared with low PCB exposure (Key Words: Cohort Studies, Endometriosis/chemically induced/ epidemiology, Environmental Exposure/adverse effects, Environmental Pollutants/ adverse effects/blood, Female, Flame Retardants/adverse effects, Humans, Michigan/epidemiology, Middle Aged, Polybrominated Biphenyls/ adverse effects/blood, Polychlorinated Biphenyls/ adverse effects/blood, Proportional Hazards Models
Study Synopsis: Female rats exposed pre-natally to testosterone have masculine traits at birth. Position in the womb next to a male sibling did not cause masculinization of females. However administration of testosterone during gestation did cause an increase in ano-genital distance, a decrease in nipple number, and at high doses the formation of prostate tissue. This research has implications for prenatal exposures to endocrine disrupting chemicals.
Scientific abstract:
In mammals, abnormal increases in fetal androgens disrupt normal development of the female phenotype. Due to the recent concern regarding environmental androgen-active chemicals, there is a need to identify sources of fetal androgen variation and sensitive developmental markers for androgenic activity in female rats. Anogenital distances (AGD), nipple retention, reproductive tract, and external genitalia are morphological parameters organized by prenatal androgens and are predictive of altered masculinized/defeminized phenotype in adult female mice and rats. The objectives of this study were to (1) characterize the natural prenatal androgen environment of rats including the magnitude of the intrauterine position (IUP) effect, (2) characterize the permanent effects of prenatal androgen exposure on female rats, and (3) determine the ability of AGD and areolas to predict these permanent androgenic alterations in female rats. Untreated male fetal rats had higher tissue testosterone (T) concentrations than females in the amniotic fluid, reproductive tract, gonad, and fetal body. The intrauterine position (IUP) of male and female fetuses did not affect T concentrations or AGD in male or female rats at gestational day (GD) 22. Female offspring exposed to 0, 1.5, and 2.5 mg/kg/day testosterone propionate (TP) on GDs 14-18 displayed increased AGD at postnatal day (PND) 2 and decreased nipples at PND 13 and as adults. TP-induced changes in neonatal AGD and infant areola number were reliable indicators of permanently altered adult phenotype in female rats. Further, females in the two high-dose groups displayed increased incidences of external genital malformations and the presence of prostatic tissue, not normally found in female rats.
Study Synopsis: Exposure to a mixture of phthalates causes reproductive harm in an additive manner. Rats exposed prenatally to a combination of DEHP and DBP had decreased testosterone levels and decreased expression of genes important for gonadal development. This research has important implications for humans who are continually exposed to low doses of a mixture of phthalates.
Scientific abstract:
Exposure to plasticizers di(n-butyl) phthalate (DBP) and diethylhexyl phthalate (DEHP) during sexual differentiation causes male reproductive tract malformations in rats and rabbits. In the fetal male rat, these two phthalate esters decrease testosterone (T) production and insulin-like peptide 3 (insl3) gene expression, a hormone critical for gubernacular ligament development. We hypothesized that co-administered DBP and DEHP would act in a cumulative dose-additive fashion to induce reproductive malformations, inhibit fetal steroid hormone production and suppress the expression of insl3 and genes responsible for steroid production. Pregnant Sprague-Dawley (SD) rats were gavaged on gestation days (GD) 14-18 with vehicle control, 500 mg/kg DBP, 500 mg/kg DEHP, or a combination of DBP and DEHP (500 mg/kg each chemical; DBP+DEHP); the dose of each individual phthalate was one-half of the effective dose predicted to cause a 50% incidence of epididymal agenesis. In experiment one, adult male offspring were necropsied, and reproductive malformations and androgen-dependent organ weights were recorded. In experiment two, GD18 testes were incubated for T production, and processed for gene expression by qrt-PCR. The DBP+DEHP dose increased the incidence of many reproductive malformations by [≥]50%, including epididymal agenesis, and reduced androgen-dependent organ weights in cumulative, dose-additive manner. Fetal T and expression of insl3 and Cyp11a were cumulatively decreased by the DBP+DEHP dose. These data indicate that individual phthalates with a similar mechanism of action, but with different active metabolites (monobutyl phthalate versus monoethylhexyl phthalate), can elicit dose additive effects when administered as a mixture.
Howdeshell KL, Furr J, Lambright CR, Rider CV, Wilson VS, Gray LE, Jr. Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes. Toxicol Sci. 2007 Sep;99(1):190-202.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. Prior studies have shown that phthalates can cause reproductive system malformation and affect hormone synthesis in male rats. The current study was designed to determine whether different phthalates acted in a cumulative manner in producing these adverse health effects. Researchers exposed pregnant rats to dibutyl phthalate (DBP) and diethylhexyl phthalate (DEHP) alone or in combination. The combination of DBP and DEHP resulted in increased rates of some malformations of the reproductive system and more acutely reduced the weight of reproductive organs compared with the effects of either chemical alone. Testosterone levels and the expression of genes involved in the production of this hormone were also reduced in a cumulative manner. These results suggest that phthalates act cumulatively when administered to rats as a mixture.
Scientific abstract:
Exposure to plasticizers di(n-butyl) phthalate (DBP) and diethylhexyl phthalate (DEHP) during sexual differentiation causes male reproductive tract malformations in rats and rabbits. In the fetal male rat, these two phthalate esters decrease testosterone (T) production and insulin-like peptide 3 (insl3) gene expression, a hormone critical for gubernacular ligament development. We hypothesized that coadministered DBP and DEHP would act in a cumulative dose-additive fashion to induce reproductive malformations, inhibit fetal steroid hormone production, and suppress the expression of insl3 and genes responsible for steroid production. Pregnant Sprague Dawley rats were gavaged on gestation days (GD) 14-18 with vehicle control, 500 mg/kg DBP, 500 mg/kg DEHP, or a combination of DBP and DEHP (500 mg/kg each chemical; DBP+DEHP); the dose of each individual phthalate was one-half of the effective dose predicted to cause a 50% incidence of epididymal agenesis. In experiment one, adult male offspring were necropsied, and reproductive malformations and androgen-dependent organ weights were recorded. In experiment two, GD18 testes were incubated for T production and processed for gene expression by quantitative real-time PCR. The DBP+DEHP dose increased the incidence of many reproductive malformations by >or=50%, including epididymal agenesis, and reduced androgen-dependent organ weights in cumulative, dose-additive manner. Fetal T and expression of insl3 and cyp11a were cumulatively decreased by the DBP+DEHP dose. These data indicate that individual phthalates with a similar mechanism of action, but with different active metabolites (monobutyl phthalate versus monoethylhexyl phthalate), can elicit dose-additive effects when administered as a mixture.
Huang PC, Kuo PL, Guo YL, Liao PC, Lee CC. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Hum Reprod. 2007 Oct;22(10):2715-22.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers investigated associations between the urine concentration of phthalate residues and thyroid hormone in 76 Taiwanese pregnant women during the second trimester of gestation. They found that women with higher monobutyl phthalate (MBP) levels in their urine had lower blood levels of the thyroid hormone thyroxine (T4). These results suggest that exposure to phthalates may be related with lower T4 in pregnant women. These findings are of particular significance because maternal T4 is essential to normal fetal brain development.
Scientific abstract:
BACKGROUND: Maternal hypothyroidism during pregnancy can cause adverse effects in the fetus. Scientific evidence has shown that probable thyroid-like function of some phthalates in vitro and in vivo, and phthalates exposure, can begin in utero. This study investigated the association between phthalate exposure and thyroid hormones in pregnant women. METHODS: Serum and spot urine samples were collected from 76 Taiwanese pregnant women at second trimester. Thyroid hormones, including thyroid-stimulating hormone (TSH), triiodothyronine (T(3)), thyroxine (T(4)) and free T(4) (FT(4)) were analysed in serum samples, and five urinary phthalate monoesters, including mono butyl phthalate (MBP), monoethyl phthalate (MEP) and mono ethylhexyl phthalate (MEHP), were measured. RESULTS: Urinary MBP, MEP and MEHP, the median levels of which were 81.8, 27.7 and 20.6 ng/ml, respectively, were the predominant substances in the urinary phthalate monoesters. Significant mild negative correlations were found between T(4) and urinary MBP (R = -0.248, P < 0.05), and between FT(4) and urinary MBP (R = -0.368, P < 0.05). After adjusting for age, BMI and gestation, urinary MBP levels showed negative associations with FT(4) and T(4) (FT(4): beta = -0.110, P < 0.001; T(4): beta=-0.112, P = 0.003). CONCLUSIONS: Exposure to di-n-butyl phthalate (DBP) may affect thyroid activity in pregnant women, but how DBP affects thyroid function is unclear. Further studies are needed to elucidate the mechanism of action and to investigate whether any other factors related to DBP exposure alter the thyroid function.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured thyroid-stimulating hormone (TSH), triiodothyronine (T3), total thyroxine (T4) and free T4 in the blood of 76 pregnant Taiwanese women during the second trimester. Phthalates, including mono butyl phthalate (MBP), monoethyl phthalate (MEP) and mono ethylhexyl phthalate (MEHP) were measured in maternal urine. Higher urine concentrations of MBP, but not MEP or MEHP, were related with lower maternal total and free T4. These results suggest that exposure to MBP during pregnancy may affect maternal thyroid function. Normal maternal thyroid hormone levels during pregnancy is essential to fetal brain development.
Scientific abstract:
BACKGROUND: Maternal hypothyroidism during pregnancy can cause adverse effects in the fetus. Scientific evidence has shown that probable thyroid-like function of some phthalates in vitro and in vivo, and phthalates exposure, can begin in utero. This study investigated the association between phthalate exposure and thyroid hormones in pregnant women. METHODS: Serum and spot urine samples were collected from 76 Taiwanese pregnant women at second trimester. Thyroid hormones, including thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4) and free T4 (FT4) were analysed in serum samples, and five urinary phthalate monoesters, including mono butyl phthalate (MBP), monoethyl phthalate (MEP) and mono ethylhexyl phthalate (MEHP), were measured. RESULTS: Urinary MBP, MEP and MEHP, the median levels of which were 81.8, 27.7 and 20.6 ng/ml, respectively, were the predominant substances in the urinary phthalate monoesters. Significant mild negative correlations were found between T4 and urinary MBP (R = 0.248, P < 0.05), and between FT4 and urinary MBP (R = 0.368, P < 0.05). After adjusting for age, BMI and gestation, urinary MBP levels showed negative associations with FT4 and T4 (FT4: [beta] = 0.110, P < 0.001; T4: [beta]=0.112, P = 0.003). CONCLUSIONS: Exposure to di-n-butyl phthalate (DBP) may affect thyroid activity in pregnant women, but how DBP affects thyroid function is unclear. Further studies are needed to elucidate the mechanism of action and to investigate whether any other factors related to DBP exposure alter the thyroid function.
Study Synopsis: A large Danish study concludes low birth weight is a risk factor for hospitalization due to infections throughout childhood. For each 500 gram decrease in birth weight, there was a 9% increased risk of hospitalization. This effect peaked during infancy but persisted up to 10 years of age. Children born at term but of low birth weight also were found to have this effect.
Scientific abstract:
Low birth weight, a result of preterm birth or intrauterine growth restriction, is a well-established indicator of survival in childhood. However, corresponding epidemiologic studies of the association between low birth weight and morbidity from infections throughout childhood are sparse. The authors evaluated the relation between birth weight and infectious diseases throughout childhood in a population-based cohort study comprising all children born in Denmark from 1977 through 2004 (n = 1.7 million). Information on birth weight, gestational age, and potential confounding variables was linked to the children in the cohort, together with information on hospitalization with infectious disease. Poisson regression yielded rate ratios of hospitalization according to birth weight. The authors found that birth weight was inversely associated with risk of infectious disease hospitalization; among children aged 0-14 years, the risk of hospitalization increased 9% for each 500-g reduction in birth weight (increase in rate ratio = 1.09, 95% confidence interval: 1.09, 1.11). The effect was found to peak in infancy and to persist until 10 years of age. It was present also in children born at term (37-41 weeks of gestation). The present study is the first to demonstrate the measurable impact of birth weight on infectious diseases throughout childhood.
Study Synopsis: Exposure to the plant estrogen, genistein, alters the reproductive function of female mice. Mice had increased uterine weight, abnormal follicles (eggs) and reduced fertility at environmentally relevant doses. These effects were transmitted to subsequent generations suggesting an irreversible and transgenerational effect.
Scientific abstract:
Studies in our laboratory have shown that developmental exposure to genistein causes deleterious effects on the reproductive system. Oral exposure to genistin (25 mg/kg) increases uterine weight at 5 days of age similar to subcutaneous injection of genistein (20 mg/kg) suggesting that subcutaneous injection of genistein is a suitable model for oral exposure to genistin. Mice treated neonatally by subcutaneous injection of genistein (0.5-50 mg/kg) exhibit altered ovarian differentiation leading to multi-oocyte follicles (MOFs). Ovarian function and estrous cyclicity were disrupted in genistein treated mice with increasing severity over time. Reduced fertility was observed in mice treated with genistein (0.5, 5, or 25 mg/kg) and infertility was observed at 50 mg/kg. Females generated from genistein 25 mg/kg females bred to control males have increased MOFs suggesting these effects can be transmitted to subsequent generations. Thus, neonatal treatment with genistein at environmentally relevant doses caused adverse consequences on reproduction in adulthood.
Study Synopsis: Using a rat model, this research team found prenatal exposure to the potent dioxin, TCDD, did not change DNA methylation patterns but did cause changes in protein levels in the mammary gland. Proteins important for detoxifying free radicals were amongst those to be altered and could increase the vulnerability of the gland to other cancer-causing substances.
Scientific abstract:
Epidemiological data are conflicting in the link between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure and breast cancer causation. We have hypothesized that timing of exposure to endocrine disruptors, such as TCDD, will alter breast cancer susceptibility. Using a carcinogen induced rat mammary cancer model, we have shown that prenatal exposure to TCDD alters mammary gland differentiation and increases susceptibility for mammary cancer. Investigations into imprinting via DNA methylation mechanisms showed that there were no changes in protein expression in DNA methyltransferases, ER-alpha, ER-beta, GST-pi, or MDGI. Using 2D gels and mass spectrometry, we have found seven proteins to be differentially regulated, including a decrease in superoxide dismutase 1 (SOD1). Down-regulation of SOD1 could provide an environment ill equipped to deal with subsequent free radical exposure. We conclude that prenatal TCDD can predispose for mammary cancer susceptibility in the adult offspring by altering the mammary proteome.
Key Words: Prenatal, TCDD, Mammary cancer, Superoxide dismutase, DNA methylation
Study Synopsis: Danish study finds that fertility treatment may compromise the reproductive health of male offspring. Men conceived through fertility treatment had 45% lower sperm counts, poorer sperm quality smaller testis size, and lower serum testosterone (not statistically significant) than men conceived naturally. Though the cause of these findings is unknown, they raise concerns about the long-term reproductive outcomes in offspring from fertility treatments.
Scientific abstract:
Little is known the about the reproductive health of offspring after fertility treatment. In 2001-2005, the authors approached young Danish men attending a compulsory physical examination to determine their fitness for military service. A total of 1,925 men volunteered, delivered a semen sample, had a physical examination performed and a blood sample drawn, and responded to a questionnaire. Their mothers were questioned about whether they had received fertility treatment in order to conceive their sons. Forty-seven mothers reported having received fertility treatment to conceive the index subject. After control for confounders, men whose mothers had received fertility treatment to conceive them had a 46% lower sperm concentration (95% confidence interval (CI): -63, -20) and a 45% lower total sperm count (95% CI: -64, -16). They had a smaller testis size (-0.9 ml, 95% CI: -2.2, 0.4), fewer motile sperm (-4.0%, 95% CI: -8.0, -0.1), and fewer morphologically normal spermatozoa (-2.0%, 95% CI: -4.1, 0.0). They also had a lower serum testosterone level and free androgen index (results not statistically significant). These findings should be viewed in light of the increasing use of fertility treatments. Although the cause of these findings is unknown, they raise concern about possible late effects of fertility treatment. Larger-scale studies of children born after fertility treatment should be performed.
Study Synopsis: Swedish researchers report that lactation is a source of considerable exposure for infants to perfluorinated chemicals. Their study found PFCs in all milk samples, with the average total of eight PFCs in milk at 0.34 ng/mL. Serum levels averaged 32 ng/mL. They observed a strong association between increased serum and increased milk concentrations.
Scientific abstract:
Background: Only limited data exist on lactation as an exposure source of persistent perfluorinated chemicals (PFCs) for children. Objectives: We studied occurrence and levels of PFCs in human milk in relation to maternal serum together with the temporal trend in milk levels between 1996 and 2004 in Sweden. Matched, individual human milk and serum samples from 12 primiparous women in Sweden were analyzed together with composite milk samples (25ū90 women/year) from 1996 to 2004. Results: Eight PFCs were detected in the serum samples, and five of them were also above the detection limits in the milk samples. Perfluorooctanesulfonate (PFOS) and perfluorohexanesulfonate (PFHxS) were detected in all milk samples at mean concentrations of 0.201 ng/mL and 0.085 ng/mL, respectively. Perfluorooctanesulfonamide (PFOSA) , perfluorooctanoic acid (PFOA) , and perfluorononanoic acid (PFNA) were detected less frequently. Discussion: The total PFC concentration in maternal serum was 32 ng/mL, and the corresponding milk concentration was 0.34 ng/mL. The PFOS milk level was on average 1% of the corresponding serum level. There was a strong association between increasing serum concentration and increasing milk concentration for PFOS (r2 = 0.7) and PFHxS (r2 = 0.8) . PFOS and PFHxS levels in composite milk samples were relatively unchanged between 1996 and 2004, with a total variation of 20 and 32% coefficient of variation, respectively. Conclusion: The calculated total amount of PFCs transferred by lactation to a breast-fed infant in this study was approximately 200 ng/day. Lactation is a considerable source of exposure for infants, and reference concentrations for hazard assessments are needed.
Study Synopsis: Flaxseed contains many beneficial components that might lower the risk of breast cancer but also contains the heavy metal and estrogen-mimicking chemical, cadmium. In this rodent study, exposure to flaxseed during pregnancy and lactation resulted in an increased number of tumors and changes in estrogen receptor expression. It was not possible to tell if the causative agent in thi study was cadmium or not.
Scientific abstract:
Flaxseed contains several dietary components that have been linked to low breast cancer risk; i.e., n-3 polyunsaturated fatty acids (PUFAs), lignans and fiber, but it also contains detectable levels of cadmium, a heavy metal that activates the estrogen receptor (ER). Since estrogenic exposures early in life modify susceptibility to develop breast cancer, we wondered whether maternal dietary intake of 5% or 10% flaxseed during pregnancy or lactation (between postpartum days 5 and 25) might affect 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis in the rat offspring. Our data indicated that both in utero and postnatal 5% and 10% flaxseed exposures shortened mammary tumor latency, and 10% flaxseed exposure increased tumor multiplicity, compared to the controls. Further, when assessed in 8-week-old rats, in utero 10% flaxseed exposure increased lobular ER-[alpha] protein levels, and both in utero and postnatal flaxseed exposures dose-dependently reduced ER-[beta] protein levels in the terminal end buds (TEBs) lobules and ducts. Exposures to flaxseed did not alter the number of TEBs or affect cell proliferation within the epithelial structures. In a separate group of immature rats that were fed 5% defatted flaxseed diet (flaxseed source different than in the diets fed to pregnant or lactating rats) for 7 days, cadmium exposure through the diet was six-fold higher than allowed for humans by World Health Organization, and cadmium significantly accumulated in the liver and kidneys of the rats. It remains to be determined whether the increased mammary cancer in rats exposed to flaxseed through a maternal diet in utero or lactation was caused by cadmium present in flaxseed, and whether the reduced mammary ER-[beta] content was causally linked to increased mammary cancer risk among the offspring.
Key Words: Flaxseed, Breast cancer, Estrogen receptor
Lee BM, Koo HJ. Hershberger assay for antiandrogenic effects of phthalates. J Toxicol Environ Health A. 2007 Aug;70(15-16):1365-70.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers administered various doses of one of six phthalates by subcutaneous injection during 10 consecutive days. They found that prostate weights were significantly decreased in animals treated with diethylhexyl phthalate (DEHP) or dibutyl phthalate (DBP) at doses of 20 mg/kg or above, diisodecyl phthalate (DIDP) at doses of 500 mg/kg, and monoethyhexyl phthalate (MEHP) at doses of 250 mg/kg. Seminal vesicles weights were also significantly decreased by DEHP, DINP and MEHP. These results suggest that phthalates possess antiandrogenic activity and affect the male reproductive system in rats.
Scientific abstract:
The antiandrogenic effects of seven phthalates, di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), butyl benzyl phthalate (BBP), di-isononyl phthalate (DINP), di-isodecyl phthalate (DIDP), di-n-heptyl phthalate (DnHP), and mono-2-ethyhexyl phthalate (MEHP), were investigated by Hershberger assay in castrated male SD rats. An androgen agonist, testosterone (0.4 mg/kg/d), was administered for 10 consecutive days by subcutaneous (s.c.) injection as a positive control. Additionally, 20, 100, or 500 mg/kg body weight (bw)/d of 6 phthalates (DEHP, DBP, BBP, DINP, DIDP, or DnHP) or 10, 50, or 250 mg/kg bw/d of MEHP, the primary metabolite of DEHP, were also administered orally in combination with testosterone (0.4 mg/kg/d, s.c.) for 10 consecutive days, respectively. In the testosterone-treated groups, glans penis, seminal vesicles, ventral prostate, and levator ani/bulbocavernosus muscles (LABC) weights were found to be significantly increased. Ventral prostate weights were significantly decreased in animals treated with DEHP or DBP at doses of 20 mg/kg bw/d or above, 500 mg/kg bw/d DIDP, and 250 mg/kg bw/d MEHP. Seminal vesicles weights were also significantly decreased by DEHP at > 100 mg/kg bw/d, DINP at > 20 mg/kg bw/d, DIDP at 500 mg/kg bw/d, or MEHP at 50 or 250 mg/kg bw/d, respectively. In addition, LABC weights were decreased by DEHP at 500 mg/kg bw/d, DINP at 500 mg/kg bw/d, and MEHP at 50 or 100 mg/kg bw/d. These data suggest that some phthalates possess antiandrogenic activity, and that multiple cross-talk between androgen, estrogen, and steroid hormone receptors occurs.
Study Synopsis: Genes involved in estrogen signaling and the making of steroid hormones were reprogrammed in developing mice exposed to arsenic through their mothers. The altered gene patterns increased the risk of liver cancer in adult male mice. The finding highlights the need to reduce pregnant women's arsenic exposure through skin, food, drink and air.
Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p < 0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17β-hydroxysteroid dehydrogenase-7 (HSD17β7; involved in estradiol production) and decreased expression of HSD17β5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood.
Study Synopsis: Exposure to DDT in the womb is not associated with a decrease in ano-genital distance. DDT is broken down to the anti-androgen, DDE, and has been associated with a decreased ano-genital distance in animal models. However, in this study of newborn boys in Mexico, where DDT has been used for malaria control, there was no change in ano-genital distance or penile dimensions as measured by their mother's blood levels of DDE. If DDE has important anti-androgenic effects in humans, it may not be manifest anatomically but may still cause infertility later in life or have an effect only at higher levels of exposure.
Scientific abstract:
The insecticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) is still used for disease control in some areas, resulting in high levels of human exposure. The main degradation product of DDT is 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), an antiandrogen. In animal experiments, in utero exposure to DDE decreases anogenital distance in male offspring. In these models, anogenital distance serves as a measure of fetal androgen action. The authors designed the present study to examine the hypothesis that in utero exposure to DDE decreases anogenital distance in newborn human males. A cross-sectional study of 781 newly delivered male infants was conducted in 2002-2003 in Chiapas, Mexico, where DDT had recently been used for malaria control. Measurements of anogenital distance and penile dimensions were taken, and a sample of the mother's blood was drawn. In this population, the range of serum DDE levels was large (0.8-398 {micro}g/liter). The authors, using two-sided tests, found no evidence that exposure in utero to DDE was related to reduced androgen action as reflected by anogenital distance or penile dimensions at birth. If DDE has important antiandrogenic action in humans, it may be manifest only at higher levels of exposure or via effects on other outcomes.
Study Synopsis: Chlorination of drinking water generates disinfection by-products (DBPs) such as trihalomethanes (THM) and haloacetic acids (HAA), which have been shown to disrupt spermatogenesis in rodents at high doses. In this study, researchers measured four types of THM and 9 types of HAA in tab water and collected information on water consumption and bathing and showering to estimate exposure. They also collected semen specimens in which they measured a number of sperm quality parameters, including sperm concentration and count. No associations were found between exposure to any of the DBPs and sperm quality. Results of this study do not support a relation between exposure to DBPs and sperm quality.
Scientific abstract:
BACKGROUND: Chlorination of drinking water generates disinfection by-products (DBPs), which have been shown to disrupt spermatogenesis in rodents at high doses, suggesting that DBPs could pose a reproductive risk to men. In this study we assessed DBP exposure and testicular toxicity, as evidenced by altered semen quality. METHODS: We conducted a cohort study to evaluate semen quality in men with well-characterized exposures to DBPs. Participants were 228 presumed fertile men with different DBP profiles. They completed a telephone interview about demographics, health history, water consumption, and other exposures and provided a semen sample. Semen outcomes included sperm concentration and morphology, as well as DNA integrity and chromatin maturity. Exposures to DBPs were evaluated by incorporating data on water consumption and bathing and showering with concentrations measured in tap water. We used multivariable linear regression to assess the relationship between exposure to DBPs and adverse sperm outcomes. RESULTS: The mean (median) sperm concentration and sperm count were 114.2 (90.5) million/mL and 362 (265) million, respectively. The mean (median) of the four trihalomethane species (THM4) exposure was 45.7 (65.3) microg/L, and the mean (median) of the nine haloacetic acid species (HAA9) exposure was 30.7 (44.2) microg/L. These sperm parameters were not associated with exposure to these classes of DBPs. For other sperm outcomes, we found no consistent pattern of increased abnormal semen quality with elevated exposure to trihalomethanes (THMs) or haloacetic acids (HAAs). The use of alternate methods for assessing exposure to DBPs and site-specific analyses did not change these results. CONCLUSIONS: The results of this study do not support an association between exposure to levels of DBPs near or below regulatory limits and adverse sperm outcomes in humans.
Main KM, Kiviranta H, Virtanen HE, Sundqvist E, Tuomisto JT, Tuomisto J, Vartiainen T, Skakkebaek NE, Toppari J. Flame retardants in placenta and breast milk and cryptorchidism in newborn boys. Environ Health Perspect. 2007 Oct;115(10):1519-26.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers compared the concentration of PBDE in the breast milk and placenta of 95 women who delivered a boy with cryptorchidism (undescended testes) with 185 women who gave birth to a healthy son. Breast milk levels of PBDEs were used to estimate prenatal exposure. There were no differences in the levels of PBDEs in placenta between cryptorchid and healthy boys. The median breast milk level of total PBDEs was however higher in women who gave birth to cryptorchid cases. Results suggest that prenatal exposure to PBDEs may be related with increased risks of cryptorchidism.
Scientific abstract:
BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are widely used in Western countries. OBJECTIVES: Because the prevalence of cryptorchidism appears to be increasing, we investigated whether exposure to PBDEs was associated with testicular maldescent. METHODS: In a prospective Danish-Finnish study, 1997-2001, all boys were examined for cryptorchidism. We analyzed whole placentas (for 95 cryptorchid/185 healthy boys) and individual breast milk samples (62/68) for 14 PBDEs and infant serum samples for gonadotropins, sex-hormone binding globulin, testosterone, and inhibin B. RESULTS: In 86 placenta-milk pairs, placenta PBDE concentrations in fat were lower than in breast milk, and a larger number of congeners were nondetectable. There was no significant difference between boys with and without cryptorchidism for individual congeners, the sum of 5 most prevalent, or all 14 congeners. The concentration of PBDEs in breast milk was significantly higher in boys with cryptorchidism than in controls (sum of BDEs 47, 153, 99, 100, 28, 66, and 154: median, 4.16 vs. 3.16 ng/g fat; p < 0.007). There was a positive correlation between the sum of PBDEs and serum luteinizing hormone (p < 0.033). The sum of PBDEs in breast milk did not differ between Denmark and Finland (median, 3.52 vs. 3.44 ng/g fat), but significant differences in some individual congeners were found. CONCLUSIONS: Two different proxies were used for prenatal PBDE exposure, and levels in breast milk, but not in placenta, showed an association with congenital cryptorchidism. Other environmental factors may contribute to cryptorchidism. Our observations are of concern because human exposure to PBDEs is high in some geographic areas.
Study Synopsis: A study of US servicemen finds an association between being tall and risk of testicular cancer. However, there was no association between amount of dairy consumption or age of puberty onset and testicular tumors. Height as an adult is thought to be determined by age 2 and could signify that exposures early in life are also important for the development of testicular cancer.
Scientific abstract:
The etiology of testicular germ cell tumors (TGCTs) is poorly understood, with cryptorchidism and family history being the only well-established risk factors. Body size, age at puberty, and dairy consumption, however, have been suggested to be related to TGCTs. To clarify the relation of these variables to TGCT risk and to one another, the authors analyzed data from 767 cases and 928 controls enrolled in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study (2002-2005). Overall, increased height was significantly related to risk (odds ratio (OR) = 1.83, 95% confidence interval (CI): 1.36, 2.45), though body mass index was not (OR = 1.06, 95% CI: 0.66, 1.69). There was no association with age at puberty, based on ages at first shaving (OR = 1.29, 95% CI: 0.96, 1.73), voice changing (OR = 0.97, 95% CI: 0.71, 1.32), and nocturnal emissions (OR = 1.00, 95% CI: 0.73, 1.37). Similarly, there was no relation with dairy consumption at any age between birth and 12th grade. These results suggest that height is a risk factor for TGCTs, but the relation is unlikely explained by childhood dairy consumption. As adult height is largely determined in the first 2 years of life, increased attention to events in this interval may help elucidate the etiology of TGCTs.
Study Synopsis: The first study to examine the connection between human exposure to phthalates and changes in thyroid hormone levels reports that men with higher levels of the phthalate breakdown product MEHP in their urine had lower levels of two major thyroid hormones, T4 and T3 in their blood. Changes in thyroid hormone levels can affect growth, development and metabolism and cause a number of human diseases. More research is needed to establish whether MEHP is causing the thyroid declines.
Background: Phthalates are used extensively in many personal-care and consumer products, resulting in widespread nonoccupational human exposure through multiple routes and media. A limited number of animal studies suggest that exposure to phthalates may be associated with altered thyroid function, but human data are lacking. Methods: Concurrent samples of urine and blood were collected from 408 men. We measured urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP) , the hydrolytic metabolite of di(2-ethylhexyl) phthalate (DEHP) , and other phthalate monoester metabolites, along with serum levels of free thyroxine (T4) , total triiodothyronine (T3) , and thyroid-stimulating hormone (TSH) . Oxidative metabolites of DEHP were measured in urine from only 208 of the men., , Results: We found an inverse association between MEHP urinary concentrations and free T4 and T3 serum levels, although the relationships did not appear to be linear when MEHP concentrations were categorized by quintiles. There was evidence of a plateau at the fourth quintile, which was associated with a 0.11 ng/dL decrease in free T4 [95% confidence interval (CI) , ū0.18 to ū0.03] and a 0.05 ng/mL decrease in T3 (95% CI, ū0.10 to 0.01) compared with the first (lowest) MEHP quintile. The inverse relationship between MEHP and free T4 remained when we adjusted for oxidative metabolite concentrations; this simultaneously demonstrated a suggestive positive association with free T4. Conclusions: Urinary MEHP concentrations may be associated with altered free T4 and/or total T3 levels in adult men, but additional study is needed to confirm the observed findings. Future studies must also consider oxidative DEHP metabolites relative to MEHP as a potential marker of metabolic susceptibility to DEHP exposure.
BACKGROUND: Phthalates are used extensively in many personal-care and consumer products, resulting in widespread nonoccupational human exposure through multiple routes and media. A limited number of animal studies suggest that exposure to phthalates may be associated with altered thyroid function, but human data are lacking. METHODS: Concurrent samples of urine and blood were collected from 408 men. We measured urinary concentrations of mono(2-ethylhexyl) phthalate (MEHP), the hydrolytic metabolite of di(2-ethylhexyl) phthalate (DEHP), and other phthalate monoester metabolites, along with serum levels of free thyroxine (T(4)), total triiodothyronine (T(3)), and thyroid-stimulating hormone (TSH). Oxidative metabolites of DEHP were measured in urine from only 208 of the men. RESULTS: We found an inverse association between MEHP urinary concentrations and free T(4) and T(3) serum levels, although the relationships did not appear to be linear when MEHP concentrations were categorized by quintiles. There was evidence of a plateau at the fourth quintile, which was associated with a 0.11 ng/dL decrease in free T(4) [95% confidence interval (CI), -0.18 to -0.03] and a 0.05 ng/mL decrease in T(3) (95% CI, -0.10 to 0.01) compared with the first (lowest) MEHP quintile. The inverse relationship between MEHP and free T(4) remained when we adjusted for oxidative metabolite concentrations; this simultaneously demonstrated a suggestive positive association with free T(4). CONCLUSIONS: Urinary MEHP concentrations may be associated with altered free T(4) and/or total T(3) levels in adult men, but additional study is needed to confirm the observed findings. Future studies must also consider oxidative DEHP metabolites relative to MEHP as a potential marker of metabolic susceptibility to DEHP exposure.
Study Synopsis: Prenatal exposure to a mixture of anti-androgenic chemicals produces changes in the structure of and genes expressed in male reproductive organs. Rats exposed to a mixture of vinclozolin, flutamide and procymidone had abnormal development of the prostate, seminal vesicles and epididymis. Exposure to low doses of each individual chemical did not cause these effects but exposure to a mixture of low doses did, indicating an additive effect. This research has important implications for similar conditions in humans, who are routinely exposed to mixtures of low doses of chemicals.
Scientific abstract:
We investigated the ability of a mixture of three androgen receptor antagonists to induce disruption of male sexual differentiation after perinatal exposure. The aim was to assess whether the joint effects of vinclozolin, flutamide, and procymidone can be predicted based on dose-response data of the individual chemicals. Chemicals were administered orally to pregnant Wistar rats from gestational day 7 to postnatal day 16. Changes in reproductive organ weights and of androgen-regulated gene expression in prostates from male rat pups were chosen as end points for extensive dose-response studies. With all end points, the joint effects of the three antiandrogens were dose additive. Histological evaluations showed that dysgenesis and hypoplasia of prostates, seminal vesicles, and epididymis were seen with the highest mixture doses. No changes were observed in any single-compound low-dose group for these lesions, nor were there histopathological changes in the testes. Pronounced dysgenesis of external genitals was observed with all doses of the mixture, and severe dysgenesis was seen with a mixture for which the individual compounds caused no effects. A combination of doses of each chemical that on its own did not produce significant reductions in the weights of seminal vesicles and PBP C3 expression induced a marked mixture effect. Thus, antiandrogens cause additive effects on end points of various molecular complexities such as alterations at the morphological and the molecular level. Exposure to antiandrogens, which appears to exert only small effects when judged on a chemical-by-chemical basis, may induce marked responses in concert with, possibly unrecognized, similarly acting chemicals.
Study Synopsis: Dioxin exposure alters gene expression patterns in endometrial cells and may lead to endometriosis. Endometriosis is a common cause of infertility and exposure to dioxin has previously been associated with development of endometriosis but the mechanism is unknown. Mice exposed to the potent dioxin, TCDD, during critical periods of development had changes in gene expression patterns identical to those seen in human endometrial cells, suggesting a decreased responsiveness to progesterone and increased invasiveness of endometrial cells.
Scientific abstract:
Whether environmental toxicants impact an individual woman's risk for developing endometriosis remains uncertain. Although the growth of endometrial glands and stroma at extra-uterine sites is associated with retrograde menstruation, our studies suggest that reduced responsiveness to progesterone may increase the invasive capacity of endometrial tissue in women with endometriosis. Interestingly, our recent studies using isolated human endometrial cells in short-term culture suggest that experimental exposure to the environmental contaminant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) can alter the expression of progesterone receptor isotypes. Compared to adult exposure, toxicant exposure during development can exert a significantly greater biological impact, potentially affecting the incidence of endometriosis in adults. To address this possibility, we exposed mice to TCDD at critical developmental time points and subsequently examined uterine progesterone receptor expression and steroid responsive transforming growth factor-[beta]2 expression in adult animals. We find that the uterine phenotype of toxicant-exposed mice is markedly similarly to the endometrial phenotype of women with endometriosis.
Study Synopsis: A common component of tobacco smoke is found to be toxic to the ovary. Cigarette smoke is known to decrease fertility rates but the mechanism for doing this is unknown. Rat ovaries exposed to levels of benzo(a)pyrene similar to those found in the blood and follicular fluid of tobacco smokers inhibited development of follicles (eggs)in the ovary.
Scientific abstract:
BACKGROUND: The adverse effects of cigarette smoking on human fertility have been well documented. However, the mechanism(s) underlying the detrimental effects of cigarette smoking are unknown. Using a novel isolated rat follicle culture assay, we tested the hypothesis that benzo-[a]-pyrene (B[a]P), a constituent of cigarette smoke, can inhibit follicle growth. METHODS: B[a]P levels were quantified in the serum and follicular fluid (FF) of women undergoing in vitro fertilization (IVF) treatment exposed to mainstream smoke (n = 19) and non-smokers (n = 10) by gas chromatography mass spectrometry. Isolated rat follicles were cultured with increasing concentrations of B[a]P (1.5-300 ng ml-1) and follicle diameter was measured daily. RESULTS: Mean ( {+/-} Standard error of the mean) B[a]P) was quantified in the serum (0.40 {+/-} 0.13 ng ml-1) and FF (1.32 {+/-} 0.68 ng ml-1) of women who smoke. IVF stimulation and outcome measures were similar between female smokers and non-smokers with the exception of implantation rate and pregnancy rate, which were both significantly lower (P < 0.05) in the MS group. B[a]P treatment significantly reduced rat follicle diameter and attenuated FSH stimulated growth in a dose-dependent manner, beginning at 1.5 ng ml-1. CONCLUSIONS: Our data suggest that B[a]P, at levels representative of those measured in human FF, may adversely affect follicle development and be an ovarian toxicant.
Study Synopsis: Mice exposed to the potent estrogen, DES, in the womb were developmentally programmed to gain weight as they aged. Obesity has been associated with infertility. Obesity is an emerging area of research in the field of endocrine disruption.
Scientific abstract:
Xenobiotic and dietary compounds with hormone-like activity can disrupt endocrine signaling pathways that play important roles during perinatal differentiation and result in alterations that are not apparent until later in life. Evidence implicates developmental exposure to environmental hormone-mimics with a growing list of health problems. Obesity is currently receiving needed attention since it has potential to overwhelm health systems worldwide with associated illnesses such as diabetes and cardiovascular disease. Here, we review the literature that proposes an association of exposure to environmental endocrine disrupting chemicals with the development of obesity. We describe an animal model of developmental exposure to diethylstilbestrol (DES), a potent perinatal endocrine disruptor with estrogenic activity, to study mechanisms involved in programming an organism for obesity. This experimental animal model provides an example of the growing scientific field termed "the developmental origins of adult disease" and suggests new targets of abnormal programming by endocrine disrupting chemicals.
Study Synopsis: Smoking during pregnancy is well-recognized to cause poor birth outcomes such as preterm labor and low birth weight. This article reviews the evidence for prenatal tobacco smoke exposure and obesity, diabetes, asthma and cancer.
Scientific abstract:
About 1 million babies are born each year after prenatal cigarette smoke (CS) exposure from maternal smoking which does not include involuntary maternal exposure to passive smoke. While past emphasis has been on immediately obvious perinatal consequences (e.g., preterm delivery, and low birthweight), smoking during pregnancy has recently emerged as a possible risk factor for later onset disease outcomes in the prenatally exposed offspring. This review brings together those epidemiologic and toxicologic studies demonstrating a link between prenatal CS exposure and subsequent disease vulnerabilities in the progeny. While disorders such as obesity, and type 2 diabetes are included in this category, this paper focuses on two immunologically-related outcomes, cancer and asthma. The review defines the current state of knowledge in this understudied area of children's health, sheds light on the seriousness of such disease vulnerabilities, and reveals gaps that need to be filled to provide a better understanding of the extent and nature of the problem.
Study Synopsis: Environmental conditions before the age of eight may determine fertility later in life. Women who migrated from Bangladesh to the UK during infancy and early childhood reach puberty earlier, are taller, and have up to 103% higher levels of the hormone progesterone as adults in comparison to women who migrated at a later age, as well as those who remained in Bangladesh. Higher hormone levels could potentially increase a woman's ability to conceive. However, fertility was not measured in any of the groups in this study.
Scientific abstract:
BACKGROUND: Average profiles of salivary progesterone in women vary significantly at the inter- and intrapopulation level as a function of age and acute energetic conditions related to energy intake, energy expenditure, or a combination of both. In addition to acute stressors, baseline progesterone levels differ among populations. The causes of such chronic differences are not well understood, but it has been hypothesised that they may result from varying tempos of growth and maturation and, by implication, from diverse environmental conditions encountered during childhood and adolescence. METHODS AND FINDINGS: To test this hypothesis, we conducted a migrant study among first- and second-generation Bangladeshi women aged 19-39 who migrated to London, UK at different points in the life-course, women still resident in Bangladesh, and women of European descent living in neighbourhoods similar to those of the migrants in London (total n = 227). Data collected included saliva samples for radioimmunoassay of progesterone, anthropometrics, and information from questionnaires on diet, lifestyle, and health. Results from multiple linear regression, controlled for anthropometric and reproductive variables, show that women who spend their childhood in conditions of low energy expenditure, stable energy intake, good sanitation, low immune challenges, and good health care in the UK have up to 103% higher levels of salivary progesterone and an earlier maturation than women who develop in less optimal conditions in Sylhet, Bangladesh (F9,178 = 5.05, p < 0.001, standard error of the mean = 0.32; adjusted R(2) = 0.16). Our results point to the period prior to puberty as a sensitive phase when changes in environmental conditions positively impact developmental tempos such as menarcheal age (F2,81 = 3.21, p = 0.03) and patterns of ovarian function as measured using salivary progesterone (F2,81 = 3.14, p = 0.04). CONCLUSIONS: This research demonstrates that human females use an extended period of the life cycle prior to reproductive maturation to monitor their environment and to modulate reproductive steroid levels in accordance with projected conditions they might encounter as adults. Given the prolonged investment of human pregnancy and lactation, such plasticity (extending beyond any intrauterine programming) enables a more flexible and finely tuned adjustment to the potential constraints or opportunities of the later adult environment. This research is the first, to our knowledge, to demonstrate a postuterine developmental component to variation in reproductive steroid levels in women.
Key Words: Adolescent, Adult, Age Factors, Anthropometry, Bangladesh, Child, Diet, Emigration and Immigration, Energy Intake, Energy Metabolism, Female, Health Status Indicators, Humans, Life Style, Linear Models, London/ethnology, Menstrual Cycle/*physiology, Ovary/physiology, Progesterone/*metabolism, Questionnaires, Saliva/chemistry
Research notes: Comment in PLoS Med. 2007 May;4(5):e190.
Study Synopsis: Fruit flies exposed to cell phone radiation for 6 minutes per day over 6 days had reproductive damage. The experiments used actual cell phones activated with someone speaking throughout the exposure. Both GSM 900 and DCS 1800 mobile telephony radiations strongly induce cell death (DNA fragmentation) in ovarian egg chambers of the exposed groups. Insects typically are thought more resistant to radiation than people.
Scientific abstract:
In the present study, the TUNEL (Terminal deoxynucleotide transferase dUTP Nick End Labeling) assay--a well known technique widely used for detecting fragmented DNA in various types of cells--was used to detect cell death (DNA fragmentation) in a biological model, the early and mid stages of oogenesis of the insect Drosophila melanogaster. The flies were exposed in vivo to either GSM 900-MHz (Global System for Mobile telecommunications) or DCS 1800-MHz (Digital Cellular System) radiation from a common digital mobile phone, for few minutes per day during the first 6 days of their adult life. The exposure conditions were similar to those to which a mobile phone user is exposed, and were determined according to previous studies of ours [D.J. Panagopoulos, A. Karabarbounis, L.H. Margaritis, Effect of GSM 900-MHz mobile phone radiation on the reproductive capacity of D. melanogaster, Electromagn. Biol. Med. 23 (1) (2004) 29-43; D.J. Panagopoulos, N. Messini, A. Karabarbounis, A.L. Philippetis, L.H. Margaritis, Radio frequency electromagnetic radiation within "safety levels" alters the physiological function of insects, in: P. Kostarakis, P. Stavroulakis (Eds.), Proceedings of the Millennium International Workshop on Biological Effects of Electromagnetic Fields, Heraklion, Crete, Greece, October 17-20, 2000, pp. 169-175, ISBN: 960-86733-0-5; D.J. Panagopoulos, L.H. Margaritis, Effects of electromagnetic fields on the reproductive capacity of D. melanogaster, in: P. Stavroulakis (Ed.), Biological Effects of Electromagnetic Fields, Springer, 2003, pp. 545-578], which had shown a large decrease in the oviposition of the same insect caused by GSM radiation. Our present results suggest that the decrease in oviposition previously reported, is due to degeneration of large numbers of egg chambers after DNA fragmentation of their constituent cells, induced by both types of mobile telephony radiation. Induced cell death is recorded for the first time, in all types of cells constituting an egg chamber (follicle cells, nurse cells and the oocyte) and in all stages of the early and mid-oogenesis, from germarium to stage 10, during which programmed cell death does not physiologically occur. Germarium and stages 7-8 were found to be the most sensitive developmental stages also in response to electromagnetic stress induced by the GSM and DCS fields and, moreover, germarium was found to be even more sensitive than stages 7-8.
Key Words: Animals, Cell Death/radiation effects*, Cellular Phone*, Drosophila melanogaster, Female, In Situ Nick-End Labeling, Male
Study Synopsis: Scientists caution that assisted reproductive technologies (ART) could transfer reproductive abnormalities to subsequent generations. ART removes many barriers to reproduction, including possible epigenetic changes to DNA, that can make a couple unable to have children. Epigenetics is an emerging area of science and the ability of chemical exposures to cause infertility through this mechanism has not yet been shown in humans.
Scientific abstract:
Demasculinization by environmental endocrine-disrupting chemicals (EDCs) is observed in many animal species but less evident in humans. Rodent studies with gestational exposure to either the fungicide vinclozolin or the insecticide methoxychlor demonstrate impaired male fertility with abnormal DNA methylation patterns in spermatozoa. Once established, these epigenetic changes may be permanent and thus paternally passed to subsequent generations. Conclusive evidence of a similar phenomenon in humans has not been established, but several observations bring up the possibility. Some, but not all, studies show an increase in male genital abnormalities after prenatal EDC exposure. Other studies demonstrate sperm abnormalities in males with EDC contact, although it is unclear as to whether this is due to prenatal or postnatal exposure. Although not examined in males with EDC exposure, one study shows gamete DNA methylation abnormalities in males with severe oligospermia. A subsequent study failed to corroborate these findings. The use of assisted reproductive techniques including intracytoplasmic sperm injection has removed natural selection barriers thus enabling reproduction in males that would otherwise be sterile. This review explores the hypothesis that prenatal EDC exposure results in transgenerational male reproductive abnormalities propagated by the use of assisted reproductive technologies.
Study Synopsis: Exposure to estrogenic compounds during prenatal development predisposes offspring to prostate cancer later in life. Prostate cancer is an adult disease but new research suggests exposures early in life or even before birth could increase the susceptibility to or increase the appearance of prostate cancer. This effect has been shown for a wide range of chemicals and doses, from low doses of the environmental estrogen, bisphenol A, to high doses of synthetic estrogens.
Scientific abstract:
Prostate morphogenesis occurs in utero in humans and during the perinatal period in rodents. While largely driven by androgens, there is compelling evidence for a permanent influence of estrogens on prostatic development. If estrogenic exposures are abnormally high during the critical developmental period, permanent alterations in prostate morphology and function are observed, a process referred to as developmental estrogenization. Using the neonatal rodent as an animal model, it has been shown that early exposure to high doses of estradiol results in an increased incidence of prostatic lesions with aging which include hyperplasia, inflammatory cell infiltration and prostatic intraepithelial neoplasia or PIN, believed to be the precursor lesion for prostatic adenocarcinoma. The present review summarizes research performed in our laboratory to characterize developmental estrogenization and identify the molecular pathways involved in mediating this response. Furthermore, recent studies performed with low-dose estradiol exposures during development as well as exposures to environmentally relevant doses of the endocrine disruptor bisphenol A show increased susceptibility to PIN lesions with aging following additional adult exposure to estradiol. Gene methylation analysis revealed a potential epigenetic basis for the estrogen imprinting of the prostate gland. Taken together, our results suggest that a full range of estrogenic exposures during the postnatal critical period - from environmentally relevant bisphenol A exposure to low-dose and pharmacologic estradiol exposures - results in an increased incidence and susceptibility to neoplastic transformation of the prostate gland in the aging male which may provide a fetal basis for this adult disease.
Study Synopsis: Drinking water contaminated with high levels of arsenic is associated with fetal loss and infant death. A large study of women in Bangledesh found a 14 percent increase in fetal loss and a 17% increase on infant death for drinking water with more than 50 µg/liter of arsenic. Previous studies have associated high levels of arsenic exposure with stillbirth and spontaneous abortion.
Scientific abstract:
The authors evaluated the effect of arsenic exposure on fetal and infant survival in a cohort of 29,134 pregnancies identified by the health and demographic surveillance system in Matlab, Bangladesh, in 1991-2000. Arsenic exposure, reflected by drinking water history and analysis of arsenic concentrations in tube-well water used by women during pregnancy, was assessed in a separate survey conducted in 2002-2003. Data on vital events, including pregnancy outcome and infant mortality, were collected by monthly surveillance at the household level. The risk of fetal loss and infant death in relation to arsenic exposure was estimated by a Cox proportional hazards model. Drinking tube-well water with more than 50 {micro}g of arsenic per liter during pregnancy significantly increased the risks of fetal loss (relative risk = 1.14, 95% confidence interval: 1.04, 1.25) and infant death (relative risk = 1.17, 95% confidence interval: 1.03, 1.32). There was a significant dose response of arsenic exposure to risk of infant death (p = 0.02). Women of reproductive age should urgently be prioritized for mitigation activities where drinking water is contaminated by arsenic.
Study Synopsis: Prenatal exposure to tobacco smoke causes poor semen quality in adult men. In this large Danish study, men who were exposed to more than 19 cigarettes daily during pregnancy had 19% lower semen volume. There were also trends, though not statistically significant, towards lower total sperm count and lower sperm concentrations.
Scientific abstract:
A few studies indicate that exposure to maternal smoking during fetal life decreases semen quality in adult life, but the results are inconsistent and retrospectively collected smoking data were used in most studies. From a Danish pregnancy cohort established in 1984-1987, 347 of 5,109 sons were selected according to their exposure to tobacco smoke in fetal life. From February 2005 to January 2006, a semen sample from the 347 men was analyzed for conventional semen characteristics according to standardized criteria by using a mobile laboratory. The authors found an inverse association between maternal smoking during pregnancy and total sperm count (p = 0.002). Men exposed to more than 19 cigarettes daily during pregnancy had approximately 19% lower semen volume (p = 0.04), 38% lower total sperm count (p = 0.11), and 17% lower sperm concentration (p = 0.47) compared with unexposed men. The odds ratio for oligospermia was 2.16 (95% confidence interval: 0.68, 6.87) among exposed men compared with the unexposed. No associations were found for sperm motility or morphology. These results indicate that prenatal exposure to tobacco smoke may have an adverse effect on semen quality and, if these associations are causal, they could explain some of the reported differences between populations and secular changes in semen quality.
Study Synopsis: Very low doses of bisphenol A increase the expression of genes in fetal mice responsible for directing production of hormone receptors in prostate tissue. The effect is seen at concentrations observed in human serum. The effect helps explain why this exposure increases sensitivity to hormones throughout the life of mice exposed in the womb, as well as why BPA causes enlarged prostates in adulthood.
BACKGROUND: Hormonal alterations during development have lifelong effects on the prostate gland. Endogenous estrogens, including 17beta-estradiol (E(2)), and synthetic estrogenic endocrine disruptors, such as bisphenol A (BPA), have similar effects on prostate development. Increasing exposure to estrogens within the low-dose, physiologic range results in permanent increases in the size and androgen responsiveness of the prostate, whereas exposure within the high-dose, pharmacologic range has the opposite effects. OBJECTIVES: We tested the hypothesis that the low-dose effects of estrogens on the developing prostate are associated with increased expression of androgen receptor (Ar) and estrogen receptor 1 (alpha) (Esr1) genes in mesenchyme cells. METHODS: Ar and Esr1 mRNA levels were quantified in primary cultures of fetal mouse prostate mesenchyme cells treated with E(2) and BPA. DISCUSSION: Ar and Esr1 mRNA expression increased in response to E(2), with thresholds of 0.001 and 0.037 nM, respectively; and in response to BPA, with a threshold of 1 nM for both mRNAs. We did not observe the expected inhibition of Ar mRNA expression by pharmacologic levels of E(2) relative to unexposed cells. CONCLUSIONS: The observed induction of gene expression occurred at concentrations within the range of free E(2) previously shown to permanently increase prostate size, thus supporting the involvement of direct effects of estrogens on gene expression in prostate mesenchyme. The effects of BPA occurred within the range of concentrations currently measured in human serum, demonstrating the vulnerability of developing tissues to xenoestrogens.
Key Words: Analysis of Variance, Animals, DNA Primers/genetics, Dose-Response Relationship-Drug, Estradiol/pharmacology*, Fetus, Gene Expression Regulation-Developmental/drug effects*, Male, Mesoderm/drug effects*, Mice, Phenols/pharmacology*, Prostate/cytology*, Receptors-Androgen/genetics, Receptors-Androgen/metabolism*, Receptors-Estrogen/genetics, Receptors-Estrogen/metabolism*, Reverse Transcriptase Polymerase Chain Reaction, DNA Primers, Phenols, Receptors-Androgen, Receptors-Estrogen, Estradiol, bisphenol A
Sagiv SK, Tolbert PE, Altshul LM, Korrick SA. Organochlorine exposures during pregnancy and infant size at birth. Epidemiology. 2007 Jan;18(1):120-9.
Study Synopsis: Organochlorines are chemicals that were primarily used as pesticides from the 1940s to the 1970s when they were banned due to concerns about their persistence in the environment, bioaccumulation in fat tissues and potential adverse health effects on wildlife and in humans. In this study, researchers measured the concentration of PCBs, DDE (the main degradation product of DDT) and hexachlorobenzene in the cord blood of 722 women residing near a PCB-contaminated site in New Bedford, Massachusetts. They found that higher exposure to PCBs was related to slightly lower birth weight. Weak associations with smaller birth length and head circumference were also detected. DDE and hexachlorobenzene were not related to birth outcomes.
Scientific abstract:
BACKGROUND: Organochlorines, including polychlorinated biphenyls (PCBs) and pesticides, are environmentally persistent contaminants that concentrate in the food chain as well in human adipose tissue and readily cross the placenta. METHODS: To follow up on studies suggesting an association of organochlorine exposure with reduced birth size, we investigated the association of PCBs and organochlorine pesticides (including p,p'-dichlorodiphenyl dichloroethene [p,p'-DDE], the major degradation product of p,p'-dichlorodiphenyl trichloroethane [p,p'-DDT], and hexachlorobenzene [HCB]), with birth weight, crown-heel length, and head circumference. We evaluated a cohort of 722 infants born between 1993 and 1998 to mothers residing near a PCB-contaminated harbor and Superfund site in New Bedford, Massachusetts. RESULTS: Small negative associations were observed for PCBs and birth weight; associations were weaker for birth length and head circumference. There was evidence for effect modification by smoking during pregnancy on the association between PCBs and birth weight. No associations were found with p,p'-DDE or HCB for any measures of birth size. CONCLUSIONS: This study supports the growing literature that demonstrates at most a weak association between very low-level organochlorine exposure and birth size.
Study Synopsis: Women who reported mixing and applying agricultural pesticides during early pregnancy have a two times higher risk of developing gestational diabetes during the pregnancy. Consistent with other studies, the strong association between first trimester pesticide exposure and gestational diabetes mellitus suggests that pesticide exposures, including 2,4,5-T and atrazine, may affect glucose metabolism and insulin resistance.
OBJECTIVE--To examine the association between pesticide use during pregnancy and gestational diabetes mellitus (GDM) among wives of licensed pesticide applicators. RESEARCH DESIGN AND METHODS--Using data from the Agricultural Health Study (AHS), we estimated the association between self-reported pesticide-related activities during the first trimester of the most recent pregnancy and GDM among 11,273 women whose pregnancy occurred within 25 years of enrollment. RESULTS--A total of 506 (4.5%) women reported having had GDM. Women who reported agricultural pesticide exposure (mixing or applying pesticides to crops or repairing pesticide application equipment) during pregnancy were more likely to report GDM (odds ratio [OR] 2.2 [95% CI 1.5-3.3]). We saw no association between residential pesticide exposure (applying pesticides in the home and garden during pregnancy) and GDM (1.0 [0.8-1.3]). Among women who reported agricultural exposure during pregnancy, risk of GDM was associated with ever-use of four herbicides (2,4,5-T; 2,4,5-TP; atrazine; or butylate) and three insecticides (diazinon, phorate, or carbofuran). CONCLUSIONS--These findings suggest that activities involving exposure to agricultural pesticides during the first trimester of pregnancy may increase the risk of GDM.
Key Words: Adolescent, Adult, Agriculture*, Body Mass Index, Continental Population Groups, Diabetes-Gestational/epidemiology*, Diabetes-Gestational/etiology, Educational Status, Female, Humans, Iowa/epidemiology, Maternal Age, Middle Aged, North Carolina/epidemiology, Parity, Pesticides/toxicity*, Pregnancy, Questionnaires, Smoking/epidemiology, Pesticides
Study Synopsis: Exposure to perfluorinated chemicals is associated with changes in male hormone levels and abnormal testicles. Rats exposed to perfluorododecanoic acid (PFDoA) had markedly decreased levels of testosterone and changes in expression of genes associated with hormone production. Changes in the ultra-structure of the testis also was noted.
Scientific abstract:
Perfluorododecanoic acid (PFDoA, C12), a synthetic perfluorinated chemical containing 12 carbons, has broad industrial applications and has been detected in sera from humans and other animals; however, few reports have addressed the effects of PFDoA exposure on male reproduction. In the present study, the effects of PFDoA exposure on testes ultrastructure, testosterone levels, and steroidogenic gene expression were investigated. Male rats were orally dosed for 14 days with 1, 5, or 10 mg PFDoA/kg/day or with vehicle. Absolute testis weight was diminished at the highest dose while relative testes weight was markedly increased at doses of 5 and 10 mg/kg/day. Total serum cholesterol levels were significantly increased at the highest dose. While luteinizing hormone was significantly decreased at the highest dose, testosterone was markedly decreased at doses of 5 and 10 mg PFDoA/kg/day. Serum levels of follicle-stimulating hormone were not significantly affected by PFDoA, and estradiol levels were markedly decreased only at 5 mg/kg/day. Leydig cells, Sertoli cells, and spermatogenic cells from rats that received 5 or 10 mg PFDoA/kg/day, exhibited apoptotic features including dense irregular nuclei, condensed chromatin, ill-defined nuclear membranes, and abnormal mitochondria. PFDoA exposure resulted in significant declines in mRNA expression of several genes involved in cholesterol transport and steroid biosynthesis at doses of 5 and 10 mg PFDoA/kg/day, while the gene expression of luteinizing hormone receptor and aromatase was not significantly changed. Our results demonstrate that PFDoA affects the reproduction function of male rats via alterations in steroidogenesis genes, testosterone levels, and testes ultrastructure.
Small CM, Cheslack-Postava K, Terrell M, Blanck HM, Tolbert P, Rubin C, Henderson A, Marcus M. Risk of spontaneous abortion among women exposed to polybrominated biphenyls. Environ Res. 2007 Oct;105(2):247-55.
Study Synopsis: Polybrominated biphenyls (PBBs) are synthetic chemicals formerly used as flame retardants. In 1973, the Michigan food supply was contaminated with PBBs when the cattle feed supplement NutriMaster was accidently replaced with the flame retardant FireMaster. More than 4,000 individuals were exposed to PBBs, 529 of which were exposed during pregnancy and were enrolled in the current study. Researchers estimated maternal exposure to PBBs and to closely related chemicals named polychlorinated biphenyls (PCBs) based on blood measurements. Women who had spontaneous abortions had similar blood PBB and PCB concentrations than those who did not. Results thus do not support the hypothesis that exposure to PBBs and PCBs is related with increased risk of spontaneous abortions.
Scientific abstract:
Accidental contamination of livestock in Michigan in 1973 with polybrominated biphenyls (PBBs) led to the establishment of a registry of exposed individuals in 1976. At the time of enrollment, serum was collected and analyzed for PBBs and polychlorinated biphenyls (PCBs). In 1997, women aged 18 years or older and active in the registry were invited to participate in a telephone interview about their health. Using generalized estimating equations to account for correlated outcomes within the same woman, we assessed the risk of spontaneous abortion among 529 women with 1344 potentially exposed pregnancies. PBB and PCB exposure were not associated with risk of spontaneous abortion after adjusting for maternal age at conception, age at menarche, and prior infertility. Compared to pregnancies with PBB exposure below the limit of detection, those with levels above 2.9 ppb had a non-significant reduced odds of spontaneous abortion (adjusted OR=0.73; 95% CI=0.47-1.13). Compared to pregnancies with PCB exposure below the limit of detection, those with levels above 6.5 ppb had little difference in risk (adjusted OR=0.91; 95% CI=0.59-1.41). Maternal age at conception above 34 years was significantly associated with elevated risk of spontaneous abortion (OR=2.46; 95% CI=1.10-5.49). The effect of prior infertility was of borderline significance (OR=1.52; 95% CI=0.98-2.38). Older age at menarche was associated with decreased risk of spontaneous abortion (adjusted OR=0.58; 95% CI: 0.38-0.89, comparing menarche at 12-13 with menarche <12). Our results do not support an association between exposure to PBBs or PCBs and risk of spontaneous abortion.
Study Synopsis: There is good evidence that uterine fibroids interfere with fertility, but poor guidelines on how to manage them for improved fertility outcomes. The relationship between uterine fibroids and infertility are inconclusive but multiple observations have shown improved conception rates after surgical treatment. Since uterine fibroids can occur in different layers of the uterus and there is variability in the number and size of lesions, treatment should be personalized to each patient's circumstances.
Scientific abstract:
Observational epidemiological studies aimed at elucidating the relationship between fibroids and infertility are inconclusive due to methodological limitations. However, two main pieces of clinical evidence support the opinion that the fibroids interfere with fertility. First, in IVF cycles, the delivery rate is reduced in patients with fibroids but is not affected in patients who have undergone myomectomy. Second, even if randomized studies are lacking, surgical treatment appears to increase the pregnancy rate: [~]50% women who undergo myomectomy for infertility, subsequently conceive. Available evidence also suggests that submucosal, intramural and subserosal fibroids interfere with fertility in decreasing order of importance. Although more limited, some data supports an impact of the number and dimension of the lesions. Drawing clear guidelines for the management of fibroids in infertile women is difficult due to the lack of large randomized trials aimed at elucidating which patients may benefit from surgery. At present, physicians should pursue a comprehensive and personalized approach clearly exposing the pros and cons of myomectomy to the patient, including the risks associated with fibroids during pregnancy on one hand, and those associated with surgery on the other hand.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. It is also used in carbonless copy paper. BPA has been shown to have the capability to mimic the hormone estrogen. In this study, researchers exposed rats to high doses of BPA during fetal development and examined them in adulthood. They found that rats exposed to BPA had an increased prevalence of mammary cancer. The observed lesions had an elevated number of estrogen receptors, suggesting that BPA may have caused cancer because of its estrogenic properties. Results suggest that exposure to high doses of BPA causes an increased risk of mammary cancer in rats.
Scientific abstract:
The hypothesis that prenatal exposure to endocrine disruptors might cause cancer arose from challenging two well-accepted notions: (i) mammalian development is merely the unfolding of a genetic programme and (ii) only mutagenic agents can cause cancer. This hypothesis required challenging genetic determinism. The ecological developmental biology (eco-devo) movement revitalized the concept of developmental plasticity through the occurrence of polyphenisms (a single genotype produces diverse phenotypes which are determined by environmental cues). Based on the principles of eco-devo and the tissue organization field theory of carcinogenesis and neoplasia, we tested the hypothesis that exposure to xenoestrogens during foetal development in rats increased the propensity to develop mammary cancer during adulthood. We chose exposure to bisphenol A (BPA) as a model for environmental oestrogen exposure. This endocrine disruptor induced the development of ductal hyperplasias and carcinoma in situ. These highly proliferative lesions contained an increased number of oestrogen receptor alpha-positive cells. Thus, foetal BPA exposure was sufficient to induce the development of oestrogen-sensitive pre-neoplastic and neoplastic lesions in the mammary gland in the absence of any additional treatment aimed at increasing tumour incidence.
Study Synopsis: Sexual behavior, if not taken into account properly, can be an important confounder in time to pregnancy studies. An often used metric in determining fertility/fecundability rates in humans is "time to pregnancy", typically defined as the number of menstrual cycles required to achieve a clinical pregnancy. However, the frequency and timing of sexual intercourse during a given cycle can greatly influence the probability of pregnancy. Well-designed studies investigating the effects of contaminants on time to pregnancy should include sexual behavioral patterns.
Scientific abstract:
Time to pregnancy, typically defined as the number of menstrual cycles required to achieve a clinical pregnancy, is widely used as a measure of couple fecundity in epidemiologic studies. Time to pregnancy studies seldom utilize detailed data on the timing and frequency of sexual intercourse and the timing of ovulation. However, the simulated models in this paper illustrate that intercourse behavior can have a large impact on time to pregnancy and, likewise, on fecundability ratios, especially under conditions of low intercourse frequency or low fecundity. Because intercourse patterns in the menstrual cycles may vary substantially among groups, it is important to consider the effects of sexual behavior. Where relevant and feasible, an assessment should be made of the timing and frequency of intercourse relative to ovulation. Day-specific probabilities of pregnancy can be used to account for the effects of intercourse patterns. Depending on the research hypothesis, intercourse patterns may be considered as a potential confounder, mediator, or outcome.
Study Synopsis: Experiments with mice show that exposure during pregnancy to very low doses of bisphenol A scrambles the chromosomes of their daughters' fertilized embryos, ie., the pregnant female's grandchildren. This 3rd-generation effect is possible because the eggs of a female mammal, including human, are formed while the female is still in the womb. Exposure to BPA at comparable levels appears widespread among people in the United States, because of its use in common consumer products, including polycarbonate plastic and food cans.
Estrogen plays an essential role in the growth and maturation of the mammalian oocyte, and recent studies suggest that it also influences follicle formation in the neonatal ovary. In the course of studies designed to assess the effect of the estrogenic chemical bisphenol A (BPA) on mammalian oogenesis, we uncovered an estrogenic effect at an even earlier stage of oocyte development-at the onset of meiosis in the fetal ovary. Pregnant mice were treated with low, environmentally relevant doses of BPA during mid-gestation to assess the effect of BPA on the developing ovary. Oocytes from exposed female fetuses displayed gross aberrations in meiotic prophase, including synaptic defects and increased levels of recombination. In the mature female, these aberrations were translated into an increase in aneuploid eggs and embryos. Surprisingly, we observed the same constellation of meiotic defects in fetal ovaries of mice homozygous for a targeted disruption of ERbeta, one of the two known estrogen receptors. This, coupled with the finding that BPA exposure elicited no additional effects in ERbeta null females, suggests that BPA exerts its effect on the early oocyte by interfering with the actions of ERbeta. Together, our results show that BPA can influence early meiotic events and, importantly, indicate that the oocyte itself may be directly responsive to estrogen during early oogenesis. This raises concern that brief exposures during fetal development to substances that mimic or antagonize the effects of estrogen may adversely influence oocyte development in the exposed female fetus.
Study Synopsis: Consumption of beef during pregnancy may alter testicular development. Son's born to mothers who ate more than seven beef meals a week during pregnancy had sperm concentrations that were 24% lower and were three times more likely to have low sperm concentrations less than 20 million/ml than son's of mothers who ate less beef. There was no association for the mother's consumption of other types of meat or the man's current meat consumption patterns. These data suggest that prenatal exposure to hormones or chemicals found in beef may affect a man's ability to reproduce later in life.
Scientific abstract:
BACKGROUND: To look at possible long-term risks from anabolic steroids and other xenobiotics in beef, we examined mens' semen quality in relation to their mother's self-reported beef consumption during pregnancy. METHODS: The study was carried out in five US cities between 1999 and 2005. We used regression analyses to examine semen parameters in 387 partners of pregnant women in relation to the amount of beef their mothers reported eating while pregnant. Mothers' beef consumption was also analysed in relation to the son's history of previous subfertility. RESULTSSperm concentration was inversely related to mothers' beef meals per week (P = 0.041). In sons of high beef consumers' (>7 beef meals/week), sperm concentration was 24.3% lower (P = 0.014) and the proportion of men with sperm concentration below 20 x 106/ml was three times higher (17.7 versus 5.7%, P = 0.002) than in men whose mothers ate less beef. A history of previous subfertility was also more frequent among sons of high beef consumers' (P = 0.015). Sperm concentration was not significantly related to mother's consumption of other meat or to the man's consumption of any meat. CONCLUSIONSThese data suggest that maternal beef consumption, and possibly xenobiotics in beef, may alter a man's testicular development in utero and adversely affect his reproductive capacity.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. In this study, researchers injected pregnant mice daily with high doses of BPA. They found that BPA reduced the number of embryos implanted in uteri and altered the structure of the placenta. BPA also caused higher rates of neonatal deaths and ultimately killed all offspring. Results suggest that high doses of BPA disrupt placental function, may cause abortions, and affects offspring survival in mice.
Scientific abstract:
The effects of bisphenol A (BPA) on placentation have not been fully determined. The aim of this study was to clarify the structural changes of the placenta, abortion rate, and survival of neonates after BPA administration in mice. BPA (10 mg/kg/day) was administered to pregnant mice (BPA mice) subcutaneously from the first day of pregnancy (Day 0) to Day 7 (8 days total). The number of embryos and weights of whole uteri were measured on Days 10 and 12. Morphological changes in the placentae were examined by light microscopy on the corresponding days of pregnancy. The number of neonates was also counted. Survival rates were periodically calculated for neonates from the first day after parturition (P-Day 0) to P-Day 56. The number of embryos and weight of the uterus on Days 10 and 12 were significantly decreased by BPA injection. No notable differences were recognized between the left and right uteri. The proportion of the labyrinthine zone per whole placenta in the BPA mice became lower than that in the controls, and that of the metrial gland was higher in the BPA mice. The intervillous spaces of the placenta were narrower in the BPA mice. Degenerative changes were found in the trophoblastic giant cells and spongiotrophoblast layers of the BPA mice. The number of BPA mouse neonates was drastically decreased within 3 days after birth, and no mice survived after P-Day 56. The results suggest that BPA not only disrupts placental functions and leads to abortion through chronic stimulation of gene expression by binding to DNA but that it also affects the mortality of neonates through indirect exposure of embryos.
Study Synopsis: Conditions related to hypertension during pregnancy, particularly pre-eclampsia, are associated with lower risk of breast cancer. A large population-based case-control study of Long Island women found a 30% decreased risk for breast cancer in women who had pre-eclampsia. Women who had multiple occurrences of pre-eclampsia had a 70% decreased risk. This reduction in risk was more pronounced for postmenopausal cases of breast cancer.
Scientific abstract:
Pregnancy conditions accompanied by high blood pressure, such as preeclampsia and pregnancy-related hypertension, have been associated with a lower risk of breast cancer in several epidemiologic studies. It is unknown whether length of gestation or multiple occurrence of these conditions alters the association with breast cancer. It is also unknown whether the inverse association between preeclampsia and breast cancer risk is modified by menopausal status at breast cancer diagnosis. Using data from a large, population-based case-control study of breast cancer conducted on Long Island, New York, during 1996-1997, the authors examined these questions among ever-parous women (1,310 cases and 1,385 controls) using multivariate logistic models. Preeclampsia was inversely associated with breast cancer (odds ratio = 0.7, 95% confidence interval: 0.5, 1.0); this association was even stronger among women who had multiple occurrences of preeclampsia (odds ratio = 0.3, 95% confidence interval: 0.1, 0.9). The risk reduction was more pronounced among postmenopausal women. Gestation length did not substantially alter the relation between preeclampsia and breast cancer risk. Pregnancy-related hypertension was also inversely associated with breast cancer risk, but the relations were not statistically significant after adjustment for preeclampsia. These data suggest that pregnancy conditions related to hypertension, particularly preeclampsia, play a role in reducing breast cancer risk. Possible biologic mechanisms underpinning these associations should be further explored.
Key Words: breast neoplasms; hypertension, pregnancy-induced; pre-eclampsia; pregnancy
Study Synopsis: Since the late 1980's, testosterone levels have declined on average 1.2% per year in Massachusetts men, or 17% overall. The pattern is consistent with other long-term trends in male reproductive health, including decreases in sperm count and increases in testicular cancer, hypospadias and cryptorchidism. The study controlled for the normal decline in testosterone levels that takes place as men age, as well as potential confounding variables like smoking and obesity.
Context: Age-specific estimates of mean testosterone (T) concentrations appear to vary by year of observation and by birth cohort, and estimates of longitudinal declines in T typically outstrip cross-sectional decreases. These observations motivate a hypothesis of a population-level decrease in T over calendar time, independent of chronologic aging. Objective. To establish the magnitude of population-level changes in serum T concentrations, and the degree to which they are explained by secular changes in relative weight and other factors. Design. A prospective cohort study of health and endocrine functioning in randomly selected men of age 45-79 y. Three data collection waves: baseline (T1: 1987-89) and two follow-ups (T2: 1995-97, T3: 2002-04). Setting. An observational study of randomly selected men residing in greater Boston, MA, USA. Participants. Data obtained on 1374, 906 and 489 men at T1, T2, and T3, respectively, totaling 2769 observations taken on 1532 men. Main outcome measures. Serum total testosterone and calculated bioavailable testosterone. Results. We observe a substantial age-independent decline in T that does not appear to be attributable to observed changes in explanatory factors, including health and lifestyle characteristics such as smoking and obesity. The estimated population-level declines are greater in magnitude than the cross-sectional declines in T typically associated with age. Conclusions. These results indicate that recent years have seen a substantial, and as yet unrecognized, age-independent population-level decrease in T in American men, potentially due to birth cohort differences or to health or environmental effects not captured in observed data.
Study Synopsis: Developmental exposure to endocrine disruptors may alter adult ovarian function by targeting steroid synthesis. Pesticides, detergents and surfactants, plastics, industrial compounds and natural plant estrogens can exert estrogenic, anti-estrogenic and anti-androgenic effects. These compounds also may cause transgenerational effects by targeting oocyte maturation and maternal sex chromosomes.
Scientific abstract:
Female reproductive function depends upon the exquisite control of ovarian steroidogenesis that enables folliculogenesis, ovulation, and pregnancy. These mechanisms are set during fetal and/or neonatal development and undergo phases of differentiation throughout pre- and post-pubescent life. Ovarian development and function are collectively regulated by a host of endogenous growth factors, cytokines, gonadotropins, and steroid hormones as well as exogenous factors such as nutrients and environmental agents. Endocrine disruptors represent one class of environmental agent that can impact female fertility by altering ovarian development and function, purportedly through estrogenic, anti-estrogenic, and/or anti-androgenic effects. This review discusses ovarian development and function and how these processes are affected by some of the known estrogenic and anti-androgenic endocrine disruptors. Recent information suggests not only that exposure to endocrine disruptors during the developmental period causes reproductive abnormalities in adult life but also that these abnormalities are transgenerational. This latter finding adds another level of importance for identifying and understanding the mechanisms of action of these agents.
Study Synopsis: Consistent with previous studies, exposure during fetal life to extremely low doses of the common plastic molecule, bisphenol A, causes harmful effects on mammary gland development in mice. BPA accelerates development and alters how the gland's tissues are formed. The changes are likely to increase vulnerability to breast cancers later in life. The doses used were chosen explicitly to be within the range of human exposure.
Humans are routinely exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials, food and beverage containers, and other plastic consumer products. Effects of perinatal BPA exposure on the mouse mammary gland have been observed in puberty and adulthood, long after the period of exposure has ended. The aim of this study was to examine fetal mammary gland development at embryonic day (E)18 and assess changes in the tissue organization and histoarchitecture after exposure to an environmentally relevant dose of BPA. In unexposed fetuses, the relative position of the fetus with respect to its female and male siblings in the uterus influenced growth of the ductal tree, which was more developed in females placed between two males than in females placed between two females. Exposure of dams to 250 ng BPA per kilogram body weight per day from E8 to E18 significantly increased ductal area and ductal extension in exposed fetuses and obliterated positional differences. In the stroma, BPA exposure promoted maturation of the fat pad and altered the localization of collagen. Within the epithelium, BPA exposure led to a decrease in cell size and delayed lumen formation. Because mammary gland development is dependent on reciprocal interactions between these compartments, the advanced maturation of the fat pad and changes in the extracellular matrix may be responsible for the altered growth, cell size, and lumen formation observed in the epithelium. These results suggest that alterations in mammary gland phenotypes observed at puberty and adulthood in perinatally exposed mice have their origins in fetal development.
Study Synopsis: Exposure to a mixture of anti-androgenic chemicals during development leads to male reproductive abnormalities. Cryptorchidism (undescended testicles), atypical sperm and sexual dysfunction were observed in rabbits exposed to DDT and vinclozolin. These outcomes are consistent with the hypothesis of testicular dysgenesis syndrome caused by exposures to endocrine disruptors during fetal development.
Scientific abstract:
Rabbit does (7-9 per group) were treated daily per orum from gestation day 15 through post-natal week 4 to provide per kg body wt 25 [mu]mol (low) or 250 [mu]mol (high) p,p'-DDT or a mixture of DDT and vinclozolin (12.5 and 125 [mu]mol each). Developmental as well as post-pubertal reproductive sequelae of male progeny were studied. Testicular descent in some pups was impaired by DDT. Serum LH or testosterone was not affected. FSH was lower in mixture- but not in DDT-exposed rabbits. Lack of sexual interest, penile erection and ejaculation were observed in some mixture rabbits. Sperm counts were unaffected, but morphologically normal spermatozoa were fewer; nuclear and acrosomal morphogenesis was disrupted. Atypical germ cells resembling carcinoma in situ were found. Also considering data for vinclozolin [Veeramachaneni DNR, Palmer JS, Amann RP, Kane CM, Higuchi TT, Pau K-YF. Disruption of sexual function, FSH secretion, and spermiogenesis in rabbits following developmental exposure to vinclozolin, a fungicide. Reproduction 2006;131:805-16], we concluded that DDT causes cryptorchidism and germ cell atypia, vinclozolin permanently disrupts FSH secretion and sexual function, and the mixture causes the full spectrum of dysgenesis.
Study Synopsis: Emerging evidence indicates genetic variations in the estrogen receptor enhance the estrogenic effects of endocrine disruptors. Genetic analysis of the estrogen receptor-alpha in Japanese men with reproductive abnormalities has demonstrated that certain haplotypes are associated with hypospadias and micropenis. A haplotype is a group of genes that are closely linked and inherited as a unit. Endocrine disruptors that bind to estrogen receptor are known to interfere with reproductive development and this new research demonstrates genetic variations in the receptor may affect an individual's susceptibility.
Scientific abstract:
BACKGROUND We have recently suggested that homozygosity for a specific AGATA' haplotype within a [~]50 kb linkage disequilibrium (LD) block of the gene for estrogen receptor {alpha} (ESR1) may raise the susceptibility to cryptorchidism by enhancing estrogenic effects of environmental endocrine disruptors (EEDs). METHODSHaplotype analysis of ESR1 was performed in 328 Japanese subjects, i.e. 70 patients with micropenis (MP), 43 patients with hypospadias (HS), 80 patients with spermatogenic failure (SF) and 135 control males. Genotyping was performed by the 5' nuclease assay. RESULTSThe LD block was identified in each of the patient groups and in the control males. The frequency of homozygotes for the specific AGATA' haplotype was markedly higher in the HS patients [P = 0.0000033, odds ratio [OR] = 11.26] and slightly higher in the MP patients (P = 0.034, OR = 3.64) than in the control males, and the AGATA' haplotype was strongly associated with HS (P = 0.0000022, OR = 11.26) and weakly associated with MP (P = 0.040, OR = 3.64) in a recessive mode. There was no significant difference between the SF patients and the control males. CONCLUSIONSOur results support the hypothesis that homozygosity for the specific ESR1 AGATA' haplotype may increase the susceptibility to the development of male genital abnormalities in response to estrogenic EEDs.
Study Synopsis: New research indicates chemokines, proteins involved in regulation of inflammation and immune response, may regulate pregnancy. Women who had miscarriages were more 25% more likely to have elevated levels of epithelial cell-derived neutrophil activating peptide (ENA)-78. ENA-78 regulates formation of new blood vessels and recruits white blood cells. This protein might be an early indicator of miscarriage risk.
Scientific abstract:
Evidence suggests that chemokines, proteins involved in regulation of inflammation and immune response, may have a regulatory function in pregnancy. The authors hypothesized that circulating levels of chemokines are associated with increased risk of miscarriage. Serum samples were obtained from women in the Collaborative Perinatal Project cohort who had had a miscarriage (n = 439) and controls (n = 373) matched by gestational age at sample collection. Concentrations of interleukin 8, epithelial cell-derived neutrophil-activating peptide (ENA)-78, macrophage inhibitory protein (MIP)-1{alpha}, MIP-1{beta}, monocyte chemotactic protein 1, and RANTES (regulated upon activation, normal T-cell-expressed, and secreted) were determined by multiplex assays, and values were standardized using the standard deviation among controls. Conditional logistic regression was used to model the relation between chemokine levels and risk of miscarriage. In multivariable analysis using all available data, the authors did not observe significant associations between any of the evaluated chemokines and miscarriage risk. In analyses using subsets of the study population based on the collection-outcome interval, elevated ENA-78 levels were associated with increased risk of miscarriage as the collection-outcome interval increased; the adjusted odds ratio was 1.25 (95% confidence interval: 1.04, 1.49) for samples collected more than 35 days prior to pregnancy outcome. The observation regarding ENA-78, which has roles in regulation of angiogenesis and leukocyte recruitment, suggests a possible role for this chemokine as an early indicator of miscarriage risk.
Study Synopsis: Prenatal exposures to DDT and organophosphate pesticides are associated with lower birth size. Pregnant women in New York City with the highest DDE levels had babies with significantly lower birth weight and head circumference, but not gestational age, than mothers with lower DDE levels. Mothers with a genetic type that does not allow them to rapidly breakdown organophosphates had babies with a statistically significant lower birth weight and shorter birth length.. Environmental exposures to pesticides during pregnancy may affect birth size, especially in genetically susceptible populations.
Scientific abstract:
Evidence is inconsistent or poorly understood for links between polychlorinated biphenyls (PCBs), 1,1'-dichloro-2,2'-bis(4-chlorophenyl)ethylene (DDE), and organophosphate (OP) pesticides and adverse pregnancy outcomes, although they are known developmental toxicants. We measured biomarkers of maternal exposure to DDE, PCB, and OP metabolites in the third trimester of pregnancy among 404 mothers in a multiethnic cohort in New York City. We also determined maternal paraoxonase (PON1), butyrylcholinesterase (BuChe), and PON1Q192R gene variant. Higher multivariate-adjusted DDE levels (but not PCB) were associated with lower birth weight (-98 g/log10 DDE, p = 0.096) and head circumference (-0.54 cm/log10 DDE, p = 0.030). DDE and PCB levels were not related to birth length, Ponderal index, or gestational age. Birth length was shorter for mothers with PON192RR slow genotype compared with PON192QQ (p = 0.026), and head circumference was inversely associated with maternal PON1 activity (p = 0.004). With slow-activity PON1 or PON192, urinary diethylphosphates (SigmaDEPs) were associated with lower birth weight and dimethylphosphates (SigmaDMPs) with shorter birth length. No associations were found between birth outcomes and BuChe. In summary, we found suggestive relationships between prenatal environmental biomarkers and birth outcomes in this population. Maternal susceptibility factors including PON1 and maternal weight contributed to the observed effects.
Study Synopsis: In a pilot study of young girls in 3 US cities, a wide spectrum of hormonally-active compounds were found, some at relatively high concentrations. Eighteen of 25 measured compounds were found in at least 94% of subjects. Phytoestrogens as a group had the highest levels and were most frequently found; phthalates were intermediate. Four phytoestrogens, four phthalates and two phenols had maximum values above 1 ppm.
Scientific abstract:
Background: Hormonally active environmental agents have been measured among U.S. children using exposure biomarkers in urine. However, little is known about their variation by race, age, sex, and geography, and no data exist for newly developed biomarkers., , Objective: Our goal was to characterize relevant, prevalent exposures for a study of female pubertal development. Methods: In a pilot study among 90 girls from New York City, New York, Cincinnati, Ohio, and northern California, we measured 25 urinary analytes representing 22 separate agents from three chemical families: phytoestrogens, phthalates, and phenols. Exposures occur chiefly from the diet and from household or personal care products., , Results: Participants represented four racial/ethnic groups (Asian, black, Hispanic, white) , with mean age of 7.77 years. Most analytes were detectable in > 94% of samples. The highest median concentrations for individual analytes in each family were for enterolactone (298 ¦g/L) , monoethylphthalate (MEP ; 83.2 ¦g/L) , and benzophenone-3 (BP3 ; 14.7 ¦g/L). Few or no data have been reported previously for four metabolites: mono(2-ethyl-5-carboxypentyl) phthalate, triclosan, bisphenol A (BPA) , and BP3 ; these were detected in 67ū100% of samples with medians of 1.8ū53.2 ¦g/L. After multivariate adjustment, two analytes, enterolactone and BPA, were higher among girls with body mass index < 85th reference percentile than those at or above the 85th percentile. Three phthalate metabolites differed by race/ethnicity [MEP, mono(2-ethylhexyl) phthalate, and mono-3-carboxypropylphthalate]. Conclusions: A wide spectrum of hormonally active exposure biomarkers were detectable and variable among young girls, with high maximal concentrations (> 1,000 ¦g/L) found for several analytes. They varied by characteristics that may be relevant to development.
Study Synopsis: In a study of over 1000 pregnant women in Michigan, those with relatively high levels of mercury measured in their hair are three times more likely to give birth very prematurely. Mercury levels were related to fish consumption, and the greatest source of mercury exposure in the population studied appeared to be canned fish.
Background: Pregnant women receive mixed messages about fish consumption in pregnancy because unsaturated fatty acids and protein in fish are thought to be beneficial, but contaminants such as methylmercury may pose a hazard. Methods: In the Pregnancy Outcomes and Community Health (POUCH) study, women were enrolled in the 15th to 27th week of pregnancy from 52 prenatal clinics in five Michigan communities. At enrollment, information was gathered on amount and category of fish consumed during the current pregnancy, and a hair sample was obtained. A segment of hair closest to the scalp, approximating exposure during pregnancy, was assessed for total mercury levels (70-90% methylmercury) in 1,024 POUCH cohort women. Results: Mercury levels ranged from 0.01 to 2.50 ¦g/g (mean = 0.29 ¦g/g ; median = 0.23 ¦g/g) . Total fish consumption and consumption of canned fish, bought fish, and sport-caught fish were positively associated with mercury levels in hair. The greatest fish source for mercury exposure appeared to be canned fish. Compared with women delivering at term, women who delivered before 35 weeks' gestation were more likely to have hair mercury levels at or above the 90th percentile (= 0.55 ¦g/g), even after adjusting for maternal characteristics and fish consumption (adjusted odds ratio = 3.0; 95% confidence interval, 1.3-6.7). Conclusion: This is the first large, community-based study to examine risk of very preterm birth in relation to mercury levels among women with low to moderate exposure. Additional studies are needed to see whether these findings will be replicated in other settings.
Key Words: fish consumption, pregnancy, preterm delivery, mercury
Study Synopsis: The widely-used synthetic insecticide permethrin dramatically reduces testosterone levels and sperm counts in adult male mice exposed for six weeks. Permethrin causes reproductive damage by altering the beginning steps of testosterone synthesis in the testes, lowering testosterone production. Permethrin is used in homes and agriculture and it can be found in dust and food. Doses used in the experiment were higher than those people would encounter regularly, but effects were seen at both doses tested.
Permethrin, a popular synthetic pyrethroid insecticide used to control noxious insects in agriculture, forestry, households, horticulture, and public health throughout the world, poses risks of environmental exposure. Here we evaluate the reproductive toxicity of cis-permethrin in adult male ICR mice that were orally administered cis-permethrin (0, 35, or 70 mg/kg{middle dot}d) for 6 wk. Caudal epididymal sperm count and sperm motility in the treated groups were statistically reduced in a dose-dependent manner. Testicular testosterone production and plasma testosterone concentration were significantly and dose-dependently decreased with an increase in LH, and a significant regression was observed between testosterone levels and cis-permethrin residues in individual mice testes after exposure. However, no significant changes were observed in body weight, reproductive organ absolute and relative weights, sperm morphology, and plasma FSH concentration after cis-permethrin treatment. Moreover, cis-permethrin exposure significantly diminished the testicular mitochondrial mRNA expression levels of peripheral benzodiazepine receptor (PBR), steroidogenic acute regulatory protein (StAR), and cytochrome P450 side-chain cleavage (P450scc) and enzyme and protein expression levels of StAR and P450scc. At the electron microscopic level, mitochondrial membrane damage was found in Leydig cells of the exposed mouse testis. Our results suggest that the insecticide permethrin may cause mitochondrial membrane impairment in Leydig cells and disrupt testosterone biosynthesis by diminishing the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone in the cells, thus reducing subsequent testosterone production.
Study Synopsis: Estimates of pesticide exposures based on questionnaires correlate only moderately with direct measurements of agricultural pesticides in farmers' urine. These results indicate that traditional approaches based upon questionnaires are likely to have many misclassifications, weakening the ability of the studies to find patterns, and increasing the likelihood that they will conclude a product is safe when it is not.
Scientific abstract:
BACKGROUND: Epidemiologists often assess lifetime pesticide exposure by questioning participants about use of specific pesticides and associated work practices. Recently, Dosemeci and colleagues proposed an algorithm to estimate lifetime average exposure intensity from questionnaire information. We evaluated this algorithm against measured urinary pesticide concentrations for farmers who applied glyphosate (n = 48), 2,4-D (n = 34), or chlorpyrifos (n = 34). METHODS: Algorithm scores were calculated separately based on trained field observers' and farmers' evaluations of application conditions. Statistical analyses included nonparametric correlations, assessment of categorical agreement, and categorical evaluation of exposure distributions. RESULTS: Based on field observers' assessments, there were moderate correlations between algorithm scores and urine concentrations for glyphosate (r = 0.47; 95% confidence interval [CI] = 0.21 to 0.66) and 2,4-D (0.45; 0.13 to 0.68). Correlations were lower when algorithm scores were based on participants' self-reports (for glyphosate, r = 0.23 [CI = -0.07 to 0.48]; for 2,4-D, r = 0.25 [-0.10 to 0.54]). For chlorpyrifos, there were contrasting correlations for liquid (0.42; 0.01 to 0.70) and granular formulations (-0.44; -0.83 to 0.29) based on both observers' and participants' inputs. Percent agreement in categorical analyses for the 3 pesticides ranged from 20% to 44%, and there was appreciable overlap in the exposure distributions across categories. CONCLUSIONS: Our results demonstrate the importance of collecting type of pesticide formulation and suggest a generic exposure assessment is likely to result in appreciable exposure misclassification for many pesticides.
Key Words: Agriculture, Environmental Monitoring, Humans, Minnesota, Occupational Exposure/*classification, Protective Clothing, Research Support, Non-U.S. Gov't, South Carolina
Study Synopsis: Danish scientists conclude that for children, there is no safe level of exposure to exogenous steroids or endocrine disruptors. Disrupted sex hormone action is believed to contributing to increasing incidence of testicular, breast and prostate cancers, as well as increased genital abnormalities in newborn boys and precocious puberty in girls.
Scientific abstract:
The current trends of increasing incidences of testis, breast and prostate cancers are poorly understood, although it is assumed that sex hormones play a role. Disrupted sex hormone action is also believed to be involved in the increased occurrence of genital abnormalities among newborn boys and precocious puberty in girls. In this article, recent literature on sex steroid levels and their physiological roles during childhood is reviewed. It is concluded that (i) circulating levels of estradiol in prepubertal children are lower than originally claimed; (ii) children are extremely sensitive to estradiol and may respond with increased growth and/or breast development even at serum levels below the current detection limits; (iii) no threshold has been established, below which no hormonal effects can be seen in children exposed to exogenous steroids or endocrine disruptors; (iv) changes in hormone levels during fetal and prepubertal development may have severe effects in adult life and (v) the daily production rates of sex steroids in children estimated by the Food and Drug Administration in 1999 and still used in risk assessments are highly overestimated and should be revised. Because no lower threshold for estrogenic action has been established, caution should be taken to avoid unnecessary exposure of fetuses and children to exogenous sex steroids and endocrine disruptors, even at very low levels.
Study Synopsis: Andrade et al. have shown that DEHP alters the activity of aromatase in young rats following perinatal exposure. This activity is crucial for masculinization of the brain. Most crucially, they show impacts at environmentally-relevant levels, far beneath the levels that have been tested following standard toxicological procedures. The pattern revealed in males on PND 1 was strikingly non-monotonic. They highlight the fact that "this biphasic response would have been overlooked if we had tested only the high dose range." This finding means that a core assumption used to design toxicological tests of hormonally-active compounds is false. High dose tests do not predict low dose effects. According to Andrade et al. "Qualitatively different effects between low and high dose exposures may occur for several reasons, including saturation of biotransformation pathways or protein binding sites, depletion of intracellular cofactors and differences in ligand affinity and in efficacy of signal transduction" (see Welshons et al. (2003) for one in-depth exploration of this). With that core assumption invalidated, there exists a strong likelihood that existing health standards for endocrine-disrupting compounds like DEHP are too weak. They have been set using high dose tests without study of possible low dose impacts. This is already clearly the case for bisphenol A, a compound that research has shown follow non-monotonic dose response curves in multiple endpoints measured.
Di-(2-ethylhexyl)-phthalate (DEHP) is a commonly used plasticizer which can act as an endocrine disruptor. It has been suggested that in addition to its antiandrogenic effects, DEHP may interfere with estrogen metabolism through suppression of aromatase enzyme activity. This enzyme catalyzes the conversion of testosterone to estradiol and plays a critical role in brain sexual differentiation. We investigated the effects of two wide ranges of DEHP doses on brain aromatase activity of male and female rat offspring. Wistar rat dams were treated daily with DEHP and peanut oil (control) by gavage from gestation day 6 to lactation day 21 at doses of 0.015, 0.045, 0.135, 0.405 and 1.215mgDEHP/kgbodyweight(bw)/day (low doses) and at 5, 15, 45, 135 and 405mgDEHP/kgbw/day (high doses). Aromatase activity was determined in hypothalamic/preoptic area (HPOA) brain sections from male and female pups on postnatal days (PNDs) 1 and 22. In males on PND 1, aromatase activity was inhibited at low doses and increased at high doses resulting in a non-monotonic dose-response profile which resembled a J-shaped curve. Inhibition was statistically significant at 0.135 and 0.405mgDEHP/kg/day, while increased activity was observed at 15, 45 and 405mg/kg/day. In contrast to findings on PND 1, aromatase activity at weaning (PND 22) was more affected in females than in males. An increase in aromatase activity was observed at only one dose in males (0.405mg/kg/day) while an increase in activity was observed at all doses in the females except for 0.045 and 5mgDEHP/kg/day. Overall, these results indicate that males and females respond differently to DEHP not only in regard to the age at which effects are manifested, but also in the shape of the dose-response curve. To our knowledge, this is the first study to report biological effects of DEHP at doses that overlap with the estimated exposure of the general human population.
Study Synopsis: An endocrine-disrupting fungicide, vinclozolin, causes chronic diseases of ageing in rats following exposure in the womb, and these disease states are inherited epigenetically across multiple generations without changes in DNA sequence. Adverse effects included increased incidence of tumors, diseases of the kidney and prostate, testis abnormalities and impaired immune function. Observations also indicated very early onset of ageing, although it was not possible to distinguish this with certainty from other diseases.
The fetal basis of adult disease is poorly understood on a molecular level and cannot be solely attributed to genetic mutations or a single etiology. Embryonic exposure to environmental compounds has been shown to promote various disease states or lesions in the first generation (F1). The current study used the endocrine disruptor vinclozolin (antiandrogenic compound) in a transient embryonic exposure at the time of gonadal sex determination in rats. Adult animals from the F1 generation and all subsequent generations examined (F1-F4) developed a number of disease states or tissue abnormalities including prostate disease, kidney disease, immune system abnormalities, testis abnormalities, and tumor development (e.g. breast). In addition, a number of blood abnormalities developed including hypercholesterolemia. The incidence or prevalence of these transgenerational disease states was high and consistent across all generations (F1-F4) and, based on data from a previous study, appears to be due in part to epigenetic alterations in the male germ line. The observations demonstrate that an environmental compound, endocrine disruptor, can induce transgenerational disease states or abnormalities, and this suggests a potential epigenetic etiology and molecular basis of adult onset disease.
The current study was designed to examine the actions of a model endocrine disruptor on embryonic testis development and male fertility. Pregnant rats (F0) that received a transient embryonic exposure to an environmental endocrine disruptor, vinclozolin, had male offspring (F1) with reduced spermatogenic capacity. The reduced spermatogenetic capacity observed in the F1 male offspring was transmitted to the subsequent generations (F2-F4). The administration of vinclozolin, an androgen receptor antagonist, at 100 mg/kg/day from embryonic day 8-14 (E8-E14) of pregnancy to only the F0 dam resulted in a transgenerational phenotype in the subsequent male offspring in the F1-F4 generations. The litter size and male/female sex ratios were similar in controls and the vinclozolin generations. The average testes/body weight index of the postnatal day 60 (P60) males was not significantly different in the vinclozolin-treated generations compared to the controls. However, the testicular spermatid number, as well as the epididymal sperm number and motility, were significantly reduced in the vinclozolin generations compared to the control animals. Postnatal day 20 (P20) testis from the vinclozolin F2 generation had no morphological abnormalities, but did have an increase in spermatogenic cell apoptosis. Although the P60 testis morphology was predominantly normal, the germ cell apoptosis was significantly increased in the testes cross sections of animals from the vinclozolin generations. The increase in apoptosis was stage-specific in the testis, with tubules at stages IX-XIV having the highest increase in apoptotic germ cells. The tubules at stages I-V also had an increase in apoptotic germ cells compared to the control samples, but tubules at stages VI-VIII had no increase in apoptotic germ cells. An outcross of a vinclozolin generation male with a wild-type female demonstrated that the reduced spermatogenic cell phenotype was transmitted through the male germ line. An outcross with a vinclozolin generation female with a wild-type male had no phenotype. A similar phenotype was observed in outbred Sprague Dawley and inbred Fisher rat strains. Observations demonstrate that a transient exposure at the time of male sex determination to the antiandrogenic endocrine disruptor vinclozolin can induce an apparent epigenetic transgenerational phenotype with reduced spermatogenic capacity.
Key Words: Epigenetic, testis, gametogenesis, male infertility, antiandrogen, apoptosis
In animal studies, exposure to persistent organochlorine pollutants (POPs) in utero and through mother's milk has been suggested to affect the onset of puberty. However, human studies are scarce and ambiguous. In the present study, information on age at menarche was collected from 545 women who had been brought up in a fishing village/family on the Swedish east coast, off the Baltic Sea, and therefore were assumed to have been exposed to POPs in utero, through breast feeding, and/or through dietary habits during their childhood. The average age at menarche for these women was compared to that of three referent groups: (a) 1252 women who also had been brought up in a fishing village/family, but on the Swedish west coast, where the fish had been considerably less contaminated; (b) 634 women from the east coast, but who had not grown up in a fishing village/family; and (c) 869 women from the west coast who had not grown up in a fishing village/family. Based on previous studies, all groups were regarded as having similar socioeconomic circumstances. Data were analyzed using analysis of variance (ANOVA). In an attempt to account for variations in environmental concentrations of POPs over time, all analyses were adjusted for year of birth. Exposed women were found to be slightly older at menarche than referent women from the same coastal area (mean age 13.0 vs 12.8yr). No differences were found between the exposed women and the two other referent groups (mean age 13.0yr in all groups).
Key Words: Age Factors, Cohort Studies, Female, Humans, Hydrocarbons, Chlorinated/poisoning, Mater, Water Pollutants, Chemical/poisoning
Study Synopsis: Study finds some evidence that organochlorines are linked to infertility in couples. This study measured serum concentrations of the DDT metabolite, DDE, and a common type of PCB, CB-153. In men and women from Greenland, an increased time to pregnancy was associated with higher levels of these compounds. However, couples from Warsaw, Kharkiv, and Sweden were not found to have this effect.
Scientific abstract:
BACKGROUND: Persistent organochlorine pollutants (POP) may affect both the female and male reproductive system in animals as well as in humans. METHODS: Blood samples were collected from pregnant women and their partners from Greenland, Warsaw and Kharkiv, and from a cohort of Swedish fishermen's wives. Blood samples were analysed for 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE). Information on the participants' fertility, measured as time to pregnancy (TTP), was collected. In total, 778 men and 1505 women were included in the analyses. RESULTS: The data from Warsaw, Kharkiv and the Swedish fishermen's wives indicated no effect of either male or female exposure to POP on TTP. However, among men and women from Greenland, there seemed to be an association between serum concentrations of CB-153 and p,p'-DDE and prolonged TTP. Due to the strong intra-individual correlation between CB-153 and p,p'-DDE in the Greenlandic population, it was not possible to determine whether the risk was associated with CB-153 or p, p'-DDE or was an interaction between the two compounds. CONCLUSIONS: The overall results of the present study create a somewhat ambiguous pattern, but give some support to the idea that dietary POP exposure might be harmful for couple fertility.
Study Synopsis: Exposure of very young salmon exposed to xenoestrogens impairs their subsequent development as smolt and reduces their migratory drive. Smolts that had been exposed earlier in development were less able to regulate their salt balance, which they need to be able to move from fresh water to salt water duirng migration.
Scientific abstract:
Groups of Atlantic salmon parr (November, Exp. 1) or pre-smolts (March, Exp. 2) were exposed to estradiol-17beta (E2 conc.: nominal 500 ngl(-1)/actual 8-16 ngl(-1)) and two doses of tert-octylphenol (OP: nominal 25 microgl(-1)/actual 4.5-6.5 microgl(-1) and OP: nominal 100 microgl(-1)/actual 10-30 microgl(-1)) for 26 days in fresh water, and the effects on physiological and behavioural aspects of parr-smolt transformation were investigated. Vitellogenesis was induced by all treatments, as indicated by elevated levels of plasma vitellogenin (Vtg) and hepatosomatic index. Elevated Vtg levels were still found in OP-100 and E2-treated fish 4-5 months after cessation of treatment, indicating a slow clearance of Vtg from circulation. Smolting was compromised by E2 and OP-100 treatment as judged by reduced gill Na(+), K(+)-ATPase activity and impaired ability to regulate plasma osmolality and muscle water content in 24-h sea water (SW) challenge tests during the period of smolting. Downstream migratory behaviour was monitored from late April to July (Exp. 2) by implanting passive integrated transponder tags into subgroups of treated and control smolts and placing them in a stream raceway. Irrespective of treatment, nocturnal downstream movement was initiated in all groups on April 23, switching to diurnal movement in late May. Average swimming speed was estimated to be higher than current speed, indicating active migration. E2 and OP-100 fish migrated at lower frequency than control fish, suggesting a reduced migratory drive. The data suggests that waterborne exposure of salmon to xenoestrogens reduce both physiological and behavioural components of smoltification, even when exposure occurs several months prior to smolting.
Recently, concern regarding perchlorate contamination has arisen in many contexts. Perchlorate has many military, commercial, and domestic applications, and it has been found in milk, drinking and irrigation water, and produce. Perchlorate is harmful at low levels, yet it remains unregulated in the United States while the U.S. Environmental Protection Agency attempts to establish acceptable exposure levels. The present study investigated potential reproductive effects on vertebrates using a model fish species, the threespine stickleback (Gasterosteus aculeatus). Sticklebacks were raised from syngamy through sexual maturity in untreated water and in three target concentrations of sodium perchlorate-treated water. Perchlorate was found to interfere with the expression of nuptial coloration, courtship behavior, and normal sexual development. Genetic testing revealed that some females were masculinized to the extent that they produced both sperm and eggs, and histological analysis showed that these individuals had intersexual gonads (ovotestes) containing both oocytes and cells undergoing spermatogenesis. In vitro fertilizations revealed that those gametes were capable of self- and cross-fertilization. However, crosses using sperm derived from genetic females died either during the blastula phase or near the onset of organogenesis. Sperm derived from genetic males produced viable fry when crossed with eggs derived from genetic females from all treatments. To our knowledge, the present study provides the first evidence that perchlorate produces androgenic effects and is capable of inducing functional hermaphroditism in a nonhermaphroditic vertebrate.
Key Words: Animals, Base Sequence, DNA Primers, Female, Hermaphroditism/*chemically induced, Male, Perchloric Acid/*toxicity, Reproduction/drug effects, Smegmamorpha, Water Pollutants, Chemical/*toxicity
Study Synopsis: Cell experiments show that arsenic interacts at extremely low levels with several hormone receptors. The dose-response curves contradict classic 'dose makes the poison' toxicology. The pattern of gene alteration at low doses is almost completely different than the pattern at high, overtly toxic doses. These results indicate the epidemiological links between low dose arsenic and a range of human health conditions, including cancer, diabetes, developmental problems and cardiovascular disease, may result from its ability to disrupt hormone mechanisms.
Scientific abstract:
Chronic intake of arsenic (As) has been associated with increased risk of cancer, diabetes, developmental and reproductive problems, and cardiovascular disease. Recent studies suggest increased health risks with drinking water levels as low as 5-10 ppb. We previously reported that As disrupts glucocorticoid receptor (GR) mediated transcription in a very complex fashion. Low As levels (0.1-0.7 microM) stimulated transcription, whereas slightly higher levels (1-3 microM) were inhibitory. The DNA binding domain (DBD) was the minimal region of GR required for the response to As. Mutations in the DBD that alter the conformation of the dimerization domain (D-loop) to a DNA-bound GR conformation abolished the stimulatory effect and enhanced the inhibitory response to As. Here we report that receptors for progesterone (PR) and mineralocorticoids display a complex As response similar to that of the GR, suggesting a common mechanism for this effect. The complex response to As is not due to altered steroid or receptor levels. Moreover, a well-characterized GR dimerization mutant displayed a wild-type biphasic response to As for several divergent reporter genes, suggesting that dimerization is not critical for the response to As. Fluorescence polarization studies with purified PR and GR demonstrated that the specific PR/GR-DNA interaction is not altered in the presence of As. These results indicate that the numerous and diverse human health effects associated with As exposure may be mediated, at least in part, through its ability to simultaneously disrupt multiple hormone receptor systems.
Study Synopsis: Sons born to mothers exposed in the womb to DES are almost 5 times more at risk to hypospadias than sons born to unexposed mothers. Paternal exposure to DES was not related. These results indicate third generation impacts of in utero exposure are of concern.
Scientific abstract:
BACKGROUND: In 2002, an increased risk of hypospadias was reported for sons of women exposed to diethylstilbestrol (DES) in utero, suggesting transgenerational effects of DES. The aim of this study was to further assess the association between parental DES exposure and hypospadias in a case-referent study. METHODS: Cases with hypospadias were retrieved from the hospital information system. Referents were recruited via the parents of cases. Both parents completed postal questionnaires. Associations were estimated by odds ratios (OR) with 95% confidence intervals (CI). Additionally, conditional logistic regression analyses were performed for a matched subset of parents. RESULTS: The final database included 583 cases and 251 referents. In the initial analyses, an indication was found for an increased risk of hypospadias when mothers were exposed to DES in utero: OR=2.3 (95% CI 0.7-7.9). Conditional logistic regression resulted in a stronger risk estimate: OR=4.9 (95% CI 1.1-22.3). Paternal exposure to DES did not increase the risk. CONCLUSIONS: The results confirm an increased risk of hypospadias when mothers were exposed to DES in utero. However, the excess risk appears to be of much smaller magnitude than in the 2002 study. Further research on the potential health risks for the third generation is of great importance.
Study Synopsis: An increasing body of evidence suggests that environmental exposures are adversely influencing female fecundity and fertility. Endocrine-disrupting compounds (EDCs) are of particular concern, due to their ability to interfere with the body's hormonal milieu.
Scientific abstract:
An increasing body of evidence suggests that environmental exposures are adversely influencing female fecundity and fertility. Endocrine-disrupting compounds (EDCs) are of particular concern, due to their ability to interfere with the body's hormonal milieu. An overview of the literature regarding the effect of EDCs on female fecundity and fertility end points such as puberty, menstruation, endometriosis, time to pregnancy, pregnancy loss, reproductive senescence, and secondary sex ratio is presented. Methodologic challenges in studying the effects EDCs on sensitive reproductive end points are discussed and include exposure to mixtures, the choice of biologic media in which to measure compounds, laboratory methods, and varying modeling techniques. Also reviewed are novel technologies for home-based biospecimen collection and testing that offer promise for field-based research aimed at addressing questions about environmental influences on female fecundity and fertility.
Study Synopsis: Studies in rats indicate the fetus is exposed to toxic breakdown products of phthalates in the womb during sensitive periods of development. Increasing levels of exposure in the mother to the phthalates DEHP and DBP, resulted in increasing levels of the more toxic metabolites, free-MEHP and free-MBP in amniotic fluid. Unlike the adult, the fetus lacks the enzymes necessary to detoxify these metabolites. MEHP levels in maternal urine may provide a good surrogate marker for fetal exposure to DEHP, but less consistent results were observed for DBP exposures.
Scientific abstract:
Two studies were designed to examine amniotic fluid and maternal urine concentrations of the di(2-ethylhexyl) phthalate (DEHP) metabolite mono(2-ethylhexyl) phthalate (MEHP) and the di-n-butyl phthalate (DBP) metabolite monobutyl phthalate (MBP) after administration of DEHP and DBP during pregnancy. In the first study, pregnant Sprague-Dawley rats were administered 0, 11, 33, 100, or 300 mg DEHP/kg/day by oral gavage starting on gestational day (GD) 7. In the second study, DBP was administered by oral gavage to pregnant Sprague-Dawley rats at doses of 0, 100, or 250 mg/kg/day starting on GD 13. Maternal urine and amniotic fluid were collected and analyzed to determine the free and glucuronidated levels of MEHP and MBP. In urine, MEHP and MBP were mostly glucuronidated. By contrast, free MEHP and free MBP predominated in amniotic fluid. Statistically significant correlations were found between maternal DEHP dose and total maternal urinary MEHP (p = 0.0117), and between maternal DEHP dose and total amniotic fluid MEHP levels (p = 0.0021). Total maternal urinary MEHP and total amniotic fluid MEHP levels were correlated (Pearson correlation coefficient = 0.968). Statistically significant differences were found in amniotic MBP levels between animals within the same DBP dose treatment group (p p < 0.0001). Amniotic fluid MBP levels increased with increasing DBP doses, and high variability in maternal urinary levels of MBP between rats was observed. Although no firm conclusions could be drawn from the urinary MBP data, the MEHP results suggest that maternal urinary MEHP levels may be useful surrogate markers for fetal exposure to DEHP.
Study Synopsis: The sex ratio at birth fell in New York City during January 2002 following the terrorist attacks on 9/11. This decline was predicted on the basis of a similar decline noted in California. The results support the hypothesis that 'population shocks' like earthquakes or political or social upheavals lead to male fetal loss.
Scientific abstract:
BACKGROUND: The human secondary sex ratio reportedly falls in populations subjected to exogenous stressors such as earthquakes or political and social upheavals. Explanations of the association include reduced conception of males and increased fetal deaths among males. The latter explanation has been supported by research reporting that the sex ratio in California fell 3 months, but not 8, 9 or 10 months, after the terrorist attacks of September 11, 2001. California's distance from the attacks raises the questions of whether the results arose from chance and would be found elsewhere. We contribute to the literature by testing the association between the secondary sex ratio and the events of September 11 in New York City. METHODS: We replicate the California tests by applying interrupted time-series methods, which control for secular trends, seasonality and other forms of autocorrelation, to 91 cohorts born in New York City during 28-day periods from January 1996 to June 2002. RESULTS: As hypothesized, the sex ratio in New York City in the period 1 January to 28 January 2002 fell to 1, which was the lowest observed value during the test period and significantly (i.e. P < 0.01, two-tailed test) below the value expected from history. CONCLUSIONS: Our findings support the male fetal loss explanation of the association between exogenous population shocks and the secondary sex ratio.
Study Synopsis: An endocrine-disrupting fungicide, vinclozolin, causes chronic diseases of ageing in rats following exposure in the womb, and these disease states are inherited epigenetically across multiple generations without changes in DNA sequence. Adverse effects included increased incidence of tumors, diseases of the kidney and prostate, testis abnormalities and impaired immune function. Observations also indicated very early onset of ageing, although it was not possible to distinguish this with certainty from other diseases.
Embryonic exposure to the endocrine disruptor vinclozolin at the time of gonadal sex determination was previously found to promote transgenerational disease states. The actions of vinclozolin appear to be due to epigenetic alterations in the male germline that are transmitted to subsequent generations. Analysis of the transgenerational epigenetic effects on the male germline (i.e. sperm) identified 25 candidate DNA sequences with altered methylation patterns in the vinclozolin generation sperm. These sequences were identified and mapped to specific genes and noncoding DNA regions. Bisulfite sequencing was used to confirm the altered methylation pattern of 15 of the candidate DNA sequences. Alterations in the epigenetic pattern (i.e. methylation) of these genes/DNA sequences were found in the F2 and F3 generation germline. Therefore, the reprogramming of the male germline involves the induction of new imprinted-like genes/DNA sequences that acquire an apparent permanent DNA methylation pattern that is passed at least through the paternal allele. The expression pattern of several of the genes during embryonic development were found to be altered in the vinclozolin F1 and F2 generation testis. A number of the imprinted-like genes/DNA sequences identified are associated with epigenetic linked diseases. In summary, an endocrine disruptor exposure during embryonic gonadal sex determination was found to promote an alteration in the epigenetic (i.e. induction of imprinted-like genes/DNA sequences) programming of the male germline, and this is associated with the development of transgenerational disease states.
Research notes: NOTE: This article was retracted in June 2009: http://www.ncbi.nlm.nih.gov/pubmed/19469050?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstract
Study Synopsis: Dioxin levels were higher in pregnant women who lived longer near the site of a former pentachlorophenol manufacturing plant in Taiwan. Those living in the area more than 3 years had dioxin levels over 40% higher than those who had been there less time. Dioxin-like PCBs were almost 80% higher.
Scientific abstract:
A large pentachlorophenol (PCP)-manufacturing plant located in southwestern Taiwan operated between 1965 and 1982. The present study was conducted to ascertain whether an increased body burden of dioxins existed in pregnant women living in an area of Tainan city contaminated by chemicals from this plant. Twenty-eight pregnant subjects, 21-39 years of age and residing in the study area between March and December of 2004 with a mean dwelling time of 6.07+/-6.11 years, were recruited. Concentrations of polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), and dioxin-like polychlorinated biphenyls (PCBs) in serum of recruited residents were determined. Pregnant women residing in the study area >3 years had significantly higher PCDD (7.48 versus 5.13 pg-toxic equivalents [TEQ]/g-lipid) and dioxin-like PCB (6.70 versus 3.74 pg-TEQ/g-lipid) values as compared to those residing < or = 3 years. Furthermore, dioxin concentrations increased with increasing dwelling time. Statistical analyses performed according to demographic characteristics and socioeconomic and dietary habits revealed that total TEQ values were significantly associated with fish consumption and smoking status. Dioxin congeners with greater degrees of chlorine substitution (e.g., HpCDD/F and OCDD/F) partitioned to greater degrees in the subjects of this study as compared to subjects in the general Taiwanese population. The findings of this study strongly implicate the activity of the PCP manufacturing plant in the observed increase in dioxin body burden. Investigation of the health consequences of this increased body burden is recommended.
Study Synopsis: Prenatal exposure to polycyclic aromatic hydrocarbons were significantly associated with lower birth weight in Caucasians in Krakow, Poland, and African-Americans in New York City. No association was found in Dominicans studied in New York City. The results also indicated a 6-fold greater susceptibility of NYC African-Americans to low level exposures.
Scientific abstract:
OBJECTIVES: Polycyclic aromatic hydrocarbons (PAHs) are ubiquitously distributed human mutagens and carcinogens. However, lack of adequate air monitoring data has limited understanding of the effects of airborne PAHs on fetal growth. To address this gap in knowledge, we examined the association between prenatal exposure to airborne PAHs and birth weight, birth length, and birth head circumference, respectively, in Krakow, Poland, and New York City (NYC). METHODS: The parallel prospective cohort studies enrolled nonsmoking, healthy, and nonoccupationally exposed women and their newborns. Personal air monitoring of pregnant women was conducted over 48 hr. To control for maternal environmental tobacco smoke (ETS) exposure, we excluded those with umbilical cord plasma cotinine concentrations > 25 ng/mL. Mean cord plasma cotinine concentrations in both ethnic groups were Key Words: Adolescent, Adult, Air Pollutants/analysis, Air Pollutants/toxicity*, Birth Weight/drug effects, Body Height/drug effects, Female, Fetal Development/drug effects*, Head/anatomy & histology, Humans, Infant-Newborn, Male, Maternal Exposure/adverse effects*, New York City, Poland, Polycyclic Hydrocarbons-Aromatic/analysis, Polycyclic Hydrocarbons-Aromatic/toxicity*, Pregnancy, Air Pollutants, Polycyclic Hydrocarbons-Aromatic
Study Synopsis: Study conducted by NIH scientists finds no association between delayed conception and poor pregnancy outcomes. There was no evidence to support an adverse relationship between conception delay and decrements in gestation or birthweight among this select sample of fertile women, even after varying the cut-point for defining conception delay. This contrasts with previous studies that have found an effect.
Scientific abstract:
Previous studies have suggested an association between delays in conception and adverse perinatal outcomes, specifically, low birthweight and preterm birth. We investigated the relationship between conception delay (defined as >6 months to become pregnant) and three perinatal outcomes: low birthweight (LBW; <2500 g), preterm birth (PTB; <37 weeks), and small-for-gestational-age (SGA; <10th percentile weight for given gestational age) using data from the Collaborative Perinatal Project. The study cohort was limited to pregnancies with a known time-to-pregnancy (n = 8465; 15%). Generalised estimating equations were used to estimate odds ratios (OR) and 95% confidence intervals [CI] for risk of adverse perinatal outcomes accounting for the clustering of pregnancy outcomes for women with more than one pregnancy. After adjusting for confounders, all ORs were close to the null (LBW, OR = 1.01; 95% CI = 0.86, 1.20), (PTB, OR = 1.10; 95% CI = 0.95, 1.27), (SGA, OR = 1.06; 95% CI = 0.91, 1.25). Thus, we found no evidence to support an adverse relationship between conception delay and decrements in gestation or birthweight among this select sample of fertile women, even after varying the cut-point for defining conception delay.
Dalsenter PR, Santana GM, Grande SW, Andrade AJ, Araujo SL. Phthalate affect the reproductive function and sexual behavior of male Wistar rats. Hum Exp Toxicol. 2006 Jun;25(6):297-303.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers exposed male rats to different doses of the plasticizer diethylhexyl phthalate (DEHP) during fetal development and lactation. They found that exposure to the highest dose (500 mg/kg) caused a reduction in the weight of organs that are sensitive to the male hormone testosterone and other androgens including the prostate and seminal vesicle. This dose also impaired male sexual behavior, reduced sperm production and sperm count. These results suggest that high doses of DEHP disrupt the development of the male reproductive tract. Effects were observed during puberty and adulthood, suggesting that the effect may be permanent.
Scientific abstract:
Phthalates are chemicals used in many industrial products (plastic toys, shampoos, soaps), and are suspected of inducing adverse effects on the male reproductive system. In the present study, we evaluated the effects of the plasticizer di-(2-ethylhexyl)-phthalate (DEHP) on the reproductive function and sexual behavior of male offspring rats, exposed in utero and during lactation (0, 20, 100 and 500 mg/kg per day by gavage). The effects produced clearly demonstrate the ability of DEHP to disrupt the androgen-regulated development of the male reproductive tract. Absolute and relative weights of androgen-dependent tissue organs (ventral prostate and seminal vesicle) were significantly reduced at the highest dose level tested (500 mg/kg per day). Impairment of male sexual behavior (500 mg/kg per day) was also observed. Moreover, the reduction in daily sperm production and epididymal sperm counts observed after administration of the highest dose suggests an impairment of the spermatogenic processes. Most of the adverse effects reported here were observed both during puberty and during adulthood, indicating permanent effects of in utero and lactational DEHP exposure.
Key Words: Animals, Diethylhexyl Phthalate/ toxicity, Dose-Response Relationship, Drug, Female, Genitalia, Male/ drug effects/growth & development, Lactation, Male, Organ Size/drug effects, Plasticizers/ toxicity, Pregnancy, Prenatal Exposure Delayed Effects, Rats, Rats, Wistar, Sexual Behavior, Animal/ drug effects
Study Synopsis: Exposure to persistent pesticides in breast milk is associated with undescended testicles. A case-control study compared breast milk samples from mothers of baby boys with cryptorchidism to milk samples from mothers with healthy boys at 1 and 3 months of age. Seventeen of twenty-one organochlorine pesticides were found to be at higher median levels in the cases, but only one, trans-chlordane, was found to be statistically different. When the eight most abundant pesticides were combined and compared between cases and controls, total pesticide level was significantly higher in boys with cryptorchidism.
Scientific abstract:
INTRODUCTION: Prenatal exposure to some pesticides can adversely affect male reproductive health in animals. We investigated a possible human association between maternal exposure to 27 organochlorine compounds used as pesticides and cryptorchidism among male children. DESIGN: Within a prospective birth cohort, we performed a case-control study; 62 milk samples from mothers of cryptorchid boys and 68 from mothers of healthy boys were selected. Milk was collected as individual pools between 1 and 3 months postpartum and analyzed for 27 organochlorine pesticides. RESULTS: Eight organochlorine pesticides were measurable in all samples (medians; nanograms per gram lipid) for cases/controls: 1,1-dichloro-2,2-bis(4-chlorophenyl) ethylene (p,p -DDE) : 97.3/83.8; beta-hexachlorocyclohexane (beta-HCH) : 13.6/12.3; hexachlorobenzene (HCB) : 10.6/8.8; alpha-endosulfan: 7.0/6.7; oxychlordane: 4.5/4.1; 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (p,p -DDT) : 4.6/4.0; dieldrin: 4.1/3.1 ; cis-heptachloroepoxide (cis-HE) : 2.5/2.2. Five compounds [octachlorostyrene (OCS); pentachlorobenzene, 1,1-dichloro-2,2-bis(4-chlorophenyl) ethane(p,p -DDD) ; o,p -DDT ; mirex] were measurable in most samples (detection rates 90.8-99.2%) but in lower concentrations. For methoxychlor, cis-chlordane, pentachloroanisole (PCA), gamma-HCH, 1,1-dichloro-2-(2-chlorophenyl) -2,2(4-chlorophenyl) ethane, trans-chlordane, alpha-HCH, and o,p -DDE, both concentrations and detection rates were low (26.5-71.5%). Heptachlor, HCH (lc delta, epsilon), aldrin, beta-endosulfan and trans-heptachloroepoxide were detected at negligible concentrations and low detection rates and were not analyzed further. Seventeen of 21 organochlorine pesticides [p,p -DDT, p,p-DDE, p,p-DDD, o,p-DDT, HCH (alpha, beta, gamma), HCB, PCA, alpha-endosulfan, cis-HE, chlordane (cis-, trans-) oxychlordane, methoxychlor, OCS, and dieldrin] were measured in higher median concentrations in case milk than in control milk. Apart from trans-chlordane (p = 0.012), there were no significant differences between cryptorchid and healthy boys for individual chemicals. However, combined statistical analysis of the eight most abundant persistent pesticides showed that pesticide levels in breast milk were significantly higher in boys with cryptorchidism (p = 0.032). CONCLUSION: The association between congenital cryptorchidism and some persistent pesticides in breast milk as a proxy for maternal exposure suggests that testicular descent in the fetus may be adversely affected.
Study Synopsis: A study of semen parameters in Mexico where DDT was used to control malaria found that exposure was related to impaired sperm quality. Men with higher DDE levels had a lower precentage of motile sperm and a greater percentage of sperm with tail defects. Sperm chromatin condensation was also affected adversely. These findings are especially important because the subjects were not involved in spraying DDT, but instead were simply living in the area.
Scientific abstract:
In response to mounting concerns about the endocrine-disrupting influence of environmental chemicals on human health, this epidemiological study was initiated to test the hypothesis that nonoccupational exposure to the estrogenic pesticide 1,1,1-trichloro-2,2-bis(chlorodiphenyl)ethane (DDT) affects male reproductive parameters. One hundred and sixteen men aged 27 years (SD = 8.2) living in malaria endemic-areas in Chiapas (Mexico), where DDT was sprayed until 2000, participated in a cross-sectional study. Semen analyses were conducted according to World Health Organization methods and a quality control program was followed. DDT exposure was defined as the level of blood plasma p,p'-dichlorodiphenyl dichloroethylene (DDE), the major metabolite of DDT. The p,p'-DDE concentration adjusted for total lipids was 100 times higher than that reported for nonexposed populations at 45 plus or minus 32 mug/g (mean +/- SD). Crude regression analysis showed that several sperm motion parameters, including the percentage of motile sperm, decreased with higher p,p'-DDE concentrations (beta = -8.38; P = .05 for squared motility), and the percentage of sperm with morphological tail defects increased with higher plasma p,p'-DDE concentration (beta = 0.003; P = .017). Insufficient sperm chromatin condensation was observed in 46.6% of participants, and the most severe category of incomplete DNA condensation was also positively correlated with p,p'-DDE concentration (r = .223; P = .044). Therefore, nonoccupational exposure to DDT, as assessed by plasma p,p'-DDE concentrations, is associated with poorer semen parameters in men, indicating adverse effects on testicular function and/or the regulation of reproductive hormones. Previously, a causal role of environmental toxicants in human male infertility has been lacking because observed effects have been the result of unusually high exposures, either occupationally or as a result of industrial accidents, resulting in unprecedented controversy (reviewed by Cheek & McLachlan, Environmental hormones and the male reproductive system. J Androl. 1998;19:5). This is the first epidemiological study demonstrating effects after nonoccupational exposures to DDT. Based on these findings, the effect of DDT on male reproductive health should not be ignored.
De Jager C, Farias P, Barraza-Villarreal A, Avila MH, Ayotte P, Dewailly E, Dombrowski C, Rousseau F, Sanchez VD, Bailey JL. Reduced seminal parameters associated with environmental DDT exposure and p,p'-DDE concentrations in men in Chiapas, Mexico: a cross-sectional study. J Androl. 2006 Jan-Feb;27(1):16-27.
Study Synopsis: DDT is an insecticide that was banned by the U.S. Environmental Protection Agency (EPA) in the 1970s due to concerns about its persistence in the environment and toxic effects on wildlife and humans. DDT has now been banned internationally by the Stockholm Convention on Persistent Organic Pollutants, except to control insects that carry diseases such as malaria. In this study, researchers measured DDE, DDT's breakdown product, in the blood of 116 men living in a malaria-endemic area in Chiapas, Mexico, where DDT was used until 2000. They found that men with higher DDE blood levels had a reduced percentage of motile sperms and an increased proportion of sperms with morphological abnormalities. These results suggest that exposure to DDT and/or DDE may be associated with altered semen quality.
Scientific abstract:
In response to mounting concerns about the endocrine-disrupting influence of environmental chemicals on human health, this epidemiological study was initiated to test the hypothesis that nonoccupational exposure to the estrogenic pesticide 1,1,1-trichloro-2,2-bis(chlorodiphenyl)ethane (DDT) affects male reproductive parameters. One hundred and sixteen men aged 27 years (SD = 8.2) living in malaria endemic-areas in Chiapas (Mexico), where DDT was sprayed until 2000, participated in a cross-sectional study. Semen analyses were conducted according to World Health Organization methods and a quality control program was followed. DDT exposure was defined as the level of blood plasma p,p'-dichlorodiphenyl dichloroethylene (DDE), the major metabolite of DDT. The p,p'-DDE concentration adjusted for total lipids was 100 times higher than that reported for nonexposed populations at 45 plus or minus 32 mug/g (mean +/- SD). Crude regression analysis showed that several sperm motion parameters, including the percentage of motile sperm, decreased with higher p,p'-DDE concentrations (beta = -8.38; P = .05 for squared motility), and the percentage of sperm with morphological tail defects increased with higher plasma p,p'-DDE concentration (beta = 0.003; P = .017). Insufficient sperm chromatin condensation was observed in 46.6% of participants, and the most severe category of incomplete DNA condensation was also positively correlated with p,p'-DDE concentration (r = .223; P = .044). Therefore, nonoccupational exposure to DDT, as assessed by plasma p,p'-DDE concentrations, is associated with poorer semen parameters in men, indicating adverse effects on testicular function and/or the regulation of reproductive hormones. Previously, a causal role of environmental toxicants in human male infertility has been lacking because observed effects have been the result of unusually high exposures, either occupationally or as a result of industrial accidents, resulting in unprecedented controversy (reviewed by Cheek & McLachlan, Environmental hormones and the male reproductive system. J Androl. 1998;19:5). This is the first epidemiological study demonstrating effects after nonoccupational exposures to DDT. Based on these findings, the effect of DDT on male reproductive health should not be ignored.
Study Synopsis: A review of scientific studies finds exposure to many different chemicals affects the pubertal development of both boys and girls. In girls, exposure to organochlorines and phthalates was associated with an earlier onset of menstruation. In boys, exposure to organochlorines and the pesticide, endosulfan were associated with delayed puberty. Many of these studies agree with experimental animal studies.
Scientific abstract:
In this overview of the literature, epidemiological research studying the effect of endocrine disrupters on the onset of puberty is summarized. In girls, earlier age at menarche was reported after exposure to polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), persistent pesticides [dichlorodiphenyltrichloroethane (DDT)] and phthalate esters. However, several other studies found no effect of these compounds on age at menarche or pubertal Tanner stages. One study reported a delaying effect of dioxin-like compounds on breast development. In boys, exposure to PCBs, PCDFs or the pesticide endosulfan was associated with delayed puberty or decreased penile length. Much of the results found in population studies are in accordance with experimental studies in animals. However, the mixture of different components with antagonistic effects (oestrogenic, anti-oestrogenic, anti-androgenic) and the limited knowledge about the most critical window for exposure (prenatal, peri-natal and pubertal) may hamper the interpretation of results.
Study Synopsis: In a study of young men from the general Flemish population, as dioxin levels double, total and free testosterone levels drop significantly. Semen volume also falls, while sperm concentration rises. The data suggest an interaction of dioxin-like compounds affect secretory function in the seminal vesicles or prostate, without altering spermatogenesis. Dioxin levels were related to fish and egg consumption.
Scientific abstract:
BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and some related environmental contaminants are aryl hydrocarbon receptor (AhR) ligands that exert reproductive and developmental toxicity in laboratory animals. In humans, fertility-related effects are less documented. OBJECTIVE: The aim of this study was to investigate the relationship between dioxin-like biological activity in serum and parameters of reproductive status in men from the general population 5 months after a polychlorinated biphenyl and dioxin food-contamination episode in Belgium. DESIGN: In the framework of the cross-sectional Flemish Environment and Health Study (FLEHS), we recruited 101 men 20-40 years of age and evaluated sperm parameters, measured sex hormones, and gathered information on a number of lifestyle factors. In addition, we determined the AhR-mediated enzymatic response elicited by individual serum samples and expressed it as TCDD equivalent concentrations (CALUX-TEQs) using an established transactivation assay. RESULTS: Age (p = 0.04) and the frequency of fish (p = 0.02) and egg (p = 0.001) consumption were independent positive determinants of serum dioxin-like activity. After correcting for possible confounders, we found that a 2-fold increase in CALUX-TEQ > 16 pg/L was associated with a 7.1% and 6.8% (both p = 0.04) decrease in total and free testosterone, respectively. We also observed a more pronounced drop in semen volume of 16.0% (p = 0.03), whereas sperm concentration rose by 25.2% (p = 0.07). No relationship was found with total sperm count or sperm morphology. CONCLUSIONS: These data suggest an interaction of dioxin-like compounds with the secretory function of the seminal vesicles or prostate, possibly indirectly through an effect on testosterone secretion, at levels not affecting spermatogenesis as such.
Study Synopsis: Scientific evidence indicates male species of both wildlife and humans are experiencing abnormal reproductive development. In human males, abnormal reproductive development is as a suite of symptoms, described collectively as testicular dysgenesis syndrome (TDS). TDS includes cryptorchidism, testicular cancer, reduced semen quality, and hypospadias. Wildlife exposed to environmental contaminants are susceptible to some of the same developmental abnormalities and subsequent symptoms as those seen in human males.
Scientific abstract:
Abnormal reproductive development in males has been linked to environmental contaminant exposure in a wide variety of vertebrates. These include humans, rodent models, and a large number of comparative wildlife species. In human males, abnormal reproductive development can manifest as a suite of symptoms, described collectively as testicular dysgenesis syndrome (TDS). TDS is also described as demasculinization or feminization of the male phenotype. The suite includes cryptorchidism, in situ germ cell carcinoma of the testis and overt testicular cancer, reduced semen quality, and hypospadias. In this paper, we review examples of TDS among comparative species. Wildlife exposed to environmental contaminants are susceptible to some of the same developmental abnormalities and subsequent symptoms as those seen in human males with TDS. There are additional end points, which are also discussed. In some cases, the symptoms are more severe than those normally seen in humans with TDS (i.e. oocytes developing within the testis) because some non-mammalian species exhibit greater innate reproductive plasticity, and are thus more easily feminized. Based on our review, we present an approach regarding the ontogeny of TDS. Namely, we suggest that male susceptibility to the androgynizing influences of environmental contaminants originates in the sexually undifferentiated embryo, which, in almost all species, including humans, consists of bipotential reproductive tissues. These tissues can develop as either male or female and their ultimate direction depends on the environment in which they develop.
Study Synopsis: Enterolactone, daidzein and genistein are naturally occurring chemicals known to have effects that mimic those of the female sex hormone estrogen. Bisphenol A, which is a synthetic chemical used in plastics, food can linings and some dental sealants, has also been found to have estrogenic effects. Researchers measured these chemicals in amniotic fluid collected from 21 women before 20 weeks gestation. All four chemicals were detected in at least two samples. Enterolactone was measured at the highest concentration, followed by daidzein, genistein and bisphenol A. Results show that these chemicals can cross the placenta in humans and that maternal exposure can result in exposure to the fetus.
Scientific abstract:
We found detectable levels of three phytoestrogens (enterolactone, daidzein and genistein) and bisphenol A (BPA) in 21 residual amniotic fluid specimens that were collected before 20 weeks gestation. Samples were obtained by amniocentesis from women who were referred to the Mount Sinai Medical center because of advanced maternal age. Phytoestrogens were present in higher concentrations than BPA. Enterolactone was detected at the highest concentration (median 95.9 microg/L), followed by daidzein and genistein (9.5 and 1.4 microg/L, respectively). BPA was present at very low concentrations (10%>LOD of 0.5 microg/L). The relative concentration of the chemicals measured in amniotic fluid were identical to those in urine reported by other studies, i.e. enterolactone>daidzein>genistein>>BPA. Amniotic fluid is a source of fetal exposure to polar xenobiotics that come from the mother.
Study Synopsis: In a large study of US women living on farms, use of pesticides is associated with a later age at menopause. Women who used pesticides underwent menopause an average of 3 months later compared to women who did not use pesticides. This increased to a 5 month delay when hormonally-active pesticides were used, such as atrazine, DDT, lindane, or mancozeb/maneb. Previous studies have found an earlier age at menopause with pesticide exposure; this may be due to differing endocrine disrupting effects in different types of pesticides or differences in study design.
Scientific abstract:
Age at menopause has implications for fertility and risk of hormonally related chronic diseases. Some pesticides disrupt reproductive hormones or are toxic to the ovary, but little is known about the association between pesticide exposure and timing of menopause. Cox proportional hazards modeling was used to examine the association between use of pesticides and age at menopause among 8,038 women living and working on farms in Iowa and North Carolina. Premenopausal women aged 35-55 years were followed from enrollment (1993-1997) to the date of their last menstrual period, or their follow-up interview (1999-2003) if still premenopausal. Women who experienced surgical menopause were censored at the date of surgery. Approximately 62% of the women reported ever mixing or applying pesticides; women who had never used pesticides were the comparison group for all analyses. After control for age, smoking status, and past use of oral contraceptives, the median time to menopause increased by approximately 3 months for women who used pesticides (hazard ratio = 0.87, 95% confidence interval: 0.78, 0.97) and by approximately 5 months for women who used hormonally active pesticides (hazard ratio = 0.77, 95% confidence interval: 0.65, 0.92). Pesticide use may be associated with a later age at menopause.
Study Synopsis: In a study of agricultural workers in California, exposure to organochlorine pesticides during pregnancy is associate with a decrease in gestational age but not preterm labor. Of 11 different organochlorine pesticides studied, only hexachlorobenze (HCB) was associated with an earlier onset of labor. There was no effect on fetal growth. Although the onset of labor occurred several days earlier, there was not an increased rate of preterm delivery.
Scientific abstract:
From 1940 through the 1970s, organochlorine compounds were widely used as insecticides in the United States. Thereafter, their use was severely restricted after recognition of their persistence in the environment, their toxicity in animals, and their potential for endocrine disruption. Although substantial evidence exists for the fetal toxicity of organochlorines in animals, information on human reproductive effects is conflicting. We investigated whether infants' length of gestation, birth weight, and crown-heel length were associated with maternal serum levels of 11 different organochlorine pesticides: p,p -dichlorodiphenyltrichloroethane (p,p -DDT), p,p -dichlorodiphenyldichloroethylene (p,p -DDE), o,p -dichlorodiphenyltrichloroethane (o,p -DDT), hexachlorobenzene (HCB), gamma-hexachlorocyclohexane (gamma-HCCH), gamma-hexachlorocyclohexane (gamma-HCCH), dieldrin, heptachlor epoxide, oxychlordane, trans-nonachlor, and mirex. Our subjects were a birth cohort of 385 low-income Latinas living in the Salinas Valley, an agricultural community in California. We observed no adverse associations between maternal serum organochlorine levels and birth weight or crown-heel length. We found decreased length of gestation with increasing levels of lipid-adjusted HCB (adjusted gamma = -0.47 weeks; p = 0.05). We did not find reductions in gestational duration associated with any of the other organochlorine pesticides. Our finding of decreased length of gestation related to HCB does not seem to have had clinical implications for this population, given its relatively low rate of preterm delivery (6.5%).
Key Words: Agriculture*, Female, Fetal Development/drug effects*, Humans, Hydrocarbons-Chlorinated/toxicity*, Interviews as Topic, Maternal Exposure*, Medical Audit, Pesticides/toxicity*, Pregnancy/drug effects*, Sensitivity and Specificity, Hydrocarbons-Chlorinated, Pesticides
Fenster L, Eskenazi B, Anderson M, Bradman A, Harley K, Hernandez H, Hubbard A, Barr DB. Association of in utero organochlorine pesticide exposure and fetal growth and length of gestation in an agricultural population. Environ Health Perspect. 2006 Apr;114(4):597-602.
Study Synopsis: Organochlorines are chemicals that were primarily used as pesticides from the 1940s to the 1970s when they were banned due to concerns about their persistence in the environment, bioaccumulation in fat tissues and potential adverse health effects on wildlife and in humans. In this study, researchers measured the concentration of DDT, DDE (DDT's breakdown product), hexachlorobenzene (a fungicide), dieldrin (an insecticide) and other organochlorine compounds in the blood of 385 pregnant women living in the Salinas Valley, California. They found that women with higher blood levels of hexachlorobenzene had shorter gestation than women with low levels. No associations were found between the blood levels of any organochlorine and birth weight or birth length. These results suggest that maternal exposure to hexachlorobenzene may be related with reduced gestational duration.
Scientific abstract:
From 1940 through the 1970s, organochlorine compounds were widely used as insecticides in the United States. Thereafter, their use was severely restricted after recognition of their persistence in the environment, their toxicity in animals, and their potential for endocrine disruption. Although substantial evidence exists for the fetal toxicity of organochlorines in animals, information on human reproductive effects is conflicting. We investigated whether infants' length of gestation, birth weight, and crown-heel length were associated with maternal serum levels of 11 different organochlorine pesticides: p,p -dichlorodiphenyltrichloroethane (p,p -DDT), p,p -dichlorodiphenyldichloroethylene (p,p -DDE), o,p -dichlorodiphenyltrichloroethane (o,p -DDT), hexachlorobenzene (HCB), gamma-hexachlorocyclohexane (gamma-HCCH), gamma-hexachlorocyclohexane (gamma-HCCH), dieldrin, heptachlor epoxide, oxychlordane, trans-nonachlor, and mirex. Our subjects were a birth cohort of 385 low-income Latinas living in the Salinas Valley, an agricultural community in California. We observed no adverse associations between maternal serum organochlorine levels and birth weight or crown-heel length. We found decreased length of gestation with increasing levels of lipid-adjusted HCB (adjusted gamma = -0.47 weeks; p = 0.05). We did not find reductions in gestational duration associated with any of the other organochlorine pesticides. Our finding of decreased length of gestation related to HCB does not seem to have had clinical implications for this population, given its relatively low rate of preterm delivery (6.5%).
Key Words: Agriculture, Female, Fetal Development/ drug effects, Humans, Hydrocarbons, Chlorinated/ toxicity, Interviews as Topic, Maternal Exposure, Medical Audit, Pesticides/ toxicity, Pregnancy/ drug effects, Sensitivity and Specificity
Study Synopsis: Recent studies have determined some mechanisms responsible for the changes seen in testicular dysgenesis syndrome (TDS). The critical effect causing TDS is a reduction in fetal testicular testosterone production. Recent research has also identified a gene, insl3, that when inhibited results in undescended testicles. Phthalate exposure has been shown to cause both these effects.
Scientific abstract:
Certain Phthalate esters have been shown to produce reproductive toxicity in male rodents with an age dependent sensitivity in effects with foetal animals being more sensitive than neonates which are in turn more sensitive than pubertal and adult animals. While the testicular effects of phthalates in rats have been known for more than 30 years, recent attention has been focused on the ability of these agents to produce effects on reproductive development in male offspring after in utero exposure. These esters and in particular di-butyl, di-(2-ethylhexyl) and butyl benzyl phthalates have been shown to produce a syndrome of reproductive abnormalities characterized by malformations of the epididymis, vas deferens, seminal vesicles, prostate, external genitalia (hypospadias), cryptorchidism and testicular injury together with permanent changes (feminization) in the retention of nipples/areolae (sexually dimorphic structures in rodents) and demasculinization of the growth of the perineum resulting in a reduced anogenital distance (AGD). Critical to the induction of these effects is a marked reduction in foetal testicular testosterone production at the critical window for the development of the reproductive tract normally under androgen control. A second Leydig cell product, insl3, is also significantly down regulated and is likely responsible for the cryptorchidism commonly seen in these phthalate-treated animals. The testosterone decrease is mediated by changes in gene expression of a number of enzymes and transport proteins involved in normal testosterone biosynthesis and transport in the foetal Leydig cell. Alterations in the foetal seminiferous cords are also noted after in utero phthalate treatment with the induction of multinucleate gonocytes that contribute to lowered spermatocyte numbers in postnatal animals. The phthalate syndrome of effects on reproductive development has parallels with the reported human testicular dysgenesis syndrome, although no cause and effect relationship exists after exposure of humans to phthalate esters. However humans are exposed to and produce the critical phthalate metabolites that have been detected in blood of the general population, in children and also human amniotic fluid.
Study Synopsis: Review of scientific evidence indicates that in those with a genetic predisposition, exposure to androgens during fetal development is associated with the polycystic ovarian syndrome (PCOS). Exposure to excess androgen leads to many of the characteristic features of PCOS, including abnormalities in reproductive hormones and insulin resistance. It is likely that, in humans with PCOS, the development of the PCOS phenotype results primarily from a genetic predisposition of the fetal ovary to hypersecrete androgen. After birth, the natural history of PCOS can be modified by nutrition.
Scientific abstract:
Summary: We have recently proposed that polycystic ovary syndrome (PCOS) has its origin in fetal life. This hypothesis is based on data from animal models (rhesus monkey or sheep that have been exposed prenatally to high doses of androgen) and is supported by clinical studies. It is suggested that, in human females, exposure to excess androgen, at any stage from fetal development of the ovary to the onset of puberty, leads to many of the characteristic features of PCOS, including abnormalities of luteinizing hormone secretion and insulin resistance. It is likely that, in humans with PCOS, the development of the PCOS phenotype results primarily from a genetic predisposition for the fetal ovary to hypersecrete androgen. At present, it is unclear whether the maternal environment directly influences the development of PCOS in the offspring. Maternal androgen excess is unlikely to affect the fetus, because the placenta presents an effective barrier, but metabolic disturbances during pregnancy could affect development of the syndrome in the fetus. In postnatal life, the natural history of PCOS can be further modified by factors affecting insulin secretion and/or action, most importantly, nutrition. We now have evidence for a disorder of early follicular development in the polycystic ovary that is consistent with an increased population of primordial follicles in the fetal ovary. It remains to be determined whether this phenomenon is the cause or the effect of increased exposure to androgen within the ovary. PCOS is the commonest endocrine disorder in women. It is not only a very prevalent cause of anovulatory infertility, menstrual disturbances and hirsutism, but it is also a major risk factor for the development of type 2 diabetes mellitus in later life. The aetiology of the syndrome remains uncertain but there is increasing evidence for a genetic basis. PCOS very often becomes clinically manifest during adolescence with maturation of the hypothalamic-pituitary-ovarian axis but the genesis of the syndrome may be during very early development - perhaps even in utero. In this review, this hypothesis is explored in the light of clinical, biochemical and genetic research.
Study Synopsis: Fetal exposure to bisphenol A at levels beneath those currently considered safe in the US and Japan impairs sexual differentiation in the brain of rats and increases depression-like behavior in males. Human exposure to this compound is widespread because of its use in polycarbonate plastic and to make resins to line metal food cans. Exposure did not affect anxiety level or avoidance behavior. This study is one of over 100 within the past 5 years showing low level adverse effects of BPA.
Scientific abstract:
Perinatal exposure to bisphenol A (BPA, 0.1 and 1 ppm in drinking water applied to mother rats for 6 weeks) has been shown to impair the sexual differentiation in exploratory behavior, but the exact critical period of this disrupting effect is still unknown. In this study, we examined the effects of prenatal exposure to BPA (0.1 ppm in drinking water applied to dams during the final week of pregnant) on emotional and learning behaviors in addition to exploratory behavior. Estimated daily intake was 15 microg/kg/day, below the reference dose (RfD) in the United States and the daily tolerable intake (TDI) in Japan (50 microg/kg/day). The rats were successively tested in open-field test, elevated plus maze test, passive avoidance test and forced swimming test during development from 6 to 9 weeks of juvenile period. Prenatal exposure to BPA mainly affected male rats and abolished sex differences in rearing behavior in the open-field test and struggling behavior in the forced swimming test. BPA increased the immobility of male rats in the forced swimming test. The avoidance learning and behaviors in the elevated plus maze were not affected. The present study demonstrates that male rats at the final week of prenatal period are sensitive to BPA, which impairs sexual differentiation in rearing and struggling behavior and facilitate depression-like behavior.
Study Synopsis: Despite the mounting evidence for links between chemical exposures and reproductive health effects, clinical providers have limited exposure to this information. Whereas journals devoted to toxicology and environmental concerns have published much information on this topic, the mainstream obstetrics and gynecolgy literature does not frequently publish these types of studies. Health care providers should have more education on this topic so they can assist individual patients as well as proactively engage in public health education relating to the impact of toxic exposures.
Scientific abstract:
Although ongoing study is required to winnow environmental ideology from scientific fact, existing evidence from recent research demonstrates a definitive link between chemical toxicants and potential health sequelae, including congenital affliction and gynaecological disorders. Amid media clamour of health risk and biological peril associated with various environmental toxicants, a spectrum of responses has emerged: some have embraced the environmental cause, some have summarily dismissed it as piffle and perhaps the majority has remained disinterested. Although journals devoted to toxicological and environmental health concerns have become prominent in academia with voluminous numbers of scientific reports being published, there has been limited exploration of the relationship between contemporary chemical exposure and reproductive medical issues in mainstream obstetrics and gynaecology literature. Providers of obstetrical and gynaecological health care need to acquire knowledge of taking an exposure history, instruction in details of precautionary avoidance, skills to provide preconception care and necessary tools to investigate and manage patients with toxicant exposure.
Study Synopsis: Pregnant women who are exposed to second-hand smoke may be at heightened risk for suffering miscarriages, according to research from Sweden. "Given the high prevalence of exposure to environmental tobacco smoke and the fact that spontaneous abortion is the most common adverse outcome of pregnancy, the public health consequences of passive smoking regarding early fetal loss may be substantial," researchers conclude in a report in the journal Epidemiology. Previous studies of passive smoke exposure in pregnancy have relied on reports from study participants themselves, and have had inconsistent results, Dr. Lena George of the Karolinska Institutet in Stockholm and colleagues note. To evaluate nicotine exposure more precisely, they measured study participants' blood levels of cotinine -- a marker for nicotine exposure. The researchers matched 463 women who had miscarried at 6 to 12 weeks of pregnancy with 864 women at the same stage of pregnancy who had not miscarried. Twenty-four percent of the women had cotinine levels indicating passive smoke exposure, compared to 19 percent of the controls. Women who smoked were more than twice as likely as nonsmokers to miscarry, the researchers found. They also found that those whose cotinine levels indicated they were exposed to second hand-smoke were 67 percent more likely to miscarry than those who weren't exposed to second-hand smoke. In an editorial accompanying the study, Dr. Michael B. Bracken calls the increased risk George and her team found for second-hand smoke "surprisingly strong."
Scientific abstract:
BACKGROUND: Studies of exposure to environmental tobacco smoke (ETS) and risk of spontaneous abortion are limited to a few studies of self-reported exposure, and the results have been inconsistent. The aim of this study was to investigate risk of early spontaneous abortion related to ETS and active smoking as defined by plasma cotinine levels. METHODS: We conducted a population-based case-control study in Uppsala County, Sweden, between January 1996 and December 1998. Cases were 463 women with spontaneous abortion at 6 to 12 completed weeks of gestation, and controls were 864 pregnant women matched to cases according to the week of gestation. Exposure status was defined by plasma cotinine concentrations: nonexposed, <0.1 ng/mL; ETS-exposed, 0.1-15 ng/mL; and exposed to active smoking, >15 ng/mL. Multivariable analysis was used to estimate the relative risk of spontaneous abortion associated with exposure to ETS and active smoking. RESULTS: Nineteen percent of controls and 24% of cases were classified as having been exposed to ETS. Compared with nonexposed women, risk of spontaneous abortion was increased among both ETS-exposed women (adjusted odds ratio = 1.67; 95% confidence interval = 1.17-2.38) and active smokers (2.11; 1.36-3.27). We could not show a differential effect of exposure to ETS or active smoking between normal and abnormal fetal karyotype abortions. CONCLUSIONS: Nonsmoking pregnant women exposed to ETS may be at increased risk of spontaneous abortion. Given the high prevalence of ETS exposure, the public health consequences of passive smoking regarding early fetal loss may be substantial.
Study Synopsis: Alaskan Native women living in villages with open dumpsites were more likely to have adverse birth outcomes. Low birth weight and intrauterine growth retardation were approximately 2 and 4 times, respectively, more likely in 'high hazard villages.'
Scientific abstract:
This retrospective cohort study evaluated adverse birth outcomes in infants whose birth records indicated maternal residence in villages containing dumpsites potentially hazardous to health and environment. Birth records from 1997 to 2001 identified 10,073 eligible infants born to mothers in 197 Alaska Native villages. Outcomes included low or very low birth weight, preterm birth, and intrauterine growth retardation. Infants from mothers in villages with intermediate (odds ratio (OR) = 1.73, 95% confidence interval (CI): 1.06, 2.84) and high (OR = 2.06, 95% CI: 1.28, 3.32) hazard dumpsites had a higher proportion of low birth weight infants than did infants from mothers in the referent category. More infants born to mothers from intermediate (OR = 4.38, 95% CI: 2.20, 8.77) and high (OR = 3.98, 95% CI: 1.93, 8.21) hazard villages suffered from intrauterine growth retardation. On average, infants weighed 36 g less (95% CI: -71.2, -0.8) and 55.4 g less (95% CI: -95.3, -15.6) when born to highly exposed mothers than did infants in the intermediate and low exposure groups, respectively, an effect even larger in births to Alaska Native mothers only. No differences in incidence were detected across exposure levels for other outcomes. This is the first study to evaluate adverse pregnancy outcomes associated with open dumpsites in Alaska Native villages.
Study Synopsis: Although 85 to 90% of couples or individuals who experience infertility have a diagnosis for their infertility, underlying causes of infertility rarely are found. Extensive literature reporting adverse effects of environmental contaminants on wildlife and laboratory animal reproductive tract development, and reproductive function and epidemiologic studies with humans, suggests that many environmental chemicals and heavy metals may contribute to infertility in people.
Scientific abstract:
Approximately 10 to 15% of the population experiences infertility. Although 85 to 90% of couples or individuals who experience infertility have a diagnosis for their infertility, underlying causes of infertility rarely are found. Extensive literature reporting adverse effects of environmental contaminants on wildlife and laboratory animal reproductive tract development, and reproductive function and epidemiologic studies with humans, suggests that many environmental chemicals and heavy metals may contribute to infertility. This article introduces the medical context in which infertility patients are evaluated and lays the foundation for health care professional and patient conversations, and medical education regarding environmental contaminants and human reproductive health for the future.
Study Synopsis: European scientists propose that interactions between genes and environment/lifestyle factors may make some individuals more susceptible to chemical exposures. There are significant differences in sperm counts, the incidence of testicular cancer and undescended testicles when comparing men from Denmark to men in Finland. Afro-Americans in the US have a much lower incidence of testicular cancer than Caucasians. It is unknown, but possible these differences are due to differnt genetic backgrounds.
Scientific abstract:
It has been hypothesized that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the so-called testicular dysgenesis syndrome (TDS). TDS was suggested to be a result of disruption of embryonal programming and gonadal development during foetal life and as aetiological factor, an impact of adverse environmental factors such as hormone disrupters, probably acting upon a susceptible genetic background, was suggested. Extensive studies considering the risk of TDS-related diseases in Denmark compared with Finland, showed higher sperm counts and lower risk of cryptorchidism and testicular cancer among Finns. However, when comparing these two populations, the question arises, to which degree this difference might be due to discrepancy in genetic background. A more obvious example of the impact of genetic factors on the risk of TDS concerns Afro-Americans having significantly lower incidence of testicular cancer when compared with Caucasians living in the USA. A yet unexplored scenario is a possible interaction between genetic and environmental/lifestyle-related factors, certain genotypes making individuals more susceptible to adverse exogenous exposures. Studying such interactions has biological, epidemiological and public health-related implications. It will help us to understand the background for the defects in male reproductive organs, facilitate proper design of epidemiological studies and add to identifying individuals susceptible to certain environmental and lifestyle-related hazards. Such 'susceptibility genes' need to be identified, those involved in the synthesis, action and metabolism of sex steroids being strong candidates.
Key Words: Comparative Study, Cryptorchidism/epidemiology/etiology, Environmental Exposure/adverse effects, Genetic Predisposition to Disease, Gonadal Dysgenesis/epidemiology/*ethnology/etiology/genetics, Humans, Hypospadias/epidemiology/etiology, Life Style, Male, Research Support, Non-U.S. Gov't, Semen/physiology, Testicular Diseases/*ethnology/etiology/genetics, Testicular Neoplasms/epidemiology/etiology, Testis/*abnormalities/drug effects
Study Synopsis: Anglers who eat fish caught in the lower Hudson River had blood mercury levels almost twice as high as those who never ate local fish. People eating local fish more than once a week had higher levels than those who ate them less frequently.
Scientific abstract:
The Hudson River has been a federally designated Superfund site for over 20 years. Discharges of industrial waste and of treated and untreated sewage and atmospheric deposition have introduced mercury and other persistent pollutants to the Hudson River ecosystem. Despite New York and New Jersey health advisories, many local anglers and their family members continue to consume fish caught from the river. To evaluate associations between body burden of mercury and local fish consumption, we conducted a cross-sectional study of 191 anglers recruited from piers and fishing clubs. Participants were administered a questionnaire to obtain information on local fish consumption, and 65% (124 individuals) provided a blood sample used to determine mercury levels. Mercury levels ranged from below the limit of detection (0.75 ng/mL) to 24.0 ng/mL. Participants who reported eating locally caught fish had significantly higher levels of mercury (mean (M)=2.4 ng/mL, standard error (SE)=1.2) than anglers who never ate locally caught fish (M=1.3 ng/mL, SE=1.1). A positive dose-response pattern was also observed, where participants who reported eating locally caught fish more than once a week had higher mercury levels (M=2.6 ng/mL, SE=1.1) than anglers eating fish less frequently (M=2.0 ng/mL, SE=1.2) or never at all (M=1.3 ng/mL, SE=1.1). These findings indicate that consumption of fish caught from the lower Hudson River area is a route of human exposure to mercury for the angling community.
Key Words: Animals, Body Burden*, Diet*, Fishes*, Humans, Mercury/pharmacokinetics*, New York, Water Pollutants-Chemical/pharmacokinetics*, Water Pollutants-Chemical, Mercury
Study Synopsis: For the first time at a national meeting of experts in endocrinology, the topic of endocrine disruption is discussed. On June 3, 2005, The Endocrine Society held an unprecedented full-day forum on endocrine-disrupting chemicals (EDCs). There were 3 major themes were recurrent at the forum. First, the timing of exposure to endocrine disruptors is critical to the outcome of that exposure, with fetal or early postnatal exposure being particularly detrimental. Second, EDCs often act at environmentally relevant doses. Third, effects of EDCs not only impact the exposed individual but may also be transmitted to subsequent generations.
Scientific abstract:
On June 3, 2005, the Endocrine Society held an unprecedented full-day "Forum on Endocrine Disrupting Chemicals." Sponsored through the generosity of the Endocrine Society, the NIEHS and the EPA, this Forum brought together basic scientists, physicians, clinicians, epidemiologists and others interested in discussing and learning about importance of endocrine disruption in the context of endocrinology. This month's Endocrinology contains a special series of eight review articles on endocrine disruption, seven of which are authored by the Forum's speakers, and the eighth providing an evolutionary perspective to epigenetics in endocrine disruption. As Forum organizers, the three of us developed and directed the programing, but more importantly, we have this opportunity to summarize and integrate the outcomes of the Forum for the Endocrine community. The review articles that follow this Introduction make it clear that the issue of endocrine disruption is pertinent to all endocrinologists. Moreover, a wide variety of endocrine-disrupting chemicals exist, such as industrial chemicals, pesticides, plant phytoestrogens, metals, and other environmental substances. Here, we provide an overview of the highlights of the science at the Forum, a synopsis of the open discussion, and we make recommendations for future research.
Grande SW, Andrade AJ, Talsness CE, Grote K, Chahoud I. A dose-response study following in utero and lactational exposure to di(2-ethylhexyl)phthalate: effects on female rat reproductive development. Toxicol Sci. 2006 May;91(1):247-54.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers exposed rats to different doses of diethylhexyl phthalate (DEHP), a commonly used phthalate plasticizer, during pregnancy and lactation. They found that high doses of DEHP caused delays in vaginal opening and age at first estrus (both indicators of puberty onset) in female offspring. The highest doses (135 and 405 mg/kg per day) also caused enlargement of the liver. Anogenital distance and nipple development were unaffected. These results show that pre- and early postnatal exposure to DEHP causes delays in puberty onset at doses of 15 mg/kg and higher in rats.
Scientific abstract:
Phthalates, a class of chemicals used as plasticizers, are economically important due to several industrial applications. Di(2-ethylhexyl)phthalate (DEHP) is the most commonly used phthalate plasticizer, and it has been described as a potent antiandrogen in males. We performed an extensive dose-response study following developmental exposure to DEHP and evaluated the effects on female reproductive development. Two wide ranges of doses that included dose levels relevant for human exposure as well as high doses typically used in toxicological studies were tested. Female Wistar rats were treated daily with DEHP and peanut oil (vehicle control) by gavage from gestation day 6 to lactation day 22. The low doses were 0.015, 0.045, 0.135, 0.405, and 1.215 mg DEHP/kg body weight (bw)/day, and the high doses were 5, 15, 45, 135, and 405 mg DEHP/kg bw/day. At the dose levels tested, no signs of maternal toxicity were observed. A significant delay in the age at vaginal opening (approximately 2 days) at 15 mg DEHP/kg bw/day and above, as well as a trend for a delay in the age at first estrus at 135 and 405 mg DEHP/kg bw/day (approximately 2 days), was observed. Liver enlargement (characteristic of phthalate exposure in rats) was limited to the 135- and 405-mg DEHP/kg bw/day doses. Anogenital distance and nipple development were unaffected. Based on the results of delayed pubertal onset, the no observed adverse effect level for female reproductive development may be set at 5 mg DEHP/kg bw/day.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers exposed female rats from weaning through their own pregnancy to daily doses of 0, 250, 500 or 1,000 mg/kg of dibutyl phthalate (DBP). Exposure to doses of 500 and 1,000 mg/kg, but not 250 mg/kg, caused midpregnancy abortions and decreased ovarian hormone production. Age at vaginal opening and first estrus, indicative of puberty onset, menstrual characteristics and fertility were not affected by exposure. These results suggest that exposure to high doses of DBP from weaning through gestation causes spontaneous abortions in rats.
Scientific abstract:
Testis function in fetal and peripubertal male rats is disrupted by subchronic exposure to phthalate esters (PEs). In contrast to the male rat, it is generally held that reproduction in female rats is much less sensitive to phthalate-induced disruption. However, the current study demonstrates that oral administration of dibutyl phthalate (DBP) to female Long Evans (LE) hooded rats from weaning, through puberty, mating, and gestation disrupts pregnancy maintenance at dose levels similar to those that affect testis function in male rats. Administration of 500 and 1000 mg DBP/kg/day, but not 250 mg DBP/kg/day, to female LE rats induced midpregnancy abortions. The percentage of females delivering live pups was reduced by more than 50% at 500 mg/kg/day and by 90% at 1000 mg/kg/day in the absence of overt toxicity, whereas the ages at vaginal opening and first estrus, estrous cyclicity, and mating indices (N mated/N paired or N pregnant/N mated) were not significantly affected. On gestational day 13, prior to the stage when litters were being aborted, ex vivo ovarian hormone production was significantly decreased by in vivo DBP treatment at 500 and 1000 mg/kg/day. These results should be considered when evaluating mechanisms of reproductive toxicity for the PE because it is likely that these reproductive alterations in the female rat arise via a mode of action similar to that operative in male rats.
Study Synopsis: The case for environmental anti-androgens altering male reproductive development continues to gather more evidence. Within the last decade, several classes of chemicals have been shown in laboratory studies to disrupt reproductive development by acting as androgen receptor (AR) antagonists and/or inhibitors of fetal Leydig cell testosterone production. New research has also revealed the presence of androgens in the environment. Effluents from pulp and paper mills and from beef cattle farms has androgenic activity.
Scientific abstract:
Summary: Within the last decade, several classes of chemicals have been shown in laboratory studies to disrupt reproductive development by acting as androgen receptor (AR) antagonists and/or inhibitors of fetal Leydig cell testosterone production. Some phthalate esters alter gubernacular differentiation by reducing insulin-like 3 (insl3) mRNA levels. We have found that AR antagonists and inhibitors of fetal testis hormone production generally induce cumulative, apparently dose-additive adverse effects when administered in mixtures. New research has also revealed the presence of androgens in the environment. Effluents from pulp and paper mills display androgenic activity of sufficient potency to masculinize and/or sex-reverse female fish. Effluent from beef cattle concentrated animal feedlot operations from the United States also displays androgenic activity in vitro, due, in part, to the presence of a steroid used to promote growth in beef cattle. In summary, we are only beginning to identify the classes of chemicals that have the potential to alter the androgen signalling pathway in utero. This review will (i) present information on the classes of environmental chemicals that display antiandrogenic and androgenic activities in vitro and in vivo, and (ii) provide an insight into how exposure to mixtures these chemicals might behave in utero.
Study Synopsis: Girls in a Mexican town imbedded in an agricultural zone with pesticide use have different patterns of breast development than those living nearby but with much less pesticide exposure. While there were no differences in a standard assessment of breast development, exposed girls had larger breasts for their stature but irregular relationship between breast size and mammary gland development. Less exposed girls showed a normal relationship.
Scientific abstract:
In several human populations, the age at which female breast development begins is reported to have declined over the last five decades. Much debate has occurred over whether this reported decline has actually occurred and what factors contribute to it. However, geographical patterns reflecting earlier developmental onset in some human populations suggest environmental factors influence this phenomenon. These factors include interactions between genetic makeup, nutrition, and possible cumulative exposure to estrogens, both endogenous as well as environmental beginning during in utero development. We examined the onset of breast development in a group of peripubertal girls from the Yaqui Valley of Sonora, Mexico. We observed that girls from valley towns, areas using modern agricultural practices, exhibited larger breast fields than those of girls living in the foothills who exhibited similar stature [e.g., weight, height, body mass index (BMI)], and genetic background. Further, girls from valley towns displayed a poorly defined relationship between breast size and mammary gland development, whereas girls from the Yaqui foothills, where traditional ranching occurs, show a robust positive relationship between breast size and mammary size. The differences noted were obtained by a medically based exam involving morphometric analysis and palpation of tissues, in contrast to visual staging alone. In fact, use of the Tanner scale, involving visual staging of breast development for puberty, detected no differences between the study populations. Mammary tissue, determined by palpation, was absent in 18.5% of the girls living in agricultural areas, although palpable breast adipose tissue was present. No relationship was seen between mammary diameter and weight or BMI in either population. These data suggest that future in-depth studies examining mammary tissue growth and fat deposition in breast tissue are required if we are to understand environmental influences on these phenomena.
The overall contribution of environmental exposures to infertility is unknown, but a growing scientific database suggests that exposure to various environmental factors, both in utero and neonatally, could dramatically affect adult fertility. Studies of various contaminant-exposed wildlife populations suggest that multiple mechanisms contribute to changes in gonadal development, maturation of germ cells, fertilization, and pregnancy; specifically, the endocrine processes supporting these events. Although great debate and extensive research has occurred during the last decade surrounding fertility, fecundity, and semen quality, much less work has focused on environmental alterations in oocyte development and maturation. Exposure of the developing ovary to estrogens, whether of pharmaceutical (e.g., diethylstilbesterol) or environmental (e.g., phytoestrogens, pesticides with estrogenic action) origin, can disrupt early oogenesis and folliculogenesis leading to a pathology termed the multioocytic follicle (polyovular follicle), which in rodents reduces fertilization and embryonic survival rates. The mechanism underlying this pathology is hypothesized to involve a disruption in the gonadotropin-estrogen-inhibin/activin signaling pathway. Given the conserved nature of vertebrate oogenesis and folliculogenesis, we suggest that perturbations of these phenomena in humans, caused by environmental contaminant exposure, could lead to altered fertility, as has been reported in wildlife and laboratory rodent models.
Study Synopsis: Descriptions of endocrine disruption have largely been associated with wildlife and driven by observations documenting estrogenic, androgenic, antiandrogenic, and antithyroid actions. These actions, in response to exposure to ecologically relevant concentrations of various environmental contaminants, have now been established in numerous vertebrate species. However, many potential mechanisms and endocrine actions have not been studied. In this paper, authors make the point that future studies should broaden the basic science approach to endocrine disruption, and expand the mechanisms and endocrine end points examined.
Scientific abstract:
Descriptions of endocrine disruption have largely been associated with wildlife and driven by observations documenting estrogenic, androgenic, antiandrogenic, and antithyroid actions. These actions, in response to exposure to ecologically relevant concentrations of various environmental contaminants, have now been established in numerous vertebrate species. However, many potential mechanisms and endocrine actions have not been studied. For example, the DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] metabolite, p,p -DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] is known to disrupt prostaglandin synthesis in the uterus of birds, providing part of the explanation for DDT-induced egg shell thinning. Few studies have examined prostaglandin synthesis as a target for endocrine disruption, yet these hormones are active in reproduction, immune responses, and cardiovascular physiology. Future studies must broaden the basic science approach to endocrine disruption, thereby expanding the mechanisms and endocrine end points examined. This goal should be accomplished even if the primary influence and funding continue to emphasize a narrower approach based on regulatory needs. Without this broader approach, research into endocrine disruption will become dominated by a narrow dogma, focusing on a few end points and mechanisms.
Study Synopsis: Smokeless tobacco use during pregnancy increases stillbirth risk, according to a cohort study in Mumbai, India. The increase in risk is at least as great as that associated with maternal cigarette smoking. Adjusting for multiple variables, the risk for users was increased 2.6 fold, and greater in earlier gestational ages.
Scientific abstract:
BACKGROUND: Maternal cigarette smoking has been causally associated with an increased risk for stillbirth. Preliminary reports suggest an increased risk for stillbirth with smokeless tobacco use during pregnancy. METHODS: We conducted a population-based prospective cohort study to investigate this association by using a house-to-house approach to recruit 1,217 women who were between 3 and 7 months' gestation. Of these, 96% were contacted after delivery to determine the pregnancy outcome. Demographic and maternal variables which were apparently associated either with stillbirth or with smokeless tobacco use (OR >or= 1.5) were included as potential confounders. Stillbirth was defined as any delivery of a dead fetus after 20 completed weeks of gestation. We used time-to-event methods to analyze the risk of stillbirth. RESULTS: Overall occurrence of stillbirth among singleton deliveries in this population was 4.1%. Smokeless tobacco use was reported by 17% of women; 8.9% of smokeless tobacco users had a stillbirth compared with 3.1% among nonusers (life-table adjusted hazard ratio = 3.1; 95% confidence interval = 1.7-5.6). After adjustment by the Cox proportional hazards procedure for age, educational and socioeconomic background, working status of mother, parity, prenatal care variables, and place of delivery, the risk for stillbirth in users was 2.6 (95% confidence interval-1.4-4.8). Most women used mishri (a pyrolyzed tobacco product often used as dentifrice), and there was a dose-response relationship between the daily frequency of use and stillbirth risk. The risk of stillbirth associated with smokeless tobacco use was greater in earlier gestational periods. CONCLUSIONS: Smokeless tobacco use during pregnancy increases stillbirth risk, with a risk at least as great as that associated with maternal cigarette smoking.
Study Synopsis: The human data on the relationship of semen quality with phthalate and pesticide exposure are limited and do not currently allow for a definitive conclusion on whether adult exposure, at background environmental levels, alters semen quality. However, the epidemiologic data support an inverse association of PCBs with reduced semen quality, specifically reduced sperm motility. The associations found were generally consistent across studies despite a range of PCB levels.
Scientific abstract:
Scientific and public concern about the potential risk of environmental chemicals to male reproductive health has been heightened by reports of downward trends in semen quality, as well as increased rates of developmental urogenital tract anomalies and testicular cancer. Of particular concern is whether some contemporary-use environmental chemicals alter semen quality. Specific toxicants of interest include phthalates and pesticides, as well as polychlorinated biphenyls (PCBs). The human data on the relationship of semen quality with phthalate and pesticide exposure are limited and do not currently allow for a definitive conclusion on whether adult exposure, at background environmental levels, alters semen quality. However, the epidemiologic data support an inverse association of PCBs with reduced semen quality, specifically reduced sperm motility. The associations found were generally consistent across studies despite a range of PCB levels. In addition to the chemicals discussed, there are additional classes of chemicals that require further study on their relation with human semen quality.
Study Synopsis: A large study of men in the Boston area finds that increases in a metabolite of the phthalate DBP are associated with impaired sperm quality, at exposure levels within the range experienced by the general population. Both sperm concentration and sperm motility were more likely to be beneath WHO reference levels at higher exposure levels to MBP, the metabolite. Metabolites of DEHP, DMB and BbZP were not associated with lowered sperm quality.
BACKGROUND: Phthalates are multifunctional chemicals used in a variety of consumer, medical, and personal care products. Previously, we reported dose-response associations of decreased semen quality with urinary concentrations of monobutyl phthalate (MBP) and monobenzyl (MBzP) phthalate, which are metabolites of dibutyl phthalate and butylbenzyl phthalate, respectively. The present study extends our work in a larger sample of men and includes measurements of di(2-ethylhexyl) phthalate (DEHP) oxidative metabolites. METHODS: Between January 2000 and May 2004, we recruited 463 male partners of subfertile couples who presented for semen analysis to the Massachusetts General Hospital. Semen parameters were dichotomized based on World Health Organization reference values for sperm concentration (<20 million/mL) and motility (<50% motile) and the Tygerberg Kruger Strict criteria for morphology (<4% normal). The comparison group was men with all 3 semen parameters above the reference values. In a single spot urine sample from each man, phthalate metabolites were measured using solid-phase extraction coupled to high-performance liquid chromatography isotope-dilution tandem mass spectrometry. RESULTS: There were dose-response relationships of MBP with low sperm concentration (odds ratio per quartile adjusted for age, abstinence time, and smoking status = 1.00, 3.1, 2.5, 3.3; P for trend = 0.04) and motility (1.0, 1.5, 1.5, 1.8; P for trend = 0.04). There was suggestive evidence of an association between the highest MBzP quartile and low sperm concentration (1.00, 1.1, 1.1, 1.9; P for trend = 0.13). There were no relationships of monoethyl phthalate, monomethyl phthalate, and the DEHP metabolites with these semen parameters. CONCLUSION: The present study confirms previous results on the relationship of altered semen quality with exposure to MBP at general population levels. We did not find associations between semen parameters and 3 DEHP metabolites.
Hauser R, Meeker JD, Duty S, Silva MJ, Calafat AM. Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology. 2006 Nov;17(6):682-91.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers recruited 463 male partners of subfertile couples who presented for semen analysis to the Massachusetts General Hospital between January 2000 and May 2004. The concentration of phthalate residues was measured in men's urine. Men with higher urine concentration of a residue called monobutyl phthalate (MBP) were more likely to have low sperm concentration and motility. Those in the highest quartile of MBP had 3-fold increased odds of low sperm concentration and 80% higher odds of low sperm motility relative to men with low urine levels. These results suggest that urine levels of MBP are related with impaired semen quality in subfertile couples.
Scientific abstract:
BACKGROUND: Phthalates are multifunctional chemicals used in a variety of consumer, medical, and personal care products. Previously, we reported dose-response associations of decreased semen quality with urinary concentrations of monobutyl phthalate (MBP) and monobenzyl (MBzP) phthalate, which are metabolites of dibutyl phthalate and butylbenzyl phthalate, respectively. The present study extends our work in a larger sample of men and includes measurements of di(2-ethylhexyl) phthalate (DEHP) oxidative metabolites. METHODS: Between January 2000 and May 2004, we recruited 463 male partners of subfertile couples who presented for semen analysis to the Massachusetts General Hospital. Semen parameters were dichotomized based on World Health Organization reference values for sperm concentration (<20 million/mL) and motility (<50% motile) and the Tygerberg Kruger Strict criteria for morphology (<4% normal). The comparison group was men with all 3 semen parameters above the reference values. In a single spot urine sample from each man, phthalate metabolites were measured using solid-phase extraction coupled to high-performance liquid chromatography isotope-dilution tandem mass spectrometry. RESULTS: There were dose-response relationships of MBP with low sperm concentration (odds ratio per quartile adjusted for age, abstinence time, and smoking status = 1.00, 3.1, 2.5, 3.3; P for trend = 0.04) and motility (1.0, 1.5, 1.5, 1.8; P for trend = 0.04). There was suggestive evidence of an association between the highest MBzP quartile and low sperm concentration (1.00, 1.1, 1.1, 1.9; P for trend = 0.13). There were no relationships of monoethyl phthalate, monomethyl phthalate, and the DEHP metabolites with these semen parameters. CONCLUSION: The present study confirms previous results on the relationship of altered semen quality with exposure to MBP at general population levels. We did not find associations between semen parameters and 3 DEHP metabolites.
Study Synopsis: Even with access to prenatal care, minority women experience higher rates of perinatal loss of pregancy. All minorities experienced higher rates of intrauterine growth restriction, preterm birth, very preterm birth, cesarean delivery, light vaginal bleeding and heavy vaginal bleeding compared with the white population. Overall adjusted odds ratio, compared to whites, were 3.5 (black), 1.5 (Hispanic) and 1.9 (other).
Scientific abstract:
OBJECTIVE: To investigate racial disparities in perinatal mortality in women with early access to prenatal care. METHODS: A prospectively collected database from a large, multicenter investigation of singleton pregnancies, the FASTER trial, was queried. Patients were recruited from an unselected obstetric population between 1999 and 2002. A total of 35,529 pregnancies with early access to prenatal care were reviewed for this analysis. The timing of perinatal loss was assessed. The following intervals were evaluated: fetal demise at less than 24 weeks of gestation, fetal demise at 24 or more weeks of gestation, and neonatal demise. Perinatal mortality was defined as the sum of these three intervals. RESULTS: The study population was 5% black, 22% Hispanic, 68% white, and 5% other. All minority races experienced higher rates of intrauterine growth restriction, preeclampsia, preterm premature rupture of membranes, gestational diabetes, placenta previa, preterm birth, very-preterm birth, cesarean delivery, light vaginal bleeding, and heavy vaginal bleeding compared with the white population. Overall perinatal mortality was 13 per 1,000 (471/35,529). The adjusted odds ratios (95% confidence intervals) for perinatal mortality (utilizing the white population as the referent race) were: black 3.5 (2.5-4.9), Hispanic 1.5 (1.2-2.1), and other 1.9 (1.3-2.8). CONCLUSION: Racial disparities in perinatal mortality persist in contemporary obstetric practice despite early access to prenatal care. LEVEL OF EVIDENCE: II-2
Heilier JF, Donnez J, Verougstraete V, Donnez O, Grandjean F, Haufroid V, Nackers F, Lison D. Cadmium, lead and endometriosis. Int Arch Occup Environ Health. 2006 Nov;80(2):149-53.
Study Synopsis: A case-control study of endometriosis patients finds no association between levels of cadmium and disease and a weak association with lead exposure. Neither urinary nor blood cadmium levels were found to be associated with endometriosis. Women with endometriosis had lower levels of blood lead than controls.
Scientific abstract:
Objectives: Cadmium (Cd) and lead (Pb) have been demonstrated to exert endocrine disrupting activities. Their possible role in endometriosis, an oestrogen-dependent disease, is unknown. Methods: We compared cadmium urinary excretion (CdU) and blood concentration of cadmium (CdB) and lead (PbB) in 119 patients with peritoneal endometriosis and/or deep endometriotic (adenomyotic) nodules of the rectovaginal septum and 25 controls. Results: The mean levels of cadmium in urine and blood did not differ among the groups. Women suffering from endometriotic diseases showed lower levels of PbB than controls. Conclusions: These data do not support a role for cadmium in the onset or the growth of endometriotic diseases but suggest a possible relationship with lead.
Study Synopsis: A paradigm shift is underway in science, pointing to fetal and early postnatal periods as vital to adult health. This new framework hypothesizes that exposure to environmental stressors/toxicants in utero or during early development alters susceptibility to disease later in life, and can affect reproductive health.
Scientific abstract:
There is a paradigm shift in science at present that indicates that the onset of many diseases, including reproductive diseases and dysfunctions, are already programmed in utero or in the early postnatal period. This new field is called the developmental basis of health and disease. Although focus has been on the role of in utero nutrition and its effects on subsequent adult-onset diseases, it is clear that exposure to environmental stressors/toxicants in utero or during early development can also increase susceptibility to disease later in life. The mechanism for this in utero and early developmental effect is thought to be altered epigenetic control of gene expression, which alters developmental programming and results in a tissue that may appear normal but is functionally compromised. Although this concept is still a hypothesis, this review addresses the current state of data relating to proving its importance and role in reproductive diseases. If the developmental basis of disease is shown to be true, then examination of the etiology of disease and prevention and intervention strategies will need to be modified to fit the new paradigm.
Study Synopsis: A review of data in the US indicates that girls are reaching puberty at an earlier age. The average age of onset of menses for African-American girls occurs at 12.1 and for Caucasian girls at 12.6 years. Compared to statistics from 25 years ago, this is about 5 months earlier in black girls and 3 months earlier in whites. The average age of breast development is occurring 1-2 years earlier. Although there are less data, there is also evidence that boys are reaching puberty at earlier ages. Better nutrition and childhood obesity may be contributing to some of the change but exposure to endocrine disruptors must also be considered.
Scientific abstract:
Tracking secular trends in the pubertal development of a country's children is important for social and public health reasons. Although comparable studies are largely lacking for US children over the last half century, existing data on girls, particularly that for menarche, indicate that the trend for earlier sexual maturatin has continued and that racial differences are significant, with African-American girls developing earlier than white girls. Data on boys, though less reliable, suggest that they may be beginning maturation earlier as well. More studies on boys with reliable methodologies are needed. Earlier development may not be healthy and may indicate environmental problems that need to be further researched and addressed.
Key Words: African Continental Ancestry Group, Child, Comparative Study, European Continental Ancestry Group, Female, Humans, Male, Menarche, *Puberty, Puberty, Precocious, Retrospective Studies, Sex Characteristics, Sex Factors, Sexual Maturation/*physiology, United States
Study Synopsis: Early life exposure to bisphenol A at environmentally-relevant levels causes neoplastic (cancerous) lesions in the prostates of adult rats, linking BPA to prostate cancer. Animals exposed perinatally to BPA and estradiol develop prostate lesions in adulthood called high-grade PIN that are generally accepted as an early stage of prostate cancer in people. For BPA, the effect requires changes in adult hormone levels that mirror estrogen changes in ageing men. The effects are associated with failures in a key gene to undergo hypermethylation, following perinatal exposure.
Early developmental perturbations have been linked to adult-onset prostate pathology, including excessive exposure to estrogenic compounds; however, the molecular basis for this imprinting event is not known. An important and controversial health concern is whether low-dose exposures to hormonally active environmental estrogens, such as bisphenol A, can promote human diseases, including prostate cancer. Here, we show that transient developmental exposure of rats to low, environmentally relevant doses of bisphenol A or estradiol increases prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis. We found permanent alterations in the DNA methylation patterns of multiple cell signaling genes, suggesting an epigenetic basis for estrogen imprinting. For phosphodiesterase type 4 variant 4 (PDE4D4), an enzyme responsible for cyclic AMP breakdown, a specific methylation cluster was identified in the 5'-flanking CpG island that was gradually hypermethylated with aging in normal prostates, resulting in loss of gene expression. Early and prolonged hypomethylation at this site following neonatal estradiol or bisphenol A exposure resulted in continued, elevated PDE4D4 expression. Cell line studies confirmed that site-specific methylation is involved in transcriptional silencing of the PDE4D4 gene and showed hypomethylation of this gene in prostate cancer cells. Importantly, the PDE4D4 alterations in the estrogen-exposed prostates were distinguishable before histopathologic changes of the gland, making PDE4D4 a candidate molecular marker for prostate cancer risk assessment as a result of endocrine disruptors. In total, these findings indicate that low-dose exposures to ubiquitous environmental estrogens affect the prostate epigenome during development and, in so doing, promote prostate disease with aging.
Study Synopsis: A study of all women registered in Denmark as working hairdressers does not find an increased risk of infertility. This study might not reveal small risks in the entire group or high risks in small subgroups. Several chemical exposures in the work environment have been hypothesized to affect female reproduction, and some are present in products used in hairdressing and related trades.
Scientific abstract:
BACKGROUND: One in seven married couples is involuntarily infertile. Several chemical exposures in the work environment have been hypothesized to affect female reproduction, and some are present in products used in hairdressing and related trades. Recent Swedish findings indicate that employment in hairdressing poses a risk for female reproductive function. This study examined the possible association between work as a hairdresser and subsequent hospital contact due to female infertility. METHODS: A cohort of all women in Denmark aged 20-44 years on 1 January 1998 (baseline) and registered as economically active hairdressers, according to national registers, was formed to calculate age-standardized risk ratios (RRs) for hospital contacts due to female infertility during a 5-year follow-up period. Hairdressers were compared to a standard population, that is, all economically active women in Denmark aged 20-44 years at baseline, and to women working as shop assistants. RESULTS: Sixty-eight cases of hospital contact due to female infertility were observed among the female hairdressers. On the basis of the standard population, the expected number was 73.27, which gives an observed RR of 0.928 (95% CI: 0.72-1.18). Hairdressers and shop assistants exhibited similar rates of hospital contact due to female infertility (1.01; 95% CI: 0.77-1.29). CONCLUSION: The findings are not corroborating the hypothesis that hairdressers are at increased risk of infertility, but small risks in the entire group or high risks in small subgroups may not be detected by the study.
Study Synopsis: Scientists calculate that health standards will be exceeded with more than one meal of farmed salmon from northern Europe every 5 months. The cancer advisories are driven by nondioxin-like PCBs and pesticides but not by dioxins or dioxin-like PCBs. Salmon farmed in North and South America trigger advisories with half to one meal per month.
Scientific abstract:
The levels of dioxins/furans, polychlorinated biphenyls (PCBs), and chlorinated pesticides were determined in farmed salmon for eight regions in Europe, North America, and South America, in salmon fillets purchased in 16 cities in Europe and North America, and in five species of wild Pacific salmon. Upon application of US Environmental Protection Agency (USEPA) methods for developing fish consumption advisories for cancer from mixtures of all of these substance for which USEPA has reported a cancer slope factor, the most stringent recommendation, for farmed salmon from northern Europe, was for consumption of at most one meal every 5 months in order to not exceed an elevated risk of cancer of more than 1 in 100,000. Farmed salmon from North and South America triggered advisories of between 0.4 and one meal per month. Retail market samples, in general, reflected levels found in regionally farmed fish, although much of the US salmon comes from Chile, which had somewhat lower contaminant levels than the North American farmed samples. Upon consideration of all of these organochlorine compounds as a mixture, even wild Pacific salmon triggered advisories of between one and less than five meals per month. The advisories are driven by the non-dioxin-like PCBs and pesticides and not by dioxins/furans and coplanar PCBs. For noncancer effects for contaminants where USEPA has provided a reference dose only endrin and PCBs triggered any significant advisory. For both of these in the worst case, farmed salmon from northern Europe, the advice was not more than three meals per month.
Key Words: Animals, Diet*, Dioxins/toxicity, Europe/epidemiology, Furans/toxicity, Gas Chromatography-Mass Spectrometry, Neoplasms/epidemiology*, North America, Pesticides/toxicity, Polychlorinated Biphenyls/toxicity, Salmon*, Water Pollutants-Chemical/toxicity, Dioxins, Furans, Pesticides, Polychlorinated Biphenyls, Water Pollutants-Chemical
Iwamoto T, Nozawa S, Yoshiike M, Hoshino T, Baba K, Matsushita T, Tanaka SN, Naka M, Skakkebaek NE, Jørgensen N. Semen quality of 324 fertile Japanese men. Hum Reprod. 2006 Mar;21(3):760-5.
Study Synopsis: A study comparing semen characteristics in Japan reports sperm quality in the Yokohama area is similar to that of Danish men, who are reported to have among the poorest in Europe. The cause for the low quality is unknown and may be due to lifestyle or other environmental factors. Ethnic differences cannot be ruled out by this study.
Scientific abstract:
BACKGROUND: A number of studies have indicated regional differences in semen quality. To examine the current status in Japan, we undertook a cross-sectional study on the semen quality of fertile Japanese men for comparison with recent European results. METHODS: Semen parameters of 324 fertile men from the Kawasaki/Yokohama area were investigated. The semen parameters were compared with those published for fertile men from four European cities, Copenhagen, Paris, Edinburgh and Turku. RESULTS: When adjusting for confounders such as ejaculation abstinence period and age, the lowest sperm concentrations were detected in men from Kawasaki/Yokohama followed by men from Copenhagen, Paris, Edinburgh and Turku, but only the differences between men from Kawasaki/Yokohama and men from Edinburgh and Turku were significant (P=0.0008 and P<0.0001, respectively). Total sperm count, percentage of motile sperm and percentage of normal sperm observed in Kawasaki/Yokohama were significantly lower than those from all European centres except for motile sperm in men from Paris. CONCLUSIONS: Japanese fertile men had a semen quality at the level of Danish men, who have been reported to have the lowest among investigated men in Europe. The low level of semen quality of the fertile Japanese men may be due to lifestyle or other environmental factors; however, ethnic differences caused by different genetic variation or combinations cannot be ruled out by this study.
Dichlorodiphenyltrichloroethane (DDT) is a persistent organochlorine compound found worldwide that causes significant anatomical, physiological and behavioural abnormalities in humans and wildlife. However, little is known about whether environmental exposure to DDT affects the brain. Here, we show that environmental exposure to DDT alters the brains of American Robins (Turdus migratorius) in several ways. Increasing levels of DDT resulted in: (i) smaller brain and relative forebrain volumes; (ii) a reduction in the size of two song nuclei, nucleus robustus arcopallialis (RA) and HVC; and (iii) a drastic reduction in neuronal size and overall volume of nucleus intercollicularis (ICo), a structure that is critical for normal sexual behaviour. These changes likely result from stress, direct neurotoxicity and androgen receptor antagonism by the primary metabolite of DDT, p,p'-DDE and this is corroborated by analyses of brain region volumes and p,p'-DDE levels. Our results therefore demonstrate that environmental exposure to DDT is correlated with significant changes in the brain and specifically those structures related to mating and song. Given the magnitude of these changes in the brain and the fact that environmental DDT exposure was restricted to early development, we conclude that both humans and wildlife that live in DDT contaminated environments may be at risk of neurological damage.
Study Synopsis: The study showed that genistein caused alterations to the, ovaries during early development, which is partly responsible for the, reproductive problems found in adult mice." Female mice were injected with three different doses of genistein during, their first five days of life. The genistein given to the mice was, comparable to what human infants might receive in a soy-based formula, which is approximately 6-9 mg/kg per day. The researchers examined the effects on days 2 through 6.
Scientific abstract:
Early in ovarian differentiation, female mouse germ cells develop in clusters called oocyte nests or germline cysts. After birth, mouse germ cell nests break down into individual oocytes that are surrounded by somatic pregranulosa cells to form primordial follicles. Previously, we have shown that mice treated neonatally with genistein, the primary soy phytoestrogen, have multi-oocyte follicles (MOFs), an effect apparently mediated by estrogen receptor 2 (ESR2, more commonly known as ERbeta). To determine if genistein treatment leads to MOFs by inhibiting breakdown of oocyte nests, mice were treated neonatally with genistein (50 mg/kg per day) on Days 1-5, and the differentiation of the ovary was compared with untreated controls. Mice treated with genistein had fewer single oocytes and a higher percentage of oocytes not enclosed in follicles. Oocytes from genistein-treated mice exhibited intercellular bridges at 4 days of age, long after disappearing in controls by 2 days of age. There was also an increase in the number of oocytes that survived during the nest breakdown period and fewer oocytes undergoing apoptosis on Neonatal Day 3 in genistein-treated mice as determined by poly (ADP-ribose) polymerase (PARP1) and deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end-labeling (TUNEL). These data taken together suggest that genistein exposure during development alters ovarian differentiation by inhibiting oocyte nest breakdown and attenuating oocyte cell death.
Summary: For many years it has been acknowledged that Danish and Norwegian men have one of the highest risks in the world for testicular cancer in sharp contrast to neighbouring Baltic men from Finland, Estonia and Lithuania. As an association between poor semen quality and testicular cancer has been established, it was suggested that men from high-risk testicular cancer areas would be more likely to have poor semen quality. However, previous studies were not able to elucidate this question due to their retrospective nature. In prospectively designed and strictly controlled studies of fertile men, the existence of regional differences in semen quality was confirmed. In addition, studies of men from the general populations were undertaken and a similar regional difference in semen quality was detected. Men from the eastern part of the Nordic-Baltic area had better semen quality than men from the western part. These findings parallel the incidence of testicular cancer in these regions. Approximately 20% of young men from Norway and Denmark had sperm concentrations below the World Health Organization reference level of 20 x 106 spermatozoa/mL, and approximately 40% had <40 x 106 spermatozoa/mL which, according to recent publications, may be the 'threshold' below which fecundity declines. In Denmark, the situation is of concern and a continued surveillance of semen quality in young men was established in 2001 by a government-supported programme.
Study Synopsis: The average ages of breast development and first menses in Danish girls has remained unchanged for the past 30 years and is about one year later than in US girls. Obesity plays a role in the timing of puberty, but the marked differences between Denmark and USA cannot be attributed exclusively to these differences. Other factors like genetic polymorphisms, nutrition, physical activity or endocrine disrupting chemicals must therefore also be considered.
Scientific abstract:
Two recent epidemiological studies (PROS and NHANES III) from the USA noted earlier sexual maturation in girls, leading to increased attention internationally to the age at onset of puberty. We studied the timing of puberty in a large cohort of healthy Danish children in order to evaluate differences between USA and Denmark, as well as to look for possible secular trends in pubertal development. Healthy Caucasian children from public schools in Denmark participated in the study which was carried out in 1991-1993. A total number of 826 boys and 1,100 girls (aged 6.0-19.9 years) were included, and pubertal stages were assessed by clinical examination according to methods of Tanner. In boys testicular volume was determined using an orchidometer. We found that age at breast development 2 (B2) was 10.88 years, and mean menarcheal age was 13.42 years. Girls with body mass index (BMI) above the median had significantly earlier puberty (age at B2 10.42 years) compared with girls with BMI below the median (age at B2 11.24 years, p < 0.0001). Similarly, menarcheal age was significantly lower in girls with BMI above the median compared with girls with BMI below the median (13.12 vs. 13.70 years, p = 0.0012). In Danish boys we found that age at genital stage 2 (G2) was 11.83 years. Both sexes were significantly taller compared with data from 1964, but timing of pubertal maturation seemed unaltered. Finally, puberty occurred much later in Denmark compared with recent data from USA. We could not detect any downwards secular trend in the timing of puberty in Denmark between 1964 and 1991-1993 as seen in the US. Obesity certainly plays a role in the timing of puberty, but the marked differences between Denmark and USA cannot be attributed exclusively to differences in BMI. A possible role of other factors like genetic polymorphisms, nutrition, physical activity or endocrine disrupting chemicals must therefore also be considered. Therefore, we believe it is crucial to monitor the pubertal development closely in Denmark in the coming decades.
Key Words: Adolescent, Adult, Body Height, Body Mass Index, Body Weight, Child, Cohort Studies, Comparative Study, Denmark, Europe, European Continental Ancestry Group, Female, Humans, Male, Menarche, *Puberty, Reference Standards, Retrospective Studies, Sexual Maturation/*physiology, United States, Urban Population
Study Synopsis: In patients undergoing fertility procedures, marijuana use in both partners was associatd with poorer outcomes. Women smoking marijuana 1 year before IVF/GIFT had 25% fewer oocytes retrieved, whereas couples had 28% fewer oocytes fertilized. Women and men who smoked in the past 15 years, had 12% and 16% smaller infants, respectively.
Scientific abstract:
OBJECTIVE: This study was undertaken to examine whether marijuana use affects in vitro fertilization and gamete intrafallopian transfer (IVF/GIFT). STUDY DESIGN: Prospective study of 221 IVF/GIFT couples. RESULTS: Amount of lifetime heavy marijuana use adversely affected IVF/GIFT. Women smoking more than 90 times in their lifetime had 27% fewer oocytes retrieved (P = .03) and 1 fewer embryo transferred (P < .05). Women smoking marijuana more than 10 times in their lifetime had infants 17% (P = .01) smaller at birth. If men smoked marijuana 11 to 90 times in their lifetime, there was a 15% decrease in infant birth weight (P = .03); if this increased to more than 90 times, there was a 23% decrease (P = .01). Timing also played a role. Women smoking marijuana 1 year before IVF/GIFT had 25% fewer oocytes retrieved (P = .03), whereas couples had 28% (P = .04) fewer oocytes fertilized. Women and men who smoked in the past 15 years, had 12% (P = .04) and 16% (P = .03) smaller infants, respectively. CONCLUSION: Both timing and amount of marijuana use negatively affected IVF/GIFT.
Study Synopsis: Is increasing exposure to phthalate plasticizers linked to unprecedented declines in fertility rates and semen quality that have been observed in people during the 2nd half of the 20th century? The general population is exposed through consumer products, as well as via diet and medical treatments. Animal studies have generated concern about possible adverse effects on people.
Scientific abstract:
Phthalates have been used as additives in industrial products since the 1930s, and are universally considered to be ubiquitous environmental contaminants. The general population is exposed to phthalates through consumer products, as well as diet and medical treatments. Animal studies showing the existence of an association between some phthalates and testicular toxicity have generated public and scientific concern about the potential adverse effects of environmental changes on male reproductive health. In particular, prenatal exposure to phthalates seems to play a relevant role in determining these adverse effects given that human exposure has been demonstrated to begin during the intrauterine life. Unprecedented declines in fertility rates and semen quality of antenatal origin have been reported during the last half of the 20th century in developed countries and increasing interest exists on the potential relationship between exposure to environmental contaminants, including phthalates, and human male reproductive health. Here we review the data that support or discounts the evidence existing to date linking phthalate exposure and the decline of human male fertility, especially in developed countries.
Study Synopsis: Carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2) and particulate matter (PM) are common air pollutants. They are part of the 6 so-called "criteria" air pollutants that the Environmental Protection Agency (EPA) is required to regulate under the Clean Air Act. In the current study, researchers estimated exposure to these 4 pollutants in 52,113 pregnant women based on geographic information systems. They found that women in the highest quartile of exposure to CO in their first trimester of pregnancy had 26% increased risks of preterm delivery. Higher exposure to NO2, SO2 and PM were related with 24%, 21% and 27% increased risks of preterm delivery. Significant associations were also found with exposure to air pollutants during the third trimester of pregnancy. These results suggest that exposure to air pollution during pregnancy may be related with an increased risk of premature births.
Scientific abstract:
The association between preterm delivery (PTD) and exposure to air pollutants has recently become a major concern. We investigated this relationship in Incheon, Republic of Korea, using spatial and temporal modeling to better infer individual exposures. The birth cohort consisted of 52,113 singleton births in 2001-2002, and data included residential address, gestational age, sex, birth date and order, and parental age and education. We used a geographic information system and kriging methods to construct spatial and temporal exposure models. Associations between exposure and PTD were evaluated using univariate and multivariate log-binomial regressions. Given the gestational age, birth date, and the mother's residential address, we estimated each mother's potential exposure to air pollutants during critical periods of the pregnancy. The adjusted risk ratios for PTD in the highest quartiles of the first trimester exposure were 1.26 [95% confidence interval (CI), 1.11-1.44] for carbon monoxide, 1.27 (95% CI, 1.04-1.56) for particulate matter with aerodynamic diameter < or = 10 microm, 1.24 (95% CI, 1.09-1.41) for nitrogen dioxide, and 1.21 (95% CI, 1.04-1.42) for sulfur dioxide. The relationships between PTD and exposures to CO, NO2, and SO2 were dose dependent (p < 0.001, p < 0.02, p < 0.02, respectively) . In addition, the results of our study indicated a significant association between air pollution and PTD during the third trimester of pregnancy. In conclusion, our study showed that relatively low concentrations of air pollution under current air quality standards during pregnancy may contribute to an increased risk of PTD. A biologic mechanism through increased prostaglandin levels that are triggered by inflammatory mediators during exposure periods is discussed.
Study Synopsis: Top obstetricians and gynecologists call for a 21st century research agenda on polycystic ovarian syndrome (PCOS). PCOS is a poorly understood and characterized disease that is associated with infertility. Developing better criteria for the disease would improve diagnosis and improve research on this disease. Laboratory research that informs clinical care and that involves a number of scientific disciplines is necessary for progress to be made in preventing this disorder.
Scientific abstract:
Notwithstanding the significant progress made in our understanding of polycystic ovary syndrome (PCOS), the field remains ripe for further discovery and more intensive translational research. Immediate priorities include developing evidence-based criteria for diagnosing PCOS and for assessing the response to the various treatments available. The basis for the identification of PCOS remains mainly expert opinion, and the lack of universally accepted evidence-based criteria limits the generalizability of research studies on PCOS. Additional important areas requiring intensive investigation include the natural history and etiology and the long-term sequelae and prevention of the disorder. Overall, this disorder is a prototype for the benefits of translational science and a transdisciplinary approach to understanding the pathophysiology and therapy for anovulatory infertility.
Study Synopsis: Direct measurements of chlorination byproducts in a municipal water supply reveal that levels in water above 70 ¦g/liter during the second trimester are associated with lower birth weight. The increased risk of low birth weight among minority women was almost double that of white women, 60% vs. 37% increase, respectively.
Scientific abstract:
Research has suggested that trihalomethane exposures during pregnancy might impair fetal growth. Most epidemiologic studies, however, relied on relatively crude exposure assessment methods and did not examine racial/ethnic subgroups. During 1999-2001, vital records data were obtained for a large, racially diverse population residing in 27 Massachusetts communities that received drinking water from a single public utility. The water system was monitored weekly for trihalomethanes and, system-wide, it maintained geographically stable total trihalomethane levels during the study period. The authors examined the effects of trimester-specific and pregnancy average exposures to total trihalomethane in drinking water on term low birth weight in all singleton births. A high average total trihalomethane exposure (> or = 70 microg/liter) during the second trimester increased the risk of term low birth weight (odds ratio = 1.50, 95% confidence interval (CI): 1.07, 2.10). The estimated risk increase for Caucasians during the second trimester was 37% (95% CI: 0.80, 2.36), while for all minority women combined (i.e., African Americans, Hispanics, and Asians) it was 60% (95% CI: 1.03, 2.47). The study data suggest that high levels (> or = 70 microg/liter) of trihalomethanes experienced during the second trimester and pregnancy overall may affect fetal growth.
Study Synopsis: Prenatal exposure to the flame retardant, pentabromodiphenyl ether (PBDE-99) interferes with sexual development in studies of rats. Exposed male rats had significantly decreased levels of sex hormones, decreased ano-genital distance, and alterations in the onset of puberty. Females had less severe effects with an overall reduction in the number of eggs in the ovary. These results support the hypothesis that PBDEs are endocrine-active compounds and interfere with sexual development.
Scientific abstract:
Increasing concentrations of polybrominated flame retardants, including polybrominated diphenyl ethers (PBDEs), in breast milk cause concern about possible developmental effects in nursed babies. Because previous studies in rats have indicated effects on sex steroids and sexually dimorphic behavior after maternal exposure to polychlorinated biphenyls (PCBs), our goal in the present study was to determine if developmental exposure to 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) induces similar endocrine-mediated effects. Pregnant rats were exposed to vehicle or PBDE-99 (1 or 10 mg/kg body weight, daily during gestational days 10-18). For comparison, we also included a group exposed to the technical PCB mixture Aroclor 1254 (30 mg/kg body weight, daily). PBDE exposure resulted in pronounced decreases in circulating sex steroids in male offspring at weaning and in adulthood. Female offspring were less affected. Anogenital distance was reduced in male offspring. Puberty onset was delayed in female offspring at the higher dose level, whereas a slight acceleration was detected in low-dose males. The number of primordial/primary ovarian follicles was reduced in females at the lower dose, whereas decline of secondary follicles was more pronounced at the higher dose. Sweet preference was dose-dependently increased in PBDE-exposed adult males, indicating a feminization of this sexually dimorphic behavior. Aroclor 1254 did not alter sweet preference and numbers of primordial/primary and secondary follicles but it did affect steroid concentrations in males and sexual development in both sexes. PBDE concentrations in tissues of dams and offspring were highest on gestational day 19. These results support the hypothesis that PBDEs are endocrine-active compounds and interfere with sexual development and sexually dimorphic behavior.
Lilienthal H, Hack A, Roth-Harer A, Grande SW, Talsness CE. Effects of developmental exposure to 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) on sex steroids, sexual development, and sexually dimorphic behavior in rats. Environ Health Perspect. 2006 Feb;114(2):194-201.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers administered different doses of the PBDE congener BDE-99 daily to pregnant rats over 9 days. Exposure to BDE-99 resulted in decreased testosterone in male offspring which lasted into adulthood. Anogenital distance, the distance between the anus and the genitalia, which is a marker of demasculinization, was also reduced in male offspring. In addition, onset of puberty was delayed in females exposed to the highest dose whereas a slight acceleration was found in males at low dose. The number of ovarian follicles, which are eggs in development, were reduced and sweet preference in males was increased by exposure, suggesting feminization. Results suggest that prenatal exposure to PBDEs interferes with sexual development and sex-based behavior.
Scientific abstract:
Increasing concentrations of polybrominated flame retardants, including polybrominated diphenyl ethers (PBDEs), in breast milk cause concern about possible developmental effects in nursed babies. Because previous studies in rats have indicated effects on sex steroids and sexually dimorphic behavior after maternal exposure to polychlorinated biphenyls (PCBs), our goal in the present study was to determine if developmental exposure to 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) induces similar endocrine-mediated effects. Pregnant rats were exposed to vehicle or PBDE-99 (1 or 10 mg/kg body weight, daily during gestational days 10-18). For comparison, we also included a group exposed to the technical PCB mixture Aroclor 1254 (30 mg/kg body weight, daily). PBDE exposure resulted in pronounced decreases in circulating sex steroids in male offspring at weaning and in adulthood. Female offspring were less affected. Anogenital distance was reduced in male offspring. Puberty onset was delayed in female offspring at the higher dose level, whereas a slight acceleration was detected in low-dose males. The number of primordial/primary ovarian follicles was reduced in females at the lower dose, whereas decline of secondary follicles was more pronounced at the higher dose. Sweet preference was dose-dependently increased in PBDE-exposed adult males, indicating a feminization of this sexually dimorphic behavior. Aroclor 1254 did not alter sweet preference and numbers of primordial/primary and secondary follicles but it did affect steroid concentrations in males and sexual development in both sexes. PBDE concentrations in tissues of dams and offspring were highest on gestational day 19. These results support the hypothesis that PBDEs are endocrine-active compounds and interfere with sexual development and sexually dimorphic behavior.
Key Words: Animals, Dose-Response Relationship, Drug, Female, Genitalia/drug effects/growth & development, Gonadal Steroid Hormones/blood, Halogenated Diphenyl Ethers, Male, Phenyl Ethers/ toxicity, Polybrominated Biphenyls/ toxicity, Pregnancy, Prenatal Exposure Delayed Effects, Rats, Rats, Long-Evans, Sex Characteristics, Sexual Behavior, Animal/ drug effects, Sexual Maturation/ drug effects
Study Synopsis: Danish scientists review recent findings on the multiple toxicities of phthalates in males. In one study, 5/6 phthalates in breast milk were associated with lower hormone levels. In a second study, elevated levels of 4 phthalates were associated with a reduction in ano-genital index (AGI). Furthermore, boys with small AGI showed a high prevalence of cryptorchidism and small genital size. Taken together these studies suggest an antivirilizing effect of phthalates in infants.
Scientific abstract:
Phthalates adversely affect the male reproductive system in animals, inducing hypospadias, cryptorchidism, reduced testosterone production and decreased sperm counts. Phthalate effects are much more severe after in utero than adult exposure. Little is known about human health effects. This study discusses two recent studies on perinatal phthalate exposure, which indicated that human testicular development might be susceptible to phthalates. One study analysed phthalate monoesters in breast milk and reproductive hormone levels in infants. Five of six phthalates [monoethyl-(MEP), monobutyl- (MBP), monomethyl- (MMP), mono-2-ethylhexyl- (MEHP) and mono-isononyl phthalate (MiNP)] showed correlation with hormone levels in healthy boys, which were indicative of lower androgen activity and reduced Leydig cell function. MEP and MBP were positively correlated with serum sex hormone-binding globulin (SHBG) levels. MMP, MEP, MBP, MEHP and MiNP were positively correlated with the LH/testosterone ratio. Another study found a reduction of the anogenital index (AGI) in infant boys with increasing levels of MBP, MEP, monobenzyl- and mono-isobutyl phthalate in maternal urine samples during late-pregnancy. Boys with small AGI showed a high prevalence of cryptorchidism and small genital size. Taken together these studies suggest an antivirilizing effect of phthalates in infants. Most of these findings are in line with animal observations. However, the possible effects of MEP appear to be limited to humans. This may be due to differences in exposure routes (inhalation and dermal absorption which circumvents liver detoxification in addition to oral) and metabolism, or this association could be spurious. As phthalates are produced as bulk chemicals worldwide, these new findings raise concern about the safety of phthalate exposure for pregnant women and infants.
Study Synopsis: New work by researchers at the Mount Sinai School of Medicine confirms that PCBs are endocrine disruptors capable of causing permanent alterations in the female reproductive tract. Newborn mice exposed to environmentally relevant levels of Aroclor 1254, a commercial mix of PCBs, had decreased expression of a regulatory gene in the uterus. There were also changes in the structure of the uterus that persisted into adulthood. These changes were similar to those seen with low level DES exposure. Finally, this study showed there was a genetic predisposition, suggesting some mice are more sensitive to these exposures.
Scientific abstract:
Polychlorinated biphenyls (PCBs) have been proposed to have a weak estrogenic activity and therefore pose a risk as potential environmental endocrine disruptors to the perinatal development of the female reproductive tract. Perinatal exposure to high concentrations of the potent synthetic estrogen diethylstilbestrol (DES) induces abnormal development of the female reproductive tract via a mechanism that acts through the down-regulation of Wnt7a (wingless-type MMTV integration site family, member 7A). To test the hypothesis that PCBs act as weak estrogens, we injected neonatal mice with a commercial PCB mixture (Aroclor 1254) or with low levels of DES and measured effects of exposure on Wnt7a expression and uterine morphology. We report here that neonatal PCB or low-level DES exposure resulted in the down-regulation of Wnt7a expression. In addition, both PCB and low-level DES exposure induced changes in the uterine myometrium and gland formation. These data reveal that weak estrogens such as the PCBs act through a Wnt7a-dependent pathway and suggest that Wnt7a regulation is a sensitive biomarker for testing weak estrogenic candidate compounds. The morphologic changes that were elicited by PCBs and DES were different immediately after exposure, suggesting that Wnt7a-independent pathways are also activated by one or both of these compounds. Although Wnt7a down-regulation is transient after estrogenic exposure, subsequent morphologic changes became more pronounced during postnatal and adult life, suggesting that the female reproductive tract is permanently reprogrammed after exposure even to weak estrogenic compounds. In addition, Wnt7a heterozygous mice were more sensitive to PCB exposure, revealing an important genetic predisposition to risks of environmental endocrine disruptors.
Study Synopsis: Bisphenol A can be used as a model agent for studying and understanding endocrine disrupting effects. Exposure before and shortly after birth causes changes in both male and female genatalia and mammary glands. These changes have been associated with an earlier onset of disease, reduced fertility and cancers.
Scientific abstract:
Epidemiological studies have reported that during the last 60 years the quantity and quality of human sperm has decreased and the incidence of male genital tract defects, testicular, prostate and breast cancer has increased. During the same time period, developmental, reproductive and endocrine effects have also been documented in wildlife species. The last six decades have witnessed a massive introduction of hormonally active synthetic chemicals into the environment leading some to postulate that the diverse outcomes documented in human and wildlife populations might be the result of extemporaneous exposure to xenoestrogens during development. The estrogen-mimic bisphenol-A (BPA) is used as a model agent for endocrine disruption. BPA is used in the manufacture of polycarbonate plastics and epoxy resins from which food and beverage containers and dental materials are made. Perinatal exposure to environmentally relevant BPA doses results in morphological and functional alterations of the male and female genital tract and mammary glands that may predispose the tissue to earlier onset of disease, reduced fertility and mammary and prostate cancer.
Study Synopsis: Male rats exposed to di(n-butyl) phthalate (DBP) have testes with both normal and abnormal areas of development. In the abnormal areas, Leydig cells normally found outside the testis are found inside the testis. Similar changes have been identified in testicular dysgenesis syndrome - a cluster of a abnormalities that includes testicular cancer, hypospadias, cryptorchidism and poor sperm quality.
Scientific abstract:
Summary: Foetal exposure of male rats to di(n-butyl) phthalate (DBP) induces testicular changes similar to testicular dysgenesis syndrome in humans, including the formation of focal 'dysgenetic areas' within post-natal testes, surrounded by otherwise normal tubules exhibiting complete spermatogenesis. We hypothesize that these dysgenetic areas form when Sertoli (and other) cells are 'trapped' during the abnormal formation of large Leydig cell (LC) clusters in foetal life and by post-natal day (d) 4 these groups of intermingled cells attempt to form seminiferous tubules. It is likely that the malformed tubules resulting correspond to the dysgenetic areas evident in later life. This also provides a plausible explanation for the occurrence of LCs within seminiferous cords/tubules in or bordering the dysgenetic areas. In our previous studies intratubular LCs (ITLCs) were identified by immunostaining for 3beta-hydroxysteroid dehydrogenase (3beta-HSD), the definitive LC cytoplasmic marker. However, the possibility remained that the 'presumptive' ITLCs were in fact Sertoli cells that had aberrantly gained the ability to express 3beta-HSD. Therefore, the aim of the present study was to fully characterize the ITLCs induced by in utero DBP exposure in d25 rats using a number of LC- (3beta-HSD, P450 side-chain cleavage enzyme, insulin-like factor 3, oestrogen receptor alpha) and Sertoli cell- (vimentin, Wilm's tumour-1) specific markers. Our results show that ITLCs express all four LC-specific markers but do not express either of the Sertoli cell markers. It is therefore concluded that the ITLCs are bona fide LCs that are abnormally located within the seminiferous tubules of DBP-exposed rats in post-natal life.
Study Synopsis: A prospective study of Danish and Finnish newborn boys exposed to phthalates finds changes in hormone profiles. Exposure to a variety of phthalates in breast milk was associated with increases in serum binding proteins and changes in hormone ratios in 3 months old boys. A significant decrease in testosterone levels was seen for boys with high levels of the metabolite of Dibutyl phthalate (DBP). DBP is found in many consumer products.
Scientific abstract:
Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. DESIGN: We obtained biologic samples from a prospective Danish-Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1-3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. RESULTS: All phthalate monoesters were found in breast milk with large variations [medians (minimum-maximum)]: mMP 0.10 (< 0.01-5.53 microg/L), mEP 0.95 (0.07-41.4 microg/L), mBP 9.6 (0.6-10,900 microg/L), mBzP 1.2 (0.2-26 microg/L), mEHP 11 (1.5-1,410 microg/L), miNP 95 (27-469 microg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001-0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21-0.323, p = 0.002-0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = -0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. CONCLUSIONS: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally. adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. DESIGN: We obtained biologic samples from a prospective Danish-Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1-3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. RESULTS: All phthalate monoesters were found in breast milk with large variations [medians (minimum-maximum)]: mMP 0.10 (< 0.01-5.53 microg/L), mEP 0.95 (0.07-41.4 microg/L), mBP 9.6 (0.6-10,900 microg/L), mBzP 1.2 (0.2-26 microg/L), mEHP 11 (1.5-1,410 microg/L), miNP 95 (27-469 microg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001-0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21-0.323, p = 0.002-0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = -0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. CONCLUSIONS: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally.
Main KM, Mortensen GK, Kaleva MM, Boisen KA, Damgaard IN, Chellakooty M, Schmidt IM, Suomi AM, Virtanen HE, Petersen DV, Andersson AM, Toppari J, Skakkebaek NE. Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environ Health Perspect. 2006 Feb;114(2):270-6.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured phthalate residues in breast milk samples collected 1-3 months after delivery of 62 boys with cryptorchidism (undescended testes) and 68 healthy controls. Blood samples were also collected from 74% of boys for hormone measurement. Although no associations were found between the breast milk concentration of phthalate residues and cryptorchidism, relationships were found between some residues and elevated sex-hormone binding globulin, luteinizing hormone (LH), LH to free testosterone ratio, and reduced free testosterone. These results suggest that prenatal exposure to phthalates may affect infant hormone levels.
Scientific abstract:
Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. DESIGN: We obtained biologic samples from a prospective Danish-Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1-3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. RESULTS: All phthalate monoesters were found in breast milk with large variations [medians (minimum-maximum)]: mMP 0.10 (< 0.01-5.53 microg/L), mEP 0.95 (0.07-41.4 microg/L), mBP 9.6 (0.6-10,900 microg/L), mBzP 1.2 (0.2-26 microg/L), mEHP 11 (1.5-1,410 microg/L), miNP 95 (27-469 microg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001-0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21-0.323, p = 0.002-0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = -0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. CONCLUSIONS: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally.
Study Synopsis: EPA's current 'reference doses' for exposure to several phthalates may be far too high, perhaps by as much as a factor of 100-fold or more. The reference dose is the level thought low enough to cause no adverse effects. This conclusion is based upon calculations, using pharmokinetic models, of the maternal exposures that would have been required to cause urinary phthalate metabolite levels associated with altered genital tract development in boys.
Phthalate diesters have been shown to be developmental and reproductive toxicants in animal studies. A recent epidemiologic study showed certain phthalates to be significantly associated with reduced anogenital distance in human male infants, the first evidence of subtle developmental effects in human male infants exposed prenatally to phthalates. We used two previously published methods to estimate the daily phthalate exposures for the four phthalates whose urinary metabolites were statistically significantly associated with developmental effects in the 214 motherinfant pairs [di-n-butyl phthalate (DnBP), diethyl phthalate (DEP), butylbenzyl phthalate (BBzP), diisobutyl phthalate (DiBP)] and for another important phthalate [di-2-ethylhexyl phthalate (DEHP)]. We estimated the median and 95th percentile of daily exposures to DBP to be 0.99 and 2.68 ?g/kg/day, respectively; for DEP, 6.64 and 112.3 ?g/kg/day; for BBzP, 0.50 and 2.47 ?g/kg/day; and for DEHP, 1.32 and 9.32 ?g/kg/day. The U.S. Environmental Protection Agency (EPA) reference doses for these chemicals are 100 (DBP), 800 (DEP), 200 (BBzP), and 20 (DEHP) ?g/kg/day. The median and 95th percentile exposure estimates for the phthalates associated with reduced anogenital distance in the study population are substantially lower than current U.S. EPA reference doses for these chemicals and could be informative to any updates of the hazard assessments and risk assessments for these chemicals.
Study Synopsis: A recent review of the impact of estrogenic contaminants in the environment finds a wide variety of effects from a diversity of compounds. Detergents, PCBs, herbicides, plasticizers and phytoestrogens all can interfere with estrogen action and interfere with normal reproductive development. New studies are providing more data on the mechanism of action of endocrine disruptors, including epigenetic effects. Bailličre's best practice & research.
Scientific abstract:
There is growing evidence of the impact of estrogenic contaminants in the environment. Studies have shown that male fish in detergent-contaminated water express female characteristics, turtles are sex-reversed by polychlorinated biphenyls (PCBs), male frogs exposed to a common herbicide form multiple ovaries, pseudohermaphroditic offspring are produced by polar bears, and seals in contaminated water have an excess of uterine fibroids. Endocrine-disrupting chemicals (those found in the external environment that can mimic or inhibit endogenous hormones) mostly exhibit estrogenic effects, but a few are anti-estrogenic or anti-androgenic. Many of these compounds are industrial contaminants, such as pesticides and plasticizers, and others are natural phytoestrogens found in plants such as soy and in herbal supplements. Recent work shows that human development can also be feminized by exposure to estrogenic chemicals. Estrogen is the key hormone in the initiation (puberty) and the end (menopause) of reproductive life in women and thus of considerable importance in women's health. The same chemicals that affect wildlife may affect breast growth and lactation, and could have a role in uterine diseases such as fibroids and endometriosis. New studies provide a mechanism of action for estrogenic chemicals and other endocrine disrupters at the molecular level (called epigenetics) that may help explain the long-term effects of endocrine disruption.
Study Synopsis: Everyday exposure of American men to common insecticides causes alterations in thyroid function. Exposure to chlorpyrifos was associated with hormone changes found in hypothyroidism, a increase in thyroid stimulating hormone (TSH) and a decrease in free T4. Proper thyroid hormone levels are essential for optimal body function, including reproduction. Exposure to these insecticides has previously been associated with abnormalities in semen parameters.
Scientific abstract:
Human exposure to contemporary-use insecticides is widespread, but effects of exposure on human endocrine function have gone largely untested to date. Samples of urine and blood were collected concurrently from 322 adult men between the years 2000 and 2003. Urine samples were analyzed for 3,5,6-trichloro-2-pyridinol (TCPY), a metabolite of chlorpyrifos and chlorpyrifos-methyl, and 1-napththol (1N), a metabolite of carbaryl and naphthalene. Serum samples were analyzed for free T4, total T3, and thyroid stimulating hormone (TSH). There was an association between TCPY and TSH, where an interquartile range (IQR) increase in TCPY was associated with a 9% (95% confidence interval 0-18%) increase in TSH. There was also a suggestive inverse association between TCPY and free T4. There were no associations between 1N and thyroid hormones. Environmental exposure to chlorpyrifos, chlorpyrifos-methyl, or its metabolite TCPY may be associated with altered thyroid function in human males.
Study Synopsis: Higher levels of the metabolites of three nonpersistent insecticides, chlorpyrifos, carbaryl and naphthalene, were correlated with reductions in testosterone of adult men from the general population. The men studied were partners seeking treatment in an infertility clinic. The researchers concluded that these reductions are of potential public health importance because of the widespread exposure to nonpersistent insecticides.
Scientific abstract:
BACKGROUND: Urinary metabolites of several nonpersistent insecticides have been measured in a high percentage of men in the general population, suggesting widespread environmental exposures to these compounds. The present study explored the association of urinary concentrations of 3,5,6-trichloro-2-pyridinol (TCPY), a metabolite of chlorpyrifos and chlorpyrifos-methyl, and 1-naphthol (1N), a metabolite of carbaryl and naphthalene, with serum reproductive hormone levels in adult men. METHODS: Subjects (n = 268) were the male partners in couples presenting to a Massachusetts infertility clinic in years 2000 through 2003. TCPY and 1N were measured in a spot urine sample from each subject and adjusted for dilution using specific gravity. Reproductive hormones (follicle-stimulating hormone, leuteinizing hormone, inhibin B, testosterone, and sex hormone-binding globulin) were measured in serum collected from subjects during the same clinic visit. RESULTS: Multiple linear regression models showed an inverse association between TCPY and testosterone concentration. An interquartile range (IQR) increase in TCPY was associated with a decline of 25 ng/dL (95% confidence interval = -40 to -10) in testosterone concentration. The association appeared to be dose-dependent when exposure was divided into quintiles. The highest TCPY quintile was associated with a testosterone decline of 83 ng/dL (-128 to -39) compared with the lowest TCPY quintile. We also found inverse associations between TCPY and free androgen index and between 1N and testosterone, and suggestive inverse associations between TCPY and leuteinizing hormone and between 1N and free androgen index. CONCLUSION: In adult men, TCPY and 1N were associated with reduced testosterone levels. On a population level, these reductions are of potential public health importance because of widespread exposure to these nonpersistent insecticides.
Study Synopsis: A review of the health effects of second-hand smoke by the California EPA concludes that exposure is causally related to breast cancer in younger women. Thirteen of 14 studies of premenopausal women reported elevated risks of breast cancer. Overall, exposure was associated with almost a 70% increase in risk. In studies with the best exposure assessments, the risk more than doubled.
Scientific abstract:
BACKGROUND.: The California Environmental Protection Agency (Cal/EPA) recently completed a health effects assessment of exposure to environmental tobacco smoke (ETS) which resulted in California listing ETS as a Toxic Air Contaminant in January 2006. As part of the assessment, studies on the association between exposure to ETS and breast cancer were reviewed. METHODS.: Twenty-six published reports (including 3 meta-analyses) evaluating the association between ETS exposure and breast cancer were reviewed. A weight-of-evidence approach was applied to evaluate the data and draw conclusions about the association between breast cancer and ETS exposure. RESULTS.: The published data indicate an association between ETS and breast cancer in younger primarily premenopausal women. Thirteen of 14 studies (10 case-control and four cohort) that allowed analysis by menopausal status reported elevated risk estimates for breast cancer in premenopausal women, seven of which were statistically significant. Our meta-analyses indicated elevated summary relative risks ranging from OR 1.68 (95% C.I. 1.31, 2.15) for all 14 studies to 2.20 (95% C.I. 1.69, 2.87) for those with the best exposure assessment. CONCLUSIONS.: Cal/EPA concluded that regular ETS exposure is causally related to breast cancer diagnosed in younger, primarily premenopausal women and that the association is not likely explained by bias or confounding.
Study Synopsis: Experiments with rats demonstrate that low level exposure to bisphenol A during fetal growth causes breast cancer in adults. At all levels tested down to 2.5 micrograms per kg body weight, BPA induced formation of aberrant cell growth patterns associated in rodents and people with breast cancer. Levels only 5 times higher than EPA's current safe level caused carcinoma in situ.
Exposure of the fetus to excess estrogen is believed to increase the risk of developing breast cancer during adult life. Fetal exposure to low doses of the xenoestrogen bisphenol A resulted in long-lasting effects in the mouse mammary gland that were manifested during adult life. It enhanced sensitivity to estradiol, decreased apoptosis, increased the number of progesterone receptor-positive epithelial cells at puberty and increased lateral branching at 4 months of age. We now report that fetal exposure to 2.5, 25, 250 and 1000mug bisphenol A/kg body weight/day induces the development of ductal hyperplasias and carcinoma in situ at postnatal day 50 and 95 in rats. These highly proliferative lesions have an increased number of estrogen receptor-alpha positive cells. Thus, fetal bisphenol A exposure is sufficient to induce the development of preneoplastic and neoplastic lesions in the mammary gland in the absence of any additional treatment aimed at increasing tumor development.
Study Synopsis: A review of research on DES demonstrates transgenerational effects A mouse model for exposure to DES has identified altered expression of genes regulated by estrogen as being an important mechanism of toxicity. Additional data suggests the propensity to develop tumors is transgenerational.
Scientific abstract:
The synthetic estrogen diethylstilbestrol (DES) is a potent perinatal endocrine disruptor. In humans and experimental animals, exposure to DES during critical periods of reproductive tract differentiation permanently alters estrogen target tissues and results in long-term abnormalities such as uterine neoplasia that are not manifested until later in life. Using the developmentally exposed DES mouse, multiple mechanisms have been identified that play a role in its carcinogenic and toxic effects. Analysis of the DES murine uterus reveals altered gene expression pathways that include an estrogen regulated component. Thus, perinatal DES exposure, especially at low doses, offers the opportunity to study effects caused by weaker environmental estrogens, and provides an example of the emerging scientific field termed "the developmental origin of adult disease". As a model endocrine disruptor, it is of particular interest that even low doses of DES increase uterine tumor incidence. Additional studies have verified that DES is not unique; when other environmental estrogens are tested at equal estrogenic doses, developmental exposure results in increased incidence of uterine neoplasia similar to that caused by DES. Interestingly, our data suggest that this increased susceptibility for tumors is passed on from the maternal lineage to subsequent generations of male and female descendants; the mechanisms involved in these transgenerational events include genetic and epigenetic events. Together our data point out the unique sensitivity of the developing organism to endocrine disrupting chemicals, the occurrence of long-term effects following developmental exposure, and the possibility for adverse effects to be transmitted to subsequent generations.
Key Words: Developmental Endocrinology and Endocrine Disruptor Section, Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, North Carolina, 27709.
Study Synopsis: Women with prenatal exposure to DES have an increased risk of breast cancer after age 40 years. The results are based upon a study of the daughters of women who took diethylstilbestrol during pregnancy. They are almost twice as likely as unexposed women to develop breast cancer. The findings support the hypothesis that prenatal hormone levels influence breast cancer risk.
Scientific abstract:
It has been hypothesized that breast cancer risk is influenced by prenatal hormone levels. Diethylstilbestrol (DES), a synthetic estrogen, was widely used by pregnant women in the 1950s and 1960s. Women who took the drug have an increased risk of breast cancer, but whether risk is also increased in the daughters who were exposed in utero is less clear. We assessed the relation of prenatal DES exposure to risk of breast cancer in a cohort of DES-exposed and unexposed women followed since the 1970s by mailed questionnaires. Eighty percent of both exposed and unexposed women completed the most recent questionnaire. Self-reports of breast cancer were confirmed by pathology reports. Cox proportional hazards regression was used to compute incidence rate ratios (IRR) for prenatal DES exposure relative to no exposure. During follow-up, 102 incident cases of invasive breast cancer occurred, with 76 among DES-exposed women (98,591 person-years) and 26 among unexposed women (35,046 person-years). The overall age-adjusted IRR was 1.40 [95% confidence interval (95% CI), 0.89-2.22]. For breast cancer occurring at ages [≥]40 years, the IRR was 1.91 (95% CI, 1.09-3.33) and for cancers occurring at ages [≥]50 years, it was 3.00 (95% CI, 1.01-8.98). Control for calendar year, parity, age at first birth, and other factors did not alter the results. These results, from the first prospective study on the subject, suggest that women with prenatal exposure to DES have an increased risk of breast cancer after age 40 years. The findings support the hypothesis that prenatal hormone levels influence breast cancer risk.
Research notes: The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Study Synopsis: Workers exposed to the phthalates DBP and DEHP in an occupational setting have higher phthalate levels and lower free testosterone levels than unexposed workers. The workers were employed in a polyvinyl chloride flooring factory in China. Within the exposed worker group, free testosterone was inversely correlated with phthalate levels.
Scientific abstract:
BACKGROUND: Observations of adverse developmental and reproductive effects in laboratory animals and wildlife have fueled increasing public concern regarding the potential for various chemicals to impair human fertility. OBJECTIVE: Our objective in this study was to assess the effect of occupational exposure to high levels of phthalate esters on the balance of gonadotropin and gonadal hormones including luteinizing hormone, follicle-stimulating hormone, free testosterone (fT), and estradiol. METHODS: We examined urine and blood samples of 74 male workers at a factory producing unfoamed polyvinyl chloride flooring exposed to di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) and compared them with samples from 63 male workers from a construction company, group matched for age and smoking status. RESULTS: Compared to the unexposed workers, the exposed workers had substantially and significantly elevated concentrations of mono-n-butyl phthalate (MBP; 644.3 vs. 129.6 microg/g creatinine, p < 0.001) and mono-2-ethylhexyl phthalate (MEHP; 565.7 vs. 5.7 microg/g creatinine, p < 0.001). fT was significantly lower (8.4 vs. 9.7 microg/g creatinine, p = 0.019) in exposed workers than in unexposed workers. fT was negatively correlated to MBP (r = -0.25, p = 0.03) and MEHP (r = -0.19, p = 0.095) in the exposed worker group. Regression analyses revealed that fT decreases significantly with increasing total phthalate ester score (the sum of quartiles of MBP and MEHP; r = -0.26, p = 0.002). CONCLUSION: We observed a modest and significant reduction of serum fT in workers with higher levels of urinary MBP and MEHP compared with unexposed workers.
Study Synopsis: Exposure to the pesticide, DDT, impairs normal hormone surges necessary for ovulation and maintenance of early pregnancy. This prospective study of Chinese women demonstrated that as blood levels of DDT and its metabolites increased, peak levels of progesterone and estrogen were lower than expected around the time of ovulation. This study provides further evidence that DDT interferes with hormonal changes during the menstrual cycle.
Scientific abstract:
The authors explored whether exposure to 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and its isomers and metabolites affects female reproductive hormones characterized by urinary pregnanediol-3-glucuronide (PdG) and estrone conjugate (E1C) levels. During 1996-1998, 287 newly married Chinese women nonsmokers intending to conceive were prospectively studied. Serum for DDT measurement was collected at enrollment, and daily menstrual diaries and urine specimens were collected for 1 year or until a clinical pregnancy was achieved. More than 500 menstrual cycles were studied totaling over 8,000 days. Day of ovulation was determined for each cycle, and the association of serum DDT levels with daily PdG and E1C levels in a +/-10-day window around ovulation was analyzed. After adjustment for covariates including age, body mass index, and occupational exposures, consistent inverse associations of most DDT forms occurred with urine E1C during the periovulation phase and with urine PdG during the luteal phase of the menstrual cycle. For example, a 10-ng/g increase in serum p,p'-DDE was associated with a 0.05-log(E1C) decrease (p = 0.03) in the periovulation phase and a 0.06-log(PdG) decrease (p = 0.03) in the luteal phase. These results support the potential for DDT to be associated with decrements in estrogen and progesterone levels at times during the menstrual cycle that are critical for ovulation and early pregnancy maintenance.
Study Synopsis: Consistent with animal studies, a study of Italian women finds a strong association between elevated PCB levels and risk of endometriosis. Women in the upper tertile of exposure were 4-fold more likely to have endometriosis than controls. Increases were seen for both dioxin-like and non-dioxin-like PCBs.
Scientific abstract:
Endometriosis has been hypothesised to be linked to persistent and toxic organochlorinated chemicals. Dioxins and dioxin-like compounds have in particular been associated with the disease, mainly on the basis of experimental studies. Data in women are conflicting. A case-control study on 80 Italian nulliparous women of reproductive age was carried out to assess whether there is a correlation between the presence of endometriosis and blood levels of polychlorobiphenyls (PCBs), a family of ubiquitary environmental pollutants which comprises congeners with dioxin-like activity. Higher levels of PCBs were found in women with endometriosis. A mean cumulative value of 410ngg(-1), lipid base, was found in cases versus the value of 250ngg(-1) observed in the control group (odds ratio for upper tertile 4.0, CI 95% 1.3-13; p=0.0003). PCB increase involved both dioxin-like (PCBs 105, 118, 156, and 167) and non-dioxin-like congeners (PCBs 101, 138, 153, 170, 180).
Study Synopsis: A case-control study of Indian women finds higher blood levels of phthalates are associated with the diagnosis of endometriosis. Women with endometriosis showed significantly higher concentrations of di-n-butyl phthalate (DnBP), butyl benzyl phthalate (BBP), di-n-octyl phthalate (DnOP) and diethyl hexyl phthalate (DEHP). Severity of endometriosis grew worse with increasing phthalate concentrations.
Scientific abstract:
Objective: To evaluate the possible association between phthalate esters (PEs) and the occurrence of endometriosis. Design: Case-control study. Setting Department of Reproductive Medicine, Bhagawan Mahavir Medical Research Centre, Maternal Health and Reproductive Institute and Department of Analytical R&D, Hetero Research Foundation, Hyderabad, Andhra Pradesh, India. Sample Blood samples were collected from 49 infertile women with endometriosis (study group); 38 age-matched women without endometriosis (control group I) but with infertility related to tubal defects, fibroids, polycystic ovaries, idiopathic infertility and pelvic inflammatory diseases diagnosed by laparoscopy and a further group of 21 age-matched women (control group II) with proven fertility and no evidence of endometriosis and other gynaecological disorders during laparoscopic sterilisation. Methods Concentrations of PEs were measured using gas chromatography. Main outcome measures Evaluation of PEs concentrations in women with endometriosis compared with women free from the disease. Results: Women with endometriosis showed significantly higher concentrations of di-n-butyl phthalate (DnBP), butyl benzyl phthalate (BBP), di-n-octyl phthalate (DnOP) and diethyl hexyl phthalate (DEHP) (mean 0.44 [SD 0.41]; 0.66 [SD 0.61]; 3.32 [SD 2.17]; 2.44 [SD 2.17] micrograms/ml) compared with control group I (mean 0.08 [SD 0.14]; 0.12 [SD 0.20]; 0; 0.50 [SD 0.80] micrograms/ml) and control group II (mean 0.15 [SD 0.21]; 0.11 [SD 0.22]; 0; 0.45 [SD 0.68] micrograms/ml). The correlation between the concentrations of PEs and different severity of endometriosis was strong and statistically significant at P < 0.05 for all four compounds (DnBP: r=+0.73, P < 0.0001; BBP: r=+0.78, P < 0.0001; DnOP: r=+0.57, P < 0.0001 and DEHP: r=+0.44, P < 0.0014). Conclusions: This study suggests that PEs may have an aetiological association with endometriosis.
Key Words: Adult, Age Factors, Body Mass Index, Case-Control Studies, Chromatography-High Pressure Liquid, Endometriosis/blood, Endometriosis/chemically induced*, Environmental Exposure/adverse effects*, Female, Humans, India, Infertility-Female/blood, Infertility-Female/chemically induced, Menarche, Phthalic Acids/blood, Phthalic Acids/toxicity*, Prospective Studies, Phthalic Acids
Study Synopsis: Adult survival was reduced in salamanders exposed to 4 parts per billion of atrazine when they were embryo and larvae. The exposures used are well beneath those regularly found in habitats near sprayed fields. These results, along with studies demonstrating gonadal impacts in frogs, raise concerns about the role of atrazine in amphibian declines.
Scientific abstract:
Most toxicology studies focus on effects of contaminants during exposure. This is disconcerting because subsequent survival may be affected. For instance, contaminant-induced mortality can be later ameliorated by reduced competition among the survivors, a concept we refer to as "density-mediated compensation." Alternatively, it can be exacerbated by toxicant effects that persist or appear after exposure, a phenomenon we term "carryover effects." We developed a laboratory framework for testing the contribution of exposure, density-mediated, and carryover effects to net survival, by exposing embryos and larvae of the streamside salamander (Ambystoma barbouri) to atrazine (0, 4, 40, 400 ppb; 3 ppb is the U.S. drinking water maximum) and quantifying survival during and 14 months after exposure. Atrazine is the most commonly used herbicide in the United States and a documented endocrine disruptor. We show that atrazine-induced mortality during exposure was ameliorated by density-dependent survival after exposure, but complete density-mediated compensation was precluded by significant carryover effects of atrazine. Consequently, salamanders exposed to >or=4 ppb of atrazine had significantly lower survival than did control animals 14 months postexposure. The greatest change in survival occurred at low exposure concentrations. These nonlinear, long-term, postexposure effects of atrazine have similarities to effects of early development exposure to other endocrine disruptors. Together with evidence of low levels of atrazine impairing amphibian gonadal development, the results here raise concerns about the role of atrazine in amphibian declines and highlight the importance of considering persistent, postexposure effects when evaluating the impact of xenobiotics on environmental health.
Key Words: Animals, Atrazine/*toxicity, Herbicides/*toxicity, Population Density, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Survival Analysis, Time Factors, *Urodela/embryology/growth & development, Water Pollutants, Chemical/toxicity
Study Synopsis: In utero exposure to bisphenol causes long-term effects on endocrine parameters of female sheep that could impact fertility. The onset of LH surge was delayed in methoxychlor-exposed females. In BPA-exposed females the LH surge was severely dampened.
Scientific abstract:
Increased occurrence of reproductive disorders has raised concerns regarding the impact of endocrine-disrupting chemicals on reproductive health, especially when such exposure occurs during fetal life. Prenatal testosterone (T) treatment leads to growth retardation, postnatal hypergonadotropism, compromised estradiol-positive feedback, polycystic ovaries, and infertility in the adult. Prenatal dihydrotestosterone treatment failed to affect ovarian morphology or estradiol-positive feedback, suggesting that effects of prenatal T may be facilitated via conversion of T to estradiol, thus raising concerns regarding fetal exposure to estrogenic endocrine-disrupting chemicals. This study tested whether fetal exposure to methoxychlor (MXC) or bisphenol A (BPA) would disrupt cyclicity in the ewe. Suffolk ewes were administered MXC (n=10), BPA (n=10) (5 mg/kg.d sc in cotton seed oil) or the vehicle (C; n=16) from d 30 to 90 of gestation. On d 60 of treatment, maternal MXC concentrations in fat tissue and BPA in blood averaged approximately 200 microg/g fat and 37.4+/-3.3 ng/ml, respectively. Birth weights of BPA offspring were lower (P<0.05) relative to C. There was no difference in the time of puberty between groups. BPA females were hypergonadotropic during early postnatal life and ended their breeding season later, compared with C. Characterization of cyclic changes after synchronization with prostaglandin F2alpha in five C, six MXC, and six BPA females found that the onset of the LH surge was delayed in MXC (P<0.05) and the LH surge magnitude severely dampened (P<0.05) in BPA sheep. These findings suggest that prenatal BPA and MXC exposure have long-term differential effects on a variety of reproductive endocrine parameters that could impact fertility.
Study Synopsis: Chlorination of drinking water generates disinfection by-products (DBPs) such as trihalomethanes (THM) and organic halides (OH). Some studies suggest that exposure to elevated levels of DBPs may be related to pregnancy loss. In this study, researchers measured DBP in the tap water of 2,409 U.S. women and collected information on water use to estimate exposure to the chemicals in early pregnancy. They found that women with high exposure to OH had a 50% increased risk of pregnancy loss. Other DBPs were not related to pregnancy loss. Results suggest that high exposure to OH, but not other DBPs, may be related with increased risks of pregnancy loss.
Scientific abstract:
Previous research has suggested that exposure to elevated levels of drinking water disinfection by-products (DBPs) may cause pregnancy loss. In 2000-2004, the authors conducted a study in three US locations of varying DBP levels and evaluated 2,409 women in early pregnancy to assess their tap water DBP concentrations, water use, other risk factors, and pregnancy outcome. Tap water concentrations were measured in the distribution system weekly or biweekly. The authors considered DBP concentration and ingested amount and, for trihalomethanes only, bathing/showering and integrated exposure that included ingestion. On the basis of 258 pregnancy losses, they did not find an increased risk of pregnancy loss in relation to trihalomethane, haloacetic acid, or total organic halide concentrations; ingested amounts; or total exposure. In contrast to a previous study, pregnancy loss was not associated with high personal trihalomethane exposure ([≥]75 {micro}g/liter and [≥]5 glasses of water/day) (odds ratio = 1.1, 95% confidence interval: 0.7, 1.7). Sporadic elevations in risk were found across DBPs, most notably for ingested total organic halide (odds ratio = 1.5, 95% confidence interval: 1.0, 2.2 for the highest exposure quintile). These results provide some assurance that drinking water DBPs in the range commonly encountered in the United States do not affect fetal survival.
Study Synopsis: Several genes are often methylated in four types of epithelial tumors, including lung, breast, colon and prostate cancers. These findings suggest, but do not prove, that loss of expression of the proteins that these genes produce helps convert normal cells to cancer cells. The results may be important for developing new tools for screening and treatment, and might yield clues about cancer prevention.
Scientific abstract:
Background: Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The rules governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor type-specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype would identify pathways important as therapeutic targets. Methods and Findings: In an effort to identify new cancer-specific methylation markers, we employed a high-throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5' CpG islands, are induced from undetectable levels by 5'-deoxycytidine in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (n=20) and adjacent nonmalignant tissue (n=20) showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. We studied the eight most frequently and specifically methylated genes from our lung cancer dataset in breast cancer (n=37), colon cancer (n=24), and prostate cancer (n=24) along with counterpart nonmalignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. Conclusions: By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation pattern we observed for these novel markers suggests that we have identified a partial promoter hypermethylation signature for these common malignancies. These data suggest that while tumors in different tissues vary substantially with respect to gene expression, there may be commonalities in their promoter methylation profiles that represent targets for early detection screening or therapeutic intervention.
Study Synopsis: A mathematical analysis of data from 32 studies contradicts a long-standing assumption in toxicology-- that there will be a safety threshold for endocrine disrupting chemicals beneath which exposure is safe. This assumption is used to justify not testing the impacts of low doses. Yet the analysis shows that even very low doses will cause effects by interacting with endogenous hormones, when the contaminants are working through the same mechanism.
Scientific abstract:
We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated on a single graph. Response rates from approximately 1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.
Study Synopsis: In experiments with human breast cancer cells, the behavior of more than 300 genes were altered more than 2-fold by either or both bisphenol A and estradiol. Several genes key for growth and development were changed only by BPA. These data indicate that BPA's effect on sexual development will be similar to, but also different from, effects of estrogen.
Scientific abstract:
Bisphenol-A (BPA) shows proliferative actions in uterus and mammary glands and may influence the development of male and female reproductive tracts in utero or during early postnatal life. Because of its ability to function as an estrogen receptor (ER) agonist, BPA has the potential to disrupt normal endocrine signaling through regulation of ER target genes. Some genes are regulated by both estradiol (E2) and BPA, but those exclusive to either agent have not been described. Using a yeast strain incorporating a vitellogenin A2 ERE-LacZ reporter gene into the genome, we found that BPA induced expression of the reporter in colonies transformed with the ERalpha expression plasmid, illustrating BPA-mediated regulation within a chromatin context. Additionally, a reporter gene transiently transfected into the endometrial cancer (Ishikawa) cell line also showed BPA activity, although at 100-fold less potency than E2. To compare global gene expression in response to BPA and E2, we used a variant of the MCF-7 breast cancer cell line stably expressing HA-tagged ERalpha. Cultures were treated for 3h with an ethanol vehicle, E2 (10(-8)M), or BPA (10(-6)M), followed by isolation of RNA and microarray analysis with the human U95A probe array (Affymetrix, Santa Clara, CA, USA). More than 300 genes were changed 2-fold or more by either or both agents, with roughly half being up-regulated and half down-regulated. A number of growth- and development-related genes, such as HOXC1 and C6, Wnt5A, Frizzled, TGFbeta-2, and STAT inhibitor 2, were found to be affected exclusively by BPA. We used quantitative real-time PCR to verify regulation of the HOXC6 gene, which showed decreased expression of approximately 2.5-fold by BPA. These results reveal novel effects by BPA and E2, raising interesting possibilities regarding the role of endocrine disruptors in sexual development.
Skakkebaek NE, Jorgensen N, Main KM, Rajpert-De Meyts E, Leffers H, Andersson AM, Juul A, Carlsen E, Mortensen GK, Jensen TK, Toppari J. Is human fecundity declining?. Int J Androl. 2006;29(1):2-11.
Study Synopsis: The decreasing trends in fertility rates in many industrialized countries are now so dramatic that they deserve much more scientific attention. Although social and behavioural factors undoubtedly play a major role, it seems premature to conclude that these trends can be ascribed to social and behavioural changes alone. Evidence suggests increasing environmental exposures and changing lifestyles are behind increased problems in male reproductive health.
Scientific abstract:
Summary: The decreasing trends in fertility rates in many industrialized countries are now so dramatic that they deserve much more scientific attention. Although social and behavioural factors undoubtedly play a major role for these trends, it seems premature, and not based on solid information, to conclude that these trends can be ascribed to social and behavioural changes alone. There is evidence to suspect that changing lifestyle and increasing environmental exposures, e.g. to endocrine disrupters, are behind the trends in occurrence of male reproductive health problems, including testis cancer, undescended testis and poor semen quality. These biological factors may also contribute to the extremely low fertility rates. However, the necessary research is complex and requires non-traditional collaboration between demographers, epidemiologists, clinicians, biologists, wild life researchers, geneticists and molecular biologists. This research effort can hardly be carried out without major support from governments and granting agencies making it possible to fund collaborative projects within novel research networks of scientists. // The decreasing trends in fertility rates in many industrialized countries are now so dramatic that they deserve much more scientific attention. Although social and behavioural factors undoubtedly play a major role, it seems premature to conclude that these trends can be ascribed to social and behavioural changes alone. Evidence suggests increasing environmental exposures and changing lifestyles are behind increased problems in male reproductive health.
Study Synopsis: Exposure to ambient levels of ozone is associated with lower sperm counts in a study of men from Los Angeles. There was a significant negative correlation between ozone levels up to 90 days before sperm donation and average sperm concentration. No other pollutant measures were significantly associated with sperm quality outcomes.
Scientific abstract:
Idiopathic male infertility may be due to exposure to environmental toxicants that alter spermatogenesis or sperm function. We studied the relationship between air pollutant levels and semen quality over a 2-year period in Los Angeles, California, by analyzing repeated semen samples collected by sperm donors. Semen analysis data derived from 5,134 semen samples from a sperm donor bank were correlated with air pollutant levels (ozone, nitrogen dioxide, carbon monoxide, and particulate matter < 10 microm in aerodynamic diameter) measured 0-9, 10-14, and 70-90 days before semen collection dates in Los Angeles between January 1996 and December 1998. A linear mixed-effects model was used to model average sperm concentration and total motile sperm count for the donation from each subject. Changes were analyzed in relationship to biologically relevant time points during spermatogenesis, 0-9, 10-14, and 70-90 days before the day of semen collection. We estimated temperature and seasonality effects after adjusting for a base model, which included donor's date of birth and age at donation. Forty-eight donors from Los Angeles were included as subjects. Donors were included if they collected repeated semen samples over a 12-month period between January 1996 and December 1998. There was a significant negative correlation between ozone levels at 0-9, 10-14, and 70-90 days before donation and average sperm concentration, which was maintained after correction for donor's birth date, age at donation, temperature, and seasonality (p < 0.01). No other pollutant measures were significantly associated with sperm quality outcomes. Exposure to ambient ozone levels adversely affects semen quality.
Key Words: Adult, Air Pollutants/analysis, Air Pollutants/toxicity*, Carbon Monoxide/analysis, Dust/analysis, Environmental Monitoring, Humans, Los Angeles/epidemiology, Male, Nitrogen Dioxide/analysis, Ozone/analysis, Ozone/toxicity*, Sperm Count*, Spermatogenesis/drug effects, Air Pollutants, Dust, Ozone, Nitrogen Dioxide, Carbon Monoxide
Study Synopsis: Exposure to ambient levels of ozone is associated with lower sperm counts in a study of men from Los Angeles. There was a significant negative correlation between ozone levels up to 90 days before sperm donation and average sperm concentration. No other pollutant measures were significantly associated with sperm quality outcomes.
Scientific abstract:
Reproductive organs from 55 male and 44 female East Greenland polar bears were examined to investigate the potential negative impact from organohalogen pollutants (OHCs). Multiple regressions normalizing for age showed a significant inverse relationship between OHCs and testis length and baculum length and weight, respectively, and was found in both subadults (dichlorodiphenyl trichloroethanes, dieldrin, chlordanes, hexacyclohexanes, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs)) and adults (hexachlorobenzene [HCB]) (all p < 0.05). Baculum bone mineral densities decreased with increasing chlordanes, DDTs, and HCB in subadults and adults, respectively (all p < 0.05). In females, a significant inverse relationship was found between ovary length and sigma PCB (p = 0.03) and sigma CHL (p < 0.01), respectively, and between ovary weight and sigma PBDE (p < 0.01) and uterine horn length and HCB (p = 0.02). The study suggests thatthere is an impact from xenoendocrine pollutants on the size of East Greenland polar bear genitalia. This may pose a riskto this polar bear subpopulation in the future because of reduced sperm and egg quality/quantity and uterus and penis size/robustness.
Suomi AM, Main KM, Kaleva M, Schmidt IM, Chellakooty M, Virtanen HE, Boisen KA, Damgaard IN, Kai CM, Skakkebaek NE, Toppari J. Hormonal changes in 3-month-old cryptorchid boys. J Clin Endocrinol Metab. 2006 Mar;91(3):953-8.
Study Synopsis: A study of Finnish and Danish boys with undescended testicles finds decreased levels of the pituitary hormone, FSH, up to 3 months after birth. Changes in hormone levels were strongest in boys with severe, persistent cryptorchidism, but were also detectable in mild and transient cryptorchidism. This is consistent with a primary testicular disorder and may result in alterations in sperm counts in adulthood. Testosterone levels remained within the normal range.
Scientific abstract:
CONTEXT: Hormonal dysregulation has been suggested to be one of many etiological factors of cryptorchidism. OBJECTIVES: The objective of this study was to assess the hypothalamic-pituitary-testicular axis in cryptorchid boys during the postnatal hormonal surge. DESIGN: This was a prospective, longitudinal, population-based study. SETTING: The study was performed at two primary obstetric centers. PARTICIPANTS: Study participants included 388 Finnish and 433 Danish boys (88 and 34 with cryptorchidism, respectively). Interventions: Clinical examinations were performed at 0 and 3 months. Blood samples were taken at 3 months. MAIN OUTCOME MEASURES: The main outcome measures were testis position and reproductive hormone levels. RESULTS: Finnish cryptorchid boys had significantly higher FSH [1.59 (0.50-3.53) vs. 1.30 (0.49-2.92) IU/liter; P < 0.0001] and lower inhibin B [426 (254-770) vs. 459 (266-742) pg/ml; P < 0.015] levels than Finnish control boys [median (2.5th-97.5th percentiles)]. Danish cryptorchid boys had higher FSH levels than controls [1.47 (0.54-3.89) vs. 1.18 (0.41-3.04) IU/liter; P = 0.018]. Inhibin B levels in healthy Danish boys were lower than those in Finnish boys [380 (233-637) pg/ml; P < 0.0001] and were not reduced in Danish crypt-orchid boys [392 (236-672) pg/ml; P = 0.851]. Changes in hormone levels were strongest in boys with severe, persistent cryptorchidism, but were also detectable in mild and transient cryptorchidism. Effects on Leydig cell function were subtle, with an increase in LH in Finnish (but not Danish) cryptorchid boys vs. controls [1.97 (0.77-5.91) vs. 1.75 (0.58-4.04) IU/liter; P < 0.021], but testosterone levels remained within the normal range. CONCLUSIONS: Our results support the hypothesis that cryptorchidism is associated with a primary testicular disorder, which could be a cause or a consequence of cryptorchidism. This malfunction is reflected by low inhibin B production in the Finnish cohort and high gonadotropin drive in both the Finnish and Danish cohorts.
Key Words: Child, Cryptorchidism/blood*, Denmark, Finland, Follicle Stimulating Hormone/blood, Humans, Longitudinal Studies, Luteinizing Hormone/blood, Male, Reference Values, Sex Hormone-Binding Globulin/analysis, Time Factors, Sex Hormone-Binding Globulin, Luteinizing Hormone, Follicle Stimulating Hormone,
Study Synopsis: Geographic differences in sperm quality may be due to differences in exposures to agricultural chemicals. Fertile men from a rural area of Missouri were found to have poorer sperm quality than men from other more urban areas of the US. Men from Missouri were found to have elevated levels of the herbicides alachlor and atrazine, and the insecticide diazinon.
Scientific abstract:
We conducted the first US study to compare semen quality among study centres using standardized methods and strict quality control. We present data on semen quality in partners of 493 pregnant women recruited through prenatal clinics in four US cities during 1999-2001. Sperm concentration, semen volume and motility were determined at the centres and morphology was assessed at a central laboratory. While between-centre differences in sperm morphology and sample volume were small, sperm concentration and motility were significantly reduced in Columbia, MO (MO) relative to men in New York, NY, Minneapolis, MN and Los Angeles, CA; total number of motile sperm was 113 x 10(6) in MO and 162, 201 and 196 x 10(6) in CA, MN and NY respectively. Differences among centres remained significant in multivariate models that controlled for abstinence time, semen analysis time, age, race, smoking, history of sexually transmitted disease and recent fever (all p-values <0.01). We hypothesized that poorer sperm concentration and motility in MO men relative to other centres might be related to agricultural pesticides that are commonly used in the mid-west. We investigated this hypothesis by conducting a nested case-control study within the MO cohort. We selected 25 men in this cohort for whom all semen parameters (concentration, % normal morphology and % motile) were low as cases and an equal number of men for whom all semen parameters were within normal limits as controls. We measured metabolites of eight non-persistent, current-use pesticides in urine samples the men had provided at the time of semen collection. Pesticide metabolite levels were elevated in cases compared with controls for the herbicides alachlor and atrazine, and for the insecticide diazinon (2-isopropoxy-4-methyl-pyrimidinol) (p-values for Wilcoxon rank test = 0.0007, 0.012, and 0.0004 for alachlor, atrazine and diazinon respectively). Men with higher levels of alachlor or diazinon were significantly more likely to be cases than men with low levels [odds ratios (OR) = 30.0, 16.7 for alachlor and diazinon respectively], as were men with atrazine over the limit of detection (OR = 11.3). These associations between current-use pesticides and reduced semen quality suggest that agricultural chemicals may have contributed to the reduced semen quality seen in fertile men from mid-Missouri.
The burden of unwanted infertility appears to be increasing, but links to environmental causes have, until recently, been difficult to establish. A large body of data suggests that sperm counts have been declining in Europe and the United States, but interpretation of these statistical trends remains controversial, and the role of the environment uncertain. We were able to show that some currently used pesticides are significantly associated with reduced sperm concentration by linking pesticide concentration in men's urine to results of their semen analysis. In a follow-up study, we showed that prenatal phthalate exposure was linked to subtle differences in genital development of male offspring that could impact the child's future fertility. Researchers are increasingly able to measure levels of environmental chemicals in human samples, and are using these to identify agents that impair fertility. These methods, rather than trend analyses, may lead more directly--and more persuasively--to identifying the role of environment in human fertility.
Study Synopsis: While first focused on the effects of estrogen mimics, research on endocrine disruption emerging over the past decade has shown many other molecular signaling pathways are also vulnerable to disruption, via several different mechanisms. Endocrine-disrupting chemicals can alter gene expression by activating or antagonizing nuclear hormone receptors, by altering degradation of hormone receptors, and by changing the sensitivity to hormone signaling. Some EDCs alter DNA methylation. Others change lipid metabolism and may contribute to the obesity epidemic.
Scientific abstract:
Endocrine-disrupting chemicals (EDC) are commonly considered to be compounds that mimic or block the transcriptional activation elicited by naturally circulating steroid hormones by binding to steroid hormone receptors. For example, the Food Quality Protection Act of 1996 defines EDC as those, that "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effect as the Administrator may designate." The definition of EDC was later expanded to include those that act on the estrogen, androgen, and thyroid hormone receptors. In this minireview, we discuss new avenues through which xenobiotic chemicals influence these and other hormone-dependent signaling pathways. EDC can increase or block the metabolism of naturally occurring steroid hormones and other xenobiotic chemicals by activating or antagonizing nuclear hormone receptors. EDC affect the transcriptional activity of nuclear receptors by modulating proteasome-mediated degradation of nuclear receptors and their coregulators. Xenobiotics and environmental contaminants can act as hormone sensitizers by inhibiting histone deacetylase activity and stimulating mitogen-activated protein kinase activity. Some endocrine disrupters can have genome-wide effects on DNA methylation status. Others can modulate lipid metabolism and adipogenesis, perhaps contributing to the current epidemic of obesity. Additional elucidation of these new modes of endocrine disruption will be key in understanding the nature of xenobiotic effects on the endocrine system.
Key Words: Animals, DNA Methylation/drug effects, Endocrine Disruptors/toxicity*, Endocrine System/drug effects*, Endocrine System/physiology, Fertility/drug effects, Hormones/metabolism, Humans, Male, Obesity/chemically induced, Proteasome Endopeptidase Complex/drug effects, Proteasome Endopeptidase Complex/metabolism, Receptors-Cytoplasmic and Nuclear/drug effects, Receptors-Cytoplasmic and Nuclear/metabolism, Species Specificity, Spermatozoa/drug effects, Steroids/metabolism, Endocrine Disruptors, Hormones, Receptors-Cytoplasmic and Nuclear, Steroids, Proteasome Endopeptidase Complex, ,
Study Synopsis: Subtle changes seen in the testis of monkeys fed soy formula milk as infants. As adults all of the males fed soy formula were fertile, however they had significantly smaller testis, an increase in Leydig cell numbers and low-normal testosterone levels. Similar changes may occur in adult men who were fed soy formula as infants.
Scientific abstract:
BACKGROUND: This marmoset study addresses concerns about feeding human male infants with soy formula milk (SFM). METHODS: From age 4 to 5 days, seven male co-twin sets were fed standard formula milk (SMA) or SFM for 5-6 weeks; blood samples were subsequently collected at 10-week intervals. Testes from co-twins killed at 120-138 weeks were fixed for cell counts. RESULTS: SFM- and SMA-fed twins showed normal weight gain; puberty started and progressed normally, based on blood testosterone measurements. Body weight, organ weights (prostate, seminal vesicles, pituitary, thymus and spleen) and penis length were comparable in co-twins. All SMA- and 6/7 SFM-fed males were fertile. Unexpectedly, testis weight (P = 0.041), Sertoli (P = 0.025) and Leydig cell (P = 0.026) numbers per testis were consistently increased in SFM-fed co-twins; the increase in Leydig cell numbers was most marked in males with consistently low-normal testosterone levels. Seminiferous epithelium volume per tubule showed a less consistent, non-significant increase in SFM-fed males; raised germ cell numbers per testis, probably due to increased Sertoli cells, conceivably resulted in larger testes. Average lumen size, although greater in SFM-fed group, was inconsistent between co-twins and the difference was not significant. CONCLUSIONS: Infant feeding with SFM has no gross adverse reproductive effects in male marmosets, though it alters testis size and cell composition, and there is consistent, if indirect, evidence for possible 'compensated Leydig cell failure'. Similar and perhaps larger changes likely occur in adult men who were fed SFM as infants.
Study Synopsis: Exposure to the fossil fuel combustion products, PAHs, is associated with smaller newborn babies. A group of non-smoking Chinese women who lived near a seasonally operating coal-fired power plant gave samples of their blood and cord blood at the time of delivery. Higher levels of PAH-DNA adducts were associated with smaller head circumference and reduced children's weight at 18, 24, and 30 months of age. Longer exposures during the months the power plant was operating were also associated with reduced growth in infants and toddlers.
Scientific abstract:
Polycyclic aromatic hydrocarbons (PAHs) are an important class of toxic pollutants released by fossil fuel combustion. Other pollutants include metals and particulate matter. PAH-DNA adducts, or benzo[a]pyrene (BaP) adducts as their proxy, provide a chemical-specific measure of individual biologically effective doses that have been associated with increased risk of cancer and adverse birth outcomes. In the present study we examined the relationship between prenatal PAH exposure and fetal and child growth and development in Tongliang, China, where a seasonally operated coal-fired power plant was the major pollution source. In a cohort of 150 nonsmoking women and their newborns enrolled between 4 March 2002 and 19 June 2002, BaP-DNA adducts were measured in maternal and umbilical cord blood obtained at delivery. The number of gestational months occurring during the period of power plant operation provided a second, more general measure of exposure to plant emissions, in terms of duration. High PAH-DNA adduct levels (above the median of detectable adduct level) were associated with decreased birth head circumference (p=0.057) and reduced children's weight at 18 months, 24 months, and 30 months of age (p<0.05), after controlling for potential confounders. In addition, in separate models, longer duration of prenatal exposure was associated with reduced birth length (p=0.033) and reduced children's height at 18 (p=0.001), 24 (p<0.001), and 30 months of age (p<0.001). The findings suggest that exposure to elevated levels of PAHs, with the Tongliang power plant being a significant source, is associated with reduced fetal and child growth in this population.
Key Words: Adult, Birth Weight, Blood Specimen Collection, Body Height, Child Development/*drug effects, Child, Preschool, China/epidemiology, Coal, DNA Adducts/adverse effects/*blood, Data Interpretation, Statistical, Environmental Pollutants/adverse effects/*blood, Female, Fetal Blood/*chemistry, Fetal Development/*drug effects, Growth/drug effects, Humans, Infant, Infant, Newborn, Polycyclic Hydrocarbons, Aromatic/adverse effects/*blood, Power Plants, Pregnancy, Pregnancy Outcome, Questionnaires, Sex Characteristics
Study Synopsis: Foreign-adopted children originating from regions other than Korea and immigrating to Denmark had a 15- to 20-fold increased risk of precocious puberty compared with Danish-born children Adoptees originating from Korea had no increased risk of precocious puberty. In addition, children immigrating with their families had no increased risk of precocious puberty.
Scientific abstract:
BACKGROUND. Studies have indicated that internationally adopted children have an increased risk of developing precocious puberty, but no epidemiologic risk estimates have previously been calculated. We aimed to assess the risk of developing precocious puberty in intercountry adoptees, children immigrating with their family, and descendants of immigrants living in Denmark. METHODS. Patients who were registered with the diagnosis of precocious puberty during the period 1993-2001 were identified through the national patient registry. The background population of children born from 1983 to 2001 were identified through the unique Danish Civil Registration System and subsequently categorized as being Danish (N = 1062333), adopted (N = 10997), immigrating with their family (N = 72181), or being descendants of immigrants (N = 128152). The incidence rate ratio of precocious puberty was estimated by log-linear Poisson regression. All rate ratios were adjusted for age and its interaction with gender and calendar year. P values were based on likelihood ratio tests, and 95% confidence intervals were calculated by Wald's test. RESULTS. In the study period, 655 children developed precocious puberty during 5627763 person-years at risk. Adopted children were followed during 39978 person-years at risk, during which 45 girls and 6 boys developed precocious puberty. The risk of developing precocious puberty was significantly increased 10 to 20 times in adopted girls compared with girls with Danish background. The risk of developing precocious puberty depended on the country of origin. In children immigrating with their family, the risk of developing precocious puberty was only marginally increased. Older age at adoption significantly increased the risk of precocious puberty in adoptees independent of region of origin. The incidence rate ratio was significantly higher in children adopted after the age of 2. In children immigrating with their family, we found no effect of age at migration. DISCUSSION. In this large, nationwide, register-based study including 655 cases of precocious puberty, we found that intercountry boys and girls were 10 to 20 times more likely to develop precocious puberty compared with the Danish reference group. Older age at adoption significantly increased the risk of precocious puberty. Uncertainty of the exact age is a well-known problem in adopted children, and systematic underestimation of age might bias the result. However, using the worst-case scenario that all children who according to the Danish Civil Registration System were adopted after 2 years of age were in fact 1 year older, we still observed a highly increased risk of precocious puberty associated with adoption and especially with adoption after 2 years of age. Surprisingly, the risk of precocious puberty was not increased in the large group of children adopted from Korea. One case of precocious puberty was identified among Korean children, whereas >20 cases of precocious puberty would have been expected if the risk for a Korean child was at the same level as observed among adopted children from India and South America. In the study population, 99% of Korean children were adopted before 2 years of age, which may contribute to explaining our finding. In Korea, children appointed for adoption are often living in foster care settings from birth to adoption, whereas most other countries are reported to take care of the children in orphanages before adoption. It can only be speculated whether a relation between preadoption living conditions and later risk of precocious puberty exists. Genetic factors play a key role in the timing of puberty, and large variations in age at menarche are observed worldwide. Age at menarche is reported to be in the same age range in South Korea as in well-off populations in other parts of the world, indicating that the different risk of precocious puberty observed between Korean and other adoptees probably cannot be explained by genetic factors alone. The finding that the risk of precocious puberty was significantly increase among adoptees in contrast to what was seen in children immigrating with their families contradicts a direct effect of migration. An increasing number of studies have shown long-term effects of certain prenatal and postnatal growth patterns, including advancement in pubertal maturation after poor intrauterine growth and catch-up growth during childhood. Different growth patterns and dietary habits between adoptees and children immigrating with their families might contribute to explain our findings. It has been hypothesized that stressful psychosocial factors in infancy and childhood may lead to earlier pubertal maturation. In general, adoptees have experienced several traumatic life events, and it may be speculated that these events alter the susceptibility for developing precocious puberty. CONCLUSIONS. Foreign-adopted children originating from regions other than Korea had a 15- to 20-fold increased risk of precocious puberty compared with Danish-born children, whereas adoptees originating from Korea had no increased risk of precocious puberty. In addition, children immigrating with their families had no increased risk of precocious puberty. The effect of country of origin might be explained by genetic factors or by different environmental exposures and living conditions in the different countries. Older age at adoption increased the risk for premature onset of puberty, which may suggest that environmental factors influence the risk of precocious pubertal development in adopted children.
Study Synopsis: Self-reported residential pesticide use is associated with a 39% increase in breast cancer risk. Increased risk was seen for lawn and garden pesticide use, but not insect repellants or products to control pet ticks, fleas or lice. This finding comes from a study on Long Island, NY, of 1,508 newly diagnosed women matched with controls. However, there was no indication that higher use caused greater risk.
Scientific abstract:
Pesticides, common environmental exposures, have been examined in relation to breast cancer primarily in occupational studies or exposure biomarker studies. No known studies have focused on self-reported residential pesticide use. The authors investigated the association between reported lifetime residential pesticide use and breast cancer risk among women living on Long Island, New York. They conducted a population-based case-control study of 1,508 women newly diagnosed with breast cancer between August 1996 and July 1997 and 1,556 randomly selected, age-frequency-matched controls. Comprehensive residential pesticide use and other risk factors were assessed by using an in-person, interviewer-administered questionnaire. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Breast cancer risk was associated with ever lifetime residential pesticide use (odds ratio = 1.39, 95% confidence interval: 1.15, 1.68). However, there was no evidence of increasing risk with increasing lifetime applications. Lawn and garden pesticide use was associated with breast cancer risk, but there was no dose response. Little or no association was found for nuisance-pest pesticides, insect repellants, or products to control lice or fleas and ticks on pets. This study is the first known to suggest that self-reported use of residential pesticides may increase breast cancer risk. Further investigation in other populations is necessary to confirm these findings.
Study Synopsis: Scientists studying the ratio of Y to X sperm in men in 4 different areas find contradictory patterns. This ratio should affect the ratio of boys to girls at birth, which in some places has dropped sharply. In Sweden, men with higher levels of the PCB CB-153 or DDE had a higher proprotion of Y-bearing sperm. In Poland, CB-153 was inversely correlated with the ratio. EHP.
Scientific abstract:
OBJECTIVE: Recent studies indicate that persistent organohalogen pollutants (POPs) may contribute to sex ratio changes in offspring of exposed populations. Our aim in the present study was to investigate whether exposure to 2,2 ,4,4 ,5,5 -hexachlorobiphenyl (PCB-153) and dichlorodiphenyldichloroethene (p,p -DDE) affects sperm Y:X chromosome distribution. SUBJECTS AND METHODS: We obtained semen and blood for analysis of PCB-153 and p,p -DDE levels from 547 men from Sweden, Greenland, Poland (Warsaw), and Ukraine (Kharkiv), with regionally different levels of POP exposure. The proportion of Y- and X-chromosome-bearing sperm in the semen samples was determined by two-color fluorescence in situ hybridization analysis. RESULTS: Swedish and Greenlandic men had on average significantly higher proportions of Y sperm (in both cohorts, 51.2%) and correspondingly higher lipid-adjusted concentrations of PCB-153 (260 ng/g and 350 ng/g, respectively) compared with men from Warsaw (50.3% and 22 ng/g) and Kharkiv (50.7% and 54 ng/g). In the Swedish cohort, log-transformed PCB-153 and log-transformed p,p -DDE variables were significantly positively associated with Y-chromosome fractions (p-values 0.04 and <0.001, respectively). On the contrary, in the Polish cohort PCB-153 correlated negatively with the proportion of Y-bearing fraction of spermatozoa (p=0.008). CONCLUSIONS: The present study indicates that POP exposure might be involved in changing the proportion of ejaculated Y-bearing spermatozoa in human populations. Intercountry differences, with different exposure situations and doses, may contribute to varying Y:X chromosome ratios.
Study Synopsis: A survey of reproductive health of women born to women exposed to DES in the womb finds an increased risk of menstrual irregularities and possible infertility. The high risk of reproductive dysfunction seen in women exposed in the womb was not observed, but many women in this third generation post exposure have not yet attempted to start their families. Findings to date include a lower number of live births compared to unexposed.
Scientific abstract:
BACKGROUND: In women, prenatal exposure to diethylstilbestrol (DES) is associated with adult reproductive dysfunction. The mouse model, which replicates many DES outcomes, suggests DES causes epigenetic alterations, which are transmissable to daughters of prenatally exposed animals. We report menstrual and reproductive characteristics in a unique cohort comprising daughters of women exposed prenatally to DES. METHODS: Menstrual and reproductive outcomes and baseline characteristics were assessed by mailed questionnaire in 793 women whose mothers had documented information regarding in utero DES exposure. RESULTS: Mean age at menarche was 12.6 years in both groups, but daughters of the exposed women attained menstrual regularization later (mean age of 16.2 years vs. 15.8 years; P = 0.05), and were more likely to report irregular menstrual periods, odds ratio (OR) = 1.54 [95% confidence interval (95% CI 1.02-2.32)]. A possible association between mothers' DES exposure and daughters' infertility was compatible with chance, age, and cohort adjusted OR = 2.19 (95% CI 0.95-5.07). We found limited evidence that daughters of the exposed had more adverse reproductive outcomes, but daughters of exposed women had fewer live births (1.6) than the unexposed (1.9) (P = 0.005). CONCLUSIONS: The high risk of reproductive dysfunction seen in women exposed to DES in utero was not observed in their daughters, but most women in our cohort have not yet attempted to start their families, and further follow-up is needed to assess their reproductive health. Our findings of menstrual irregularity and possible infertility in third-generation women are preliminary but compatible with speculation regarding transgenerational transmission of DES-related epigenetic alterations in humans.
van den Hazel P, Zuurbier M, Babisch W, Bartonova A, Bistrup ML, Bolte G, Busby C, Butter M, Ceccatelli S, Fucic A, Hanke W, Johansson C, Kohlhuber M, Leijs M, Lundqvist C, Moshammer H, Naginiene R, Preece A, Ronchetti R, Salines G, Saunders M, Schoeters G, Stilianakis N, ten Tusscher G, Koppe JG. Today's epidemics in children: Possible relations to environmental pollution and suggested preventive measures. Acta Paediatr Suppl. 2006 Oct;95(453):18-25.
Study Synopsis: Public health officials in the Netherlands recommend preventive measures for childhood diseases. These recommendations include: immediate research on endocrine disruption and prematurity; promotion of breast-feeding; and avoidance of exposure to persistent pollutants. The officials also recommend pre-conception counseling to avoid potentially harmful substances.
Scientific abstract:
Background: Facts and hypotheses on the relationship between some children's diseases or disorders and external stressors during the developmental stage of a child, both prenatally and postnatally are described in literature. In this paper the following changes in patterns and causes of the main childhood illnesses are summarized and recommendations for actions are made.PrematurityIntra-uterine growth restrictionTesticular dysgenesis syndromeType I and Type II diabetesAsthma, atopy and hay feverAutismAttention deficit hyperactivity disorder (ADHD)Learning disabilitiesCancerObesityHearing problemsResults: Literature provides a growing amount of information on changing patterns in childhood diseases.Conclusions: The following recommendations for action are formulated:Immediate research on endocrine disrupters in relation to prematurityDiabetes: avoid Maillard Compounds in liquid baby food and in food in general: promote breastfeedingAsthma: avoid exposure to smoking, the use of chemical household products, dioxin and dioxin-like chemicals, and avoid air pollution with high levels of particulate matter, especially around conception, during pregnancy and in the first years of lifeAutism: more research on incidence and causesADHD and learning disabilities: more research on prevalence and causes. Preventions: 1) preconception counselling to avoid potentially harmful substances; 2) controlling and further lowering levels of polychlorinated biphenyls, lead and methyl mercuryCancer: promote breastfeeding, carry out research into effects of foetal exposure to internal fission-product radionuclidesObesity: stop smoking in pregnancy, avoid parental obesity, longer night sleepHearing problems: lower noise levels in discotheques, promote the day-evening-night level to avoid noise (longer night sleep).
Study Synopsis: At environmentally- relevant levels, the anti-bacterial agent triclosan interferes with thyroid control of metamorphosis in frogs. This is the first demonstration of low-level impacts of triclosan on thyroid hormone function. Exposure to as little as 0.15 micrograms/L triclosan caused an earlier metamorphosis than normal, with effects on the tadpole brain and tail. The study raises new questions about human health risks from triclosan.
Scientific abstract:
We investigated whether exposure to environmentally relevant concentrations of the bactericidal agent, triclosan, induces changes in the thyroid hormone-mediated process of metamorphosis of the North American bullfrog, Rana catesbeiana and alters the expression profile of thyroid hormone receptor (TR) alpha and beta, basic transcription element binding protein (BTEB) and proliferating nuclear cell antigen (PCNA) gene transcripts. Premetamorphic tadpoles were immersed in environmentally relevant concentrations of triclosan and injected with 1 x 10(-11)mol/g body weight 3,5,3'-triiodothyronine (T3) or vehicle control. Morphometric measurements and steady-state mRNA levels obtained by quantitative polymerase chain reaction were determined. mRNA abundance was also examined in Xenopus laevis XTC-2 cells treated with triclosan and/or 10nM T3. Tadpoles pretreated with triclosan concentrations as low as 0.15+/-0.03 microg/L for 4 days showed increased hindlimb development and a decrease in total body weight following T3 administration. Triclosan exposure also resulted in decreased T3-mediated TRbeta mRNA expression in the tadpole tail fin and increased levels of PCNA transcript in the brain within 48 h of T3 treatment whereas TRalpha and BTEB were unaffected. Triclosan alone altered thyroid hormone receptor alpha transcript levels in the brain of premetamorphic tadpoles and induced a transient weight loss. In XTC-2 cells, exposure to T3 plus nominal concentrations of triclosan as low as 0.03 microg/L for 24h resulted in altered thyroid hormone receptor mRNA expression. Exposure to low levels of triclosan disrupts thyroid hormone-associated gene expression and can alter the rate of thyroid hormone-mediated postembryonic anuran development.
Study Synopsis: A novel endocrine disruptor has been identified that has dual mechanisms of action by acting as an antiandrogen both by blocking the androgen receptor and by inhibiting fetal steroidogenesis. Prochloraz is an imidazole fungicide that is widely used in Europe, Australia, Asia and South America for gardening and agriculture. In studies of rats exposed in the womb, prochloraz feminizes the male offspring by decreasing testosterone concentrations, causing nipple retention and feminized behavior. These effects are due, at least in part, to diminished fetal steroidogenesis.
Scientific abstract:
Prochloraz is an imidazole fungicide that is widely used in Europe, Australia, Asia and South America within gardening and agriculture. Screening studies have shown that prochloraz elicits multiple mechanisms of action in vitro, as it antagonizes the androgen and the oestrogen receptor, agonizes the Ah receptor and inhibits aromatase activity. In vivo prochloraz acts as an antiandrogen in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions in the prostate and increasing luteinizing hormone levels. In order to investigate the developmental effects of prochloraz, pregnant Wistar dams were dosed perinatally with 30 mg/kg prochloraz. Results showed that prochloraz significantly reduced plasma and testicular testosterone levels in gestational day 21 male foetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. In male pups a significant increase in nipple retention was found, and the weight of the bulbourethral glands was decreased. Behavioural studies showed that the activity level and sweet preference of adult males were significantly increased, indicating that exposure during gestation and lactation causes permanent effects in adulthood. Overall, these results indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis. Thus, a novel endocrine disruptor has been identified that is mechanistically interesting as it elicits dual mechanisms of action and acts as an antiandrogen both by blocking the androgen receptor and by inhibiting fetal steroidogenesis. That a fungicide with such effects is so widely used is a cause for concern, and its use should be reduced, thereby minimizing the risk of human exposure.
Study Synopsis: A detailed analysis of the studies industry uses to defend bisphenol A reveals deep flaws and strong biases against finding adverse effects. Not only is industry's own research flawed, but they have repeatedly chosen to ignore all but a handful of the studies on low level effects of bisphenol A that have been published in the peer-reviewed scientific literature. Most Americans are exposed to this contaminant at levels that cause effects in animals.
Over six-billion pounds per year of the monomer bisphenol A (BPA) are used to manufacture polycarbonate plastic products, resins lining cans, dental sealants, and polyvinyl chloride plastic products. There are 109 published studies as of July 2005 that report significant effects of low doses of BPA in experimental animals, with many adverse effects occurring at blood levels in animals within and below average blood levels in humans; 40 studies report effects below the current reference dose of 50 microg/kg/day that is still assumed to be safe by the US-FDA and US-EPA in complete disregard of the published findings. The extensive list of significant findings from government-funded studies is compared to the 11 published studies that were funded by the chemical industry, 100% of which conclude that BPA causes no significant effects. We discuss the importance of appropriate controls in toxicological research and that positive controls are required to determine whether conclusions from experiments that report no significant effects are valid or false.
Key Words: Animals, Diethylstilbestrol/toxicity, Environmental Pollutants/*toxicity, Estrogens, Non-Steroidal/*toxicity, Female, Humans, Male, Phenols/*toxicity, *Research Design, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Risk Assessment, Toxicity Tests/*methods, United States, United States Environmental Protection Agency, United States Food and Drug Administration
Study Synopsis: Exposure to high levels of arsenic in West Bengal, India is associated with an increase in stillbirth. Exposure to high concentrations of arsenic (=200 µg/liter) during pregnancy was associated with a sixfold increased risk of stillbirth. Women with skin lesions caused by arsenic had a 13-fold increase in stillbirth. There was only a weak association with neonatal death and no association was found between arsenic and miscarriage or overall infant mortality.
Scientific abstract:
Between 2001 and 2003, the authors studied pregnancy outcomes and infant mortality among 202 married women in West Bengal, India. Reproductive histories were ascertained using structured interviews. Arsenic exposure during each pregnancy, including all water sources used, was assessed; this involved measurements from 409 wells. Odds ratios for spontaneous abortion, stillbirth, neonatal mortality, and infant mortality were estimated with logistic regression based on the method of generalized estimating equations. Exposure to high concentrations of arsenic (> or =200 microg/liter) during pregnancy was associated with a sixfold increased risk of stillbirth after adjustment for potential confounders (odds ratio (OR) = 6.07, 95% confidence interval (CI): 1.54, 24.0; p = 0.01). Arsenic-related skin lesions were found in 12 women who had a substantially increased risk of stillbirth (OR = 13.1, 95% CI: 3.17, 54.0; p = 0.002). The odds ratio for neonatal death was 2.81 (95% CI: 0.73, 10.8). No association was found between arsenic exposure and spontaneous abortion (OR = 1.01, 95% CI: 0.38, 2.70) or overall infant mortality (OR = 1.33, 95% CI: 0.43, 4.04). This study adds to the limited evidence that exposure to high concentrations of arsenic during pregnancy increases the risk of stillbirth. However, there was no indication of the increased rates of spontaneous abortion and overall infant mortality that have been reported in some studies. After adjusting for socioeconomic variables and other potential confounders, the research team found a six-fold increase in risk of stillbirth among women drinking water during pregnancy with arsenic levels > 200 _g/liter. And among those women who were found to have developed arsenic-caused skin lesions, the risk of having a stillbirth was increased 13-fold. The risk of neonatal death was increased more than twofold at exposure levels of > 200 _g/liter compared with levels below 50 _g/liter, but the confidence interval was wide and included unity. No association between arsenic and spontaneous abortion was found and no increase in overall infant mortality was seen with prenatal arsenic exposure or exposure during the first year of life.
Key Words: Arsenic Poisoning/complications*, Arsenic Poisoning/epidemiology*, Confounding Factors (Epidemiology), Female, Humans, India/epidemiology, Infant Mortality*, Infant-Newborn, Interviews as Topic, Logistic Models, Pregnancy, Pregnancy Outcome/epidemiology*, Risk Factors, Water Pollutants-Chemical/analysis*, Water Pollutants-Chemical
Study Synopsis: Human exposures to the plasticizer, bisphenol A, are occurring a doses shown to cause adverse effects in animal studies. Although the industry manufacturing this chemical claim it is a "weak estrogen", laboratory studies have shown BPA disrupts estrogen action at very low concentrations, in the ppt - ppb range. Similar concentrations have been measured in human blood, including the cord blood of developing infants. Widespread exposure to BPA at current levels could be causing adverse effects to the human reproductive tract.
Scientific abstract:
Over 6-billion pounds per year of the estrogenic monomer bisphenol A (BPA) are used to manufacture polycarbonate plastic products, resins lining metal cans, dental sealants and in blends with other types of plastic products. The ester bond linking BPA molecules in polycarbonate and resins undergoes hydrolysis, resulting in the release of free BPA into food, beverages and the environment, and numerous monitoring studies now show almost ubiquitous human exposure to biologically active levels of this chemical. BPA exerts estrogenic effects through the classical nuclear estrogen receptors, and BPA acts as a selective estrogen receptor modulator (SERM). However, BPA also initiates rapid responses via estrogen receptors presumably associated with the plasma membrane. Similar to estradiol, BPA causes changes in some cell functions at concentrations between 1 pM and 1 nm, and the mean and median range of unconjugated BPA measured by multiple techniques in human pregnant maternal, fetal and adult blood and other tissues exceeds these levels. In contrast to these published findings, BPA manufacturers persist in describing BPA as a weak estrogen and insist there is little concern with human exposure levels. Our concern with human exposure to BPA derives from 1) identification of molecular mechanisms mediating effects in human and animal tissues at very low doses, 2) in vivo effects in experimental animals caused by low doses within the range of human exposure, and 3) widespread human exposure to levels of BPA that cause adverse effects in animals.
Study Synopsis: A common plastic molecule to which virtually all Americans are exposed may interfere with the standard medical treatment for prostate cancer, according to new experiments with human prostate tumors implanted into mice. The doses of the plastic molecule, bisphenol A, were chosen specifically to be within the range of common human exposures. Tumor sizes and PSA levels were significantly greater in exposed animals just one month after treatment.
Prostatic adenocarcinomas depend on androgen for growth and survival. First line treatment of disseminated disease exploits this dependence by specifically targeting androgen receptor function. Clinical evidence has shown that androgen receptor is reactivated in recurrent tumors despite the continuance of androgen deprivation therapy. Several factors have been shown to restore androgen receptor activity under these conditions, including somatic mutation of the androgen receptor ligand-binding domain. We have shown previously that select tumor-derived mutants of the androgen receptor are receptive to activation by bisphenol A (BPA), an endocrine-disrupting compound that is leached from polycarbonate plastics and epoxy resins into the human food supply. Moreover, we have shown that BPA can promote cell cycle progression in cultured prostate cancer cells under conditions of androgen deprivation. Here, we challenged the effect of BPA on the therapeutic response in a xenograft model system of prostate cancer containing the endogenous BPA-responsive AR-T877A mutant protein. We show that after androgen deprivation, BPA enhanced both cellular proliferation rates and tumor growth. These effects were mediated, at least in part, through androgen receptor activity, as prostate-specific antigen levels rose with accelerated kinetics in BPA-exposed animals. Thus, at levels relevant to human exposure, BPA can modulate tumor cell growth and advance biochemical recurrence in tumors expressing the AR-T877A mutation.
Study Synopsis: Recreational use of marijuana is likely to reduce male fertility. Human donor sperm exposed to the active cannabinoid in marijuana, THC, had significantly decreased motility and fertilizing potential. These effects occurred at concentrations of THC associated with recreational use. The effects were more pronounced in sperm of poorer quality.
Scientific abstract:
OBJECTIVE: To investigate effects of delta-9-tetrahydrocannabinol (THC) on human sperm function in vitro. DESIGN: Laboratory analysis of sperm motility after exposure to THC using computer-assisted semen analysis and acrosome reaction by fluoroscein isothiocyanate-labeled peanut agglutinin staining. SETTING: An assisted reproductive technology unit. PATIENT(S): Seventy-eight male patients. INTERVENTION(S): Sperm were divided into 90% (the best fertilizing potential used in assisted conception) and 45% (the poorer subpopulation) fractions by density centrifugation and incubated with THC at concentrations equivalent to therapeutic (0.032 microM) and recreational (0.32 and 4.8 microM) plasma levels at 37 degrees C for 3 h. MAIN OUTCOME MEASURE(S): Sperm motility and spontaneous and induced acrosome reactions. RESULT(S): Percentage progressive motility was decreased dose dependently in the 90% fraction (by 2%-21%; P<.05; P<.001). The 45% fraction showed a greater decrease in percentage progressive motility (by 28% at 0.032 microM; 56% at 4.8 microM; P=.004 and P=.01 res). Straight line velocity and the average path velocity also were reduced (by 10%, in the 90% LAYER) in both fractions. Spontaneous acrosome reactions were reduced in the 90% (17% at 0.032 microM, 35% at 4.8 microM P=.004 and P<.001 resp) and more markedly in the 45% fractions (17%-35%; P<.001). When the acrosome reaction was artificially induced (90% fraction) by A23187, THC (4.8 microM) resulted in a 57% inhibition (P<.001). CONCLUSION(S): The use of THC as a recreational drug may adversely affect male fertility.
Study Synopsis: Growing evidence indicates endocrine disrupting chemicals not only interact with hormone receptors but also modulate the activity of steroidogenic enzymes. This review summarizes the evidence for EDCs as modulators of steroidogenic enzymes, identifies the structure/activity relationship in terms of inhibiting specific enzyme activity, questions whether experimental observations can equate with natural in vivo exposure or dietary intake of EDCs, and finally looks at the mechanisms through which these chemicals may disrupt normal steroidogenesis. Bailličre's best practice & research.
Scientific abstract:
Endocrine-disrupting chemicals (EDCs) are typically identified as compounds that can interact with oestrogen or androgen receptors and thus act as agonists or antagonists of endogenous hormones. Growing evidence shows that they may also modulate the activity/expression of steroidogenic enzymes. These are expressed not only in the adrenal glands and gonads but also in many tissues that have the ability to convert circulating precursors into active hormones. In this way, EDCs may impact both on sexual differentiation and development and on hormone-dependent cancers. This review summarizes the evidence for EDCs as modulators of steroidogenic enzymes, identifies the structure/activity relationship in terms of inhibiting specific enzyme activity, questions whether experimental observations can equate with natural in vivo exposure or dietary intake of EDCs, and finally looks at the mechanisms through which these chemicals may disrupt normal steroidogenesis. In summarizing the evidence, the question of whether or not the dietary intake of these endocrine disrupters could pose a threat to human sexual development and health will be addressed.
Study Synopsis: As men get older, their sperm deteriorates increasing the risk of abnormal pregnancies. Compared with men in their 20's, those who were over 40 had almost twice as much sperm DNA fragmentation, which is associated with failures of fertility, conception and sustained pregnancy. Age did not have an effect on the amount of aneuploidy or sex ratio. However, for a gene that causes dwarfism, the researchers found a 2 percent increase in the frequency of the mutation for each year of increasing age.
Scientific abstract:
This study compares the relative effects of advancing male age on multiple genomic defects in human sperm [DNA fragmentation index (DFI), chromatin integrity, gene mutations, and numerical chromosomal abnormalities], characterizes the relationships among these defects and with semen quality, and estimates the incidence of susceptible individuals for a well characterized nonclinical nonsmoking group of 97 men (22-80 years). Adjusting for confounders, we found major associations between age and the frequencies of sperm with DFI and fibroblast growth factor receptor 3 gene (FGFR3) mutations associated with achondroplasia (P < 0.01) with no evidence for age thresholds. However, we found no associations between age and the frequencies of sperm with immature chromatin, aneuploidies/diploidies, FGFR2 mutations (Apert syndrome), or sex ratio in this cohort. There were also no consistent correlations among genomic and semen-quality endpoints, except between DFI and sperm motility (r = -0.65, P < 0.001). These findings suggest there are multiple spermatogenic targets for genomically defective sperm with substantially variable susceptibilities to age. Our findings predict that as healthy males age, they have decreased pregnancy success with trends beginning in their early reproductive years, increased risk for producing offspring with achondroplasia mutations, and risk of fathering offspring with Apert syndrome that may vary across cohorts, but with no increased risk for fathering aneuploid offspring (Down, Klinefelter, Turner, triple X, and XYY syndromes) or triploid embryos. Our findings also suggest that the burden of genomic damage in sperm cannot be inferred from semen quality, and that a small fraction of men are at increased risk for transmitting multiple genetic and chromosomal defects.
Study Synopsis: Your infertility may be the result of an environmental exposure that your great-grandmother experienced while she was in her mother's womb. Scientists working with rats have discovered a new mechanism by which fertility impairments can be passed down multiple generations through exposure to endocrine disrupting compounds, even though exposure only took place in the first generation.
Transgenerational effects of environmental toxins require either a chromosomal or epigenetic alteration in the germ line. Transient exposure of a gestating female rat during the period of gonadal sex determination to the endocrine disruptors vinclozolin (an antiandrogenic compound) or methoxychlor (an estrogenic compound) induced an adult phenotype in the F1 generation of decreased spermatogenic capacity (cell number and viability) and increased incidence of male infertility. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined (that is, F1 to F4). The effects on reproduction correlate with altered DNA methylation patterns in the germ line. The ability of an environmental factor (for example, endocrine disruptor) to reprogram the germ line and to promote a transgenerational disease state has significant implications for evolutionary biology and disease etiology.
Study Synopsis: Prenatal estrogen exposure is associated with the development of uterine fibroids, benign tumors of the uterus. Women exposed to DES prenatally were found to have approximately a 25% higher incidence of uterine fibroids than women who were not exposed. Women exposed to DES also tended to have larger fibroids than women who were not exposed.
Scientific abstract:
Early life exposure to DES causes uterine leiomyomata in laboratory animals. We examined the relationship between prenatal DES exposure and development of uterine leiomyomata in women. Among randomly selected study participants (819 black women, 504 white women), leiomyoma status was determined by ultrasound screening (70%) or surgical record review (7%). We relied on self-report of prior diagnosis in 13%. Leiomyoma status could not be ascertained for 10% and they were excluded from analyses. Prenatal DES exposure was assessed by interview. All five of the black women who reported DES exposure had leiomyomata. Among white women, 76% who reported prenatal DES exposure had leiomyomata compared with 52% of the unexposed (adjusted odds ratio for whites: 2.4; 95% confidence interval CI: 1.1-5.4). Exposed women tended to have larger tumors. Results were robust to sensitivity analyses. Findings support experimental animal data and indicate a role for prenatal estrogen exposure in the etiology of human uterine leiomyoma.
Key Words: Adult, Carcinogens/*adverse effects, Diethylstilbestrol/*adverse effects, District of Columbia/epidemiology, Female, Humans, Leiomyoma/*chemically induced/epidemiology/pathology, Maternal Exposure/*adverse effects, Middle Aged, Odds Ratio, Pregnancy, *Prenatal Exposure Delayed Effects, Research Support, U.S. Gov't, P.H.S., Uterine Neoplasms/*chemically induced/epidemiology/pathology
Although prenatal factors are associated with testicular cancer etiology, few studies have examined the reproductive profiles of men prior to diagnosis. This case--control study investigated fertility patterns prior to testicular cancer diagnosis by comparing pregnancies fathered by 201 men with testicular cancer and those fathered by 204 age- and neighborhood-matched controls. Regardless of histology, men with testicular cancer were less likely to have ever fathered a live-born infant (OR 0.67, 95% CI 0.42--1.06) and had fewer offspring than control men (means 1.8 and 2.1, respectively). Cases were more likely than controls to report having an infertility diagnosis (OR 9.47, 95% CI 1.19--75.2) or a low sperm count (OR 5.85, 95% CI 1.28--26.7) prior to cancer diagnosis. No differences were observed for pregnancy loss. These results indicate that men with testicular cancer may have impaired fecundity and fertility as evidenced by an infertility diagnosis or low sperm count and fewer live births. Further research is needed to determine the extent to which reproductive factors are involved in the etiology of testicular cancer.
Study Synopsis: The theory that finger length can predict male reproductive function is disproven. Because genes controlling finger development also control differentiation of genitalia, it was proposed that finger length may correlate with testicular function. However, in a study of young, normal Danish men, no correlation was found.
Scientific abstract:
BACKGROUND: It has been suggested that finger length may correlate with function or disorders of the male reproductive system. This is based on the HOXA and HOXD genes' common embryological control of finger development and differentiation of the genital bud. The objective of this study was to explore the association between the ratio of 2nd to 4th finger length (2D:4D ratio) and testis function in a sample of young Danish men from the general population. METHODS: Semen samples and finger measurements were obtained from a total of 360 young Danish men in addition to blood samples for sex hormone analysis to describe the possible association between 2D:4D and semen and sex-hormone parameters. RESULTS: A statistically significant inverse association with the 2D:4D was found only in relation to hormone levels of FSH in the group of young men with a 2D:4D >1 (P = 0.036) and a direct association with the total sperm count in the group of young men with a 2D:4D < or = 1 (P = 0.045). CONCLUSION: The statistically significant results may be 'false positives' (type I error) rather than representing true associations. This relatively large study of young, normal Danish men shows no reliable association between 2D:4D finger ratio and testicular function. Measurements of finger lengths do not have the power to predict the testicular function of adult men.
Mice conceived 6 weeks after paternal exposure to ionizing radiation were fathered by sperm that were Type B spermatogonia at the time of irradiation. Previous studies of these offspring showed that this paternal F0 germ cell irradiation led to decreased embryonic cell proliferation rates, altered enzyme activities, protein levels and whole-body weights. In the present study, we examined four generations of CD1 mice following paternal F0 irradiation of the Type B spermatogonia (1.0 Gy, (137)Cs gamma rays) to determine the stability of the heritable effects. Offspring were evaluated for changes in protein kinase C and mitogen-activated protein kinase enzyme activities and Trp53 and p21(waf1) protein levels. Two or more endpoints were significantly altered in all four generations of offspring from the irradiated F0 sire (P Key Words: Animals, Cell Cycle Proteins/metabolism, Cyclin-Dependent Kinase Inhibitor p21, Female, *Gamma Rays, *Genomic Instability, Male, Mice, Mice, Inbred Strains, Mitogen-Activated Protein Kinase Kinases/metabolism, Protein Kinase C/metabolism, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Spermatogonia/*radiation effects, Tumor Suppressor Protein p53/metabolism
Increasing rates of cryptorchidism and hypospadias in human populations may be caused by exogenous environmental agents. We conducted a case-control study of serum levels of p,p'-dichlorodiphenyltrichloroethane (DDT) and its major metabolite, p,p'-dichlorodiphenyldichloroethylene (DDE), and cryptorchidism and hypospadias in the Child Health and Development Study, a longitudinal cohort of pregnancies that occurred between 1959 and 1967, a period when DDT was produced and used in the United States. Serum was available from the mothers of 75 male children born with cryptorchidism, 66 with hypospadias, and 4 with both conditions. We randomly selected 283 controls from the cohort of women whose male babies were born without either of these conditions. Overall, we observed no statistically significant relationships or trends between outcomes and serum measures. After adjusting for maternal race, triglyceride level, and cholesterol level, compared with boys whose mothers had serum DDE levels < 27.0 ng/mL, boys whose mothers had serum DDE levels > or = 61.0 ng/mL had odds ratios of 1.34 [95% confidence interval (CI), 0.51-3.48] for cryptorchidism and 1.18 (95% CI, 0.46-3.02) for hypospadias. For DDT, compared with boys whose mothers had serum DDT levels < 10.0 ng/mL, boys whose mothers had serum DDT levels > or = 20.0 ng/mL had adjusted odds ratios of 1.01 (95% CI, 0.44-2.28) for cryptorchidism and 0.79 (95% CI, 0.33-1.89) for hypospadias. This study does not support an association of DDT or DDE and hypospadias or cryptorchidism.
CONTEXT: Hypospadias is one of the most frequent male congenital malformations and may be part of the testicular dysgenesis syndrome. OBJECTIVE: The aim of the study was to investigate the prevalence of hypospadias in Denmark and evaluate the relationship to anthropometrical measurements at birth and reproductive hormone levels at 3 months of age. DESIGN: A prospective cohort study was conducted with 3-yr follow-up (1997-2004). SETTING: The population-based study was conducted at the University Hospital of Copenhagen. PARTICIPANTS: A total of 1072 Danish boys were consecutively recruited antenatally, with 74.4% completing the study. MAIN OUTCOME MEASURES: The study examined the position of the urethral meatus, anthropometrical measurements, placental weight, and reproductive hormone levels. RESULTS: The Danish birth prevalence of hypospadias was significantly higher than in a concomitant Finnish study (1.03 vs. 0.27%; P = 0.012). At 3 yr, the true prevalence was found to be 4.64% because additional mild cases were detected when physiological phimosis dissolved. Weight for gestational age (percentage deviation from expected mean) (-5.00 vs. -0.59%; P = 0.030) and placental weight (567 vs. 658 g; P = 0.023) were significantly lower, and FSH was significantly higher (1.48 vs. 1.15 IU/liter; P = 0.007) in boys with hypospadias, compared with healthy boys. CONCLUSIONS: We found a surprisingly high total rate of hypospadias of 4.6% in this large prospective cohort study. Seventy-two percent of the cases were apparent only after the prepuce could be retracted. Hypospadias were associated with elevated serum FSH levels at 3 months. We also confirmed an association between fetal growth impairment and hypospadias; however, it is yet unknown whether this indicates a causal relationship or a shared pathogenic factor.
Endocrine disruptors (EDs) are exogenous environmental molecules that may affect the synthesis, secretion, transport, metabolism, binding, action, and catabolism of natural hormones in the body. EDs may thus interact with the endocrine system of animals and humans and can exert this effect even when present in minute amounts. EDs have adverse impacts on a number of developmental functions in wildlife and humans. Critical periods of urogenital tract and nervous system development in-utero and during early post-natal life are especially sensitive to hormonal disruption. Furthermore a wide range of hormone-dependent organs (pituitary gland, hypothalamus, reproductive tract) are targets of EDs disrupting effects in adult subjects, possibly resulting in cell transformation and cancer. At present about 60 chemicals have been identified and characterized as EDs and belong to three main groups: (a) synthetic compounds utilized in industry, agriculture and consumer products; (b) synthetic molecules used as pharmaceutical drugs and (c) natural chemicals found in human and animal food (phytoestrogens). In the present review we will give special attention to the family of Polychlorinated biphenyls (also indicated as PCBs) because of their persistence in the environment, ability to concentrate up the food chain, continued detection in environmental matrices, and ability to be stored in the adipose tissue of animals as well as humans. The detrimental effects of these compounds, and of EDs more in general, on health and reproduction will be discussed, presenting experimental data aimed at understanding the molecular mechanisms involved in their action.
Study Synopsis: An experimental analysis of the effect of estrogenic chemicals on feminization of male fish shows that concentrations of chemicals that show no effect when applied singly may provoke substantial effects when acting in combination. The study provides strong evidence of the capacity for estrogenic chemicals to act in combination even at the low-effect concentrations encountered in the environment. The scientists who carried out the research conclude that the failure of current risk assessment practice to incorporate the combined effects of chemicals in mixtures "will undoubtedly lead to the underestimation of potential hazards and hence erroneous conclusions regarding the risk that they pose." Other research has established that mixtures are ubiquitous.
Scientific abstract:
Existing environmental risk assessment procedures are limited in their ability to evaluate the combined effects of chemical mixtures. We investigated the implications of this by analyzing the combined effects of a multicomponent mixture of five estrogenic chemicals using vitellogenin induction in male fathead minnows as an end point. The mixture consisted of estradiol, ethynylestradiol, nonylphenol, octylphenol, and bisphenol A. We determined concentration-response curves for each of the chemicals individually. The chemicals were then combined at equipotent concentrations and the mixture tested using fixed-ratio design. The effects of the mixture were compared with those predicted by the model of concentration addition using biomathematical methods, which revealed that there was no deviation between the observed and predicted effects of the mixture. These findings demonstrate that estrogenic chemicals have the capacity to act together in an additive manner and that their combined effects can be accurately predicted by concentration addition. We also explored the potential for mixture effects at low concentrations by exposing the fish to each chemical at one-fifth of its median effective concentration (EC50). Individually, the chemicals did not induce a significant response, although their combined effects were consistent with the predictions of concentration addition. This demonstrates the potential for estrogenic chemicals to act additively at environmentally relevant concentrations. These findings highlight the potential for existing environmental risk assessment procedures to underestimate the hazard posed by mixtures of chemicals that act via a similar mode of action, thereby leading to erroneous conclusions of absence of risk.
Key Words: Animals, Cyprinidae, Drug Synergism, Estradiol/*toxicity, Estrogens/toxicity, Estrogens, Non-Steroidal/toxicity, Ethinyl Estradiol/*toxicity, Female, Forecasting, Fresh Water, Male, Phenols/*toxicity, Research Support, Non-U.S. Gov't, Vitellogenins/*biosynthesis/blood, Water Pollutants, Chemical/toxicity
Buck Louis GM, Weiner JM, Whitcomb BW, Sperrazza R, Schisterman EF, Lobdell DT, Crickard K, Greizerstein H, Kostyniak PJ. Environmental pcb exposure and risk of endometriosis. Hum Reprod. 2005 Jan;20(1):279-85.
Study Synopsis: Polychlorinated biphenyls (PCBs) are synthetic chemicals formerly used in electrical transformers, inks, plastics and other consumer products. PCBs persist in the environment, accumulate in human fatty tissue and are detected in the blood of virtually all human populations. In this study, researchers measured the blood levels of PCBs in 84 women undergoing laparoscopy to diagnose endometriosis, a condition characterized by the growth of tissue normally found in the uterus on other organs or structures. Endometriosis may cause infertility, abdominal pain and abnormal menses. Women with endometriosis had higher blood concentrations of PCBs suspected of inhibiting the effects of the hormone estrogen. Results of this study suggest that blood levels of anti-estrogenic PCBs may be associated with endometriosis. It is however possible that the higher blood PCB levels observed in women with endometriosis may be due to a reduced capability to eliminate PCBs. In addition, these results may not be applicable to the general population as only women undergoing laparoscopy were enrolled in this study.
Scientific abstract:
BACKGROUND: Hormonally active environmental agents have recently been associated with the development of endometriosis. METHODS: We undertook a study to assess the relationship between endometriosis, an estrogen-dependent gynaecological disease, and 62 individual polychlorinated biphenyl (PCBs) congeners. We enrolled 84 eligible women aged 18-40 years undergoing laparoscopy for study, which included an interview and blood specimen (n=79; 94%). Thirty-two women had visually confirmed endometriosis at laparoscopy while 52 did not. Blood specimens were run in batches of 14 including four quality control samples for toxicological analysis. Each PCB congener was adjusted for recovery; batch-specific reagent blanks were subtracted. All PCB concentrations were log transformed and expressed in ng/g serum first as a sum and then as tertiles by purported estrogenic or anti-estrogenic activity of PCB congeners. RESULTS: Using unconditional logistic regression analysis, a significantly elevated odds ratio (OR) was observed for women in the third tertile of anti-estrogenic PCBs [OR 3.77; 95% confidence interval (CI) 1.12-12.68]. Risk remained elevated after controlling for gravidity, current cigarette smoking and serum lipids (OR 3.30; 95% CI 0.87-12.46). CONCLUSIONS: These data suggest that anti-estrogenic PCBs may be associated with the development of endometriosis.
Cagnacci A, Pansini FS, Bacchi-Modena A, Giulini N, Mollica G, Aloysio DD, Vadora E, Volpe A. Seasonal onset of the menopause. Maturitas. 2005;51(4):393-6.
Scientific abstract:
OBJECTIVES: A seasonal rhythm of reproduction is evident in humans. Herein it was investigated whether also the cessation of woman's fertile life follows a seasonal rhythm. METHODS: A retrospective study was performed on 2436 women in postmenopause for more than 12 months, in our menopause centres. Time of menopause was stratified for month and season. The variation was compared to the seasonal rhythm of 14,310 conceptions. RESULTS: The onset of menopause was more frequent (p<0.0001) in winter (32.5%) than in spring (20.8%), autumn (20.3%) and summer (26.2%), in which a minor peak was also observed (p<0.0001 vs. spring and autumn). The two peaks were temporally coincident with the transitions between the high to low and low to high rate of conceptions. CONCLUSIONS: The present data show that in women, like reproduction also the onset of menopause shows a seasonal modulation.
Study Synopsis: New research of Italian women finds season of birth influences the timing of menopause. Those born in March underwent menopause 15 months earlier at age 49 compared those born in October reaching menopause at over 50 years. These results leave open the question of whether environmental factors linked to seasons are capable of interfering with the timing of a woman's ovarian exhaustion by an action exerted in the prenatal period.
Scientific abstract:
BACKGROUND: Seasons may influence prenatal growth and future fertility. This study investigated whether season and month of birth influenced the timing of menopause in a group of women attending three Italian menopause clinics. METHODS and RESULTS: Age at menopause of 2822 post-menopausal women (>12 months of amenorrhoea) was stratified by month and season of birth. Mean age at menopause was 49.42 years (SEM: 0.78 years). Menopause occurred earlier for women born in the spring (age 49.04+/-0.15 years) than in the autumn (49.97+/-0.14 years). The earliest menopause was found in women born in March (48.9+/-0.25 years) and the latest in women born in October (50.3+/-0.25 years). The effect of season of birth on age at menopause remained even when considering factors that in our analysis were capable of significantly interfering with the timing of menopause, such as age at menarche, body mass index, smoking habit, level of education and type of job. CONCLUSIONS: Taking into consideration the retrospective design of the study, and a possible recall bias, the present data seem to suggest that environmental factors linked to seasons are capable of interfering with the timing of a woman's ovarian exhaustion by an action exerted in the prenatal period.
Key Words: Age Factors, Female, Fertility, Humans, Infant, Newborn, Linear Models, *Menopause, Middle Aged, *Parturition, Retrospective Studies, *Seasons
Study Synopsis: Metabolites of bisphenol A were detected in 95% of samples examined in a survey of the chemical's presence in Americans. The study also detected nonylphenol in 51% of samples examined. The concentrations were similar to those observed in other human studies. Bisphenol A has been shown by experimental research to alter physiological pathways important to a wide range of diseases at extremely low levels.
Bisphenol A (BPA) is used to manufacture polycarbonate plastic and epoxy resins, which are used in baby bottles, as protective coatings on food containers, and for composites and sealants in dentistry. 4-Nonylphenol (NP) is used to make nonylphenol ethoxylates, nonionic surfactants applied as emulsifying, wetting, dispersing, or stabilizing agents in industrial, agricultural, and domestic consumer products. The potential for human exposure to BPA and NP is high because of their widespread use. We measured BPA and NP in archived urine samples from a reference population of 394 adults in the United States using isotope-dilution gas chromatography/mass spectrometry. The concentration ranges of BPA and NP were similar to those observed in other human populations. BPA was detected in 95% of the samples examined at concentrations > or = 0.1 microg/L urine; the geometric mean and median concentrations were 1.33 microg/L (1.36 microg/g creatinine) and 1.28 microg/L (1.32 microg/g creatinine), respectively; the 95th percentile concentration was 5.18 microg/L (7.95 microg/g creatinine). NP was detected in 51% of the samples examined > or = 0.1 microg/L. The median and 95th percentile concentrations were < 0.1 microg/L and 1.57 microg/L (1.39 microg/g creatinine), respectively. The frequent detection of BPA suggests widespread exposure to this compound in residents of the United States. The lower frequency of detection of NP than of BPA could be explained by a lower exposure of humans to NP, by different pharmacokinetic factors (i.e., absorption, distribution, metabolism, elimination), by the fact that 4-n-nonylphenol--the measured NP isomer--represents a small percentage of the NP used in commercial mixtures, or a combination of all of the above. Additional research is needed to determine the best urinary biomarker(s) to assess exposure to NP. Despite the sample population's nonrepresentativeness of the U.S. population (although sample weights were used to improve the extent to which the results represent the U.S. population) and relatively small size, this study provides the first reference range of human internal dose levels of BPA and NP in a demographically diverse human population.
Key Words: Adult, Comparative Study, Environmental Monitoring/statistics & numerical data, Environmental Pollutants/*urine, Female, Humans, Male, Middle Aged, Phenols/*urine, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., United States
Study Synopsis: Research in Denmark finds that low sperm counts in an earlier study was not the result of sexual immaturity in the study population. In 2000, a Danish study of young military recruits reported that many of them had low sperm counts, lower than earlier Danish measurements from prior decades. This new study finds that sperm count of a subset of these young men did not increase as they were tracked over the next four years. Hence the low sperm counts are unlikely to be due to sexual immaturity.
Scientific abstract:
BACKGROUND: Several recent studies have reported low sperm concentration in young men recruited from the general population, but it is unknown whether the semen quality of these young men reflects that of more mature men or is reduced due to relative immaturity. We conducted a longitudinal follow-up study to address this question. METHODS: We followed 158 young men (median age = 19.1 years at entry) for up to 4 years and requested quarterly semen samples (total 1838 semen samples) and yearly genital examinations. We examined longitudinal changes in sperm concentration, semen volume, percentage of immotile sperm and percentage of morphologically normal sperm. We used general linear models in which each man served as his own control which also controlled for age, smoking, urogenital infections or disorders, fever and abstinence time. RESULTS: We found no evidence that sperm concentration, total sperm count or percentage of morphologically normal sperm changed appreciably during the 4 years of follow-up. Semen volume appeared to increase slightly with age, perhaps due to greater acceptance of the study protocol by participants. Sperm motility also improved somewhat, although this may, at least in part, reflect a trend in motility measurement. CONCLUSIONS: In this analysis of 1838 semen samples from 158 young men from the Copenhagen area, sperm concentration, total sperm count and sperm morphology did not change significantly during 4 years of follow-up, suggesting that previously reported low sperm concentration and poor sperm morphology among young Danish men are unlikely to be the result of immaturity.
Key Words: Adolescent, Adult, Age Distribution, Denmark/epidemiology, Fever/epidemiology, Follow-Up Studies, Genital Diseases, Male/epidemiology, Humans, Longitudinal Studies, Male, Oligospermia/*epidemiology, Research Support, Non-U.S. Gov't, Seasons, Semen/*cytology, Sexual Abstinence, Sexual Maturation, Sperm Count/*statistics & numerical data, Testis/anatomy & histology
Study Synopsis: CDC study reports the number of women reporting difficulty getting pregnant is increasing. In 2002, about 7.3 million U.S. women self-reported impaired fecundity compared with 6.1 million women in 1995, and 4.9 million in 1988. Although the trend of couples to delay childbirth until later ages may account for some of the increases, a previous Survey found an increasing number of younger women reported difficulty conceiving, suggesting that age alone does not explain the increased rates.
Scientific abstract:
OBJECTIVE: This report presents national estimates of fertility, family planning, and reproductive health indicators among females 15-44 years of age in the United States in 2002 from Cycle 6 of the National Survey of Family Growth (NSFG). For selected indicators, data are also compared with earlier cycles of the NSFG. METHODS: Descriptive tables of numbers and percentages are presented and interpreted. Data were collected through in-person interviews of the household population 15-44 years of age in the United States between March 2002 and March 2003. The sample included 7,643 females and 4,928 males, and this report focuses on data from the female sample. The overall response rate for the Cycle 6 NSFG was 79 percent, and the response rate for women was 80 percent. RESULTS: Given the range of topics covered in the report, only selected findings are listed here. About 14 percent of recent births to women 15-44 years of age in 2002 were unwanted at time of conception, an increase from the 9 percent seen for recent births in 1995. Among recent births, 64 percent occurred within marriage, 14 percent within cohabiting unions, and 21 percent to women who were neither married nor cohabiting. The overall rate of breastfeeding initiation among recent births increased from 55 to 67 percent between 1995 and 2002. About 50 percent of women 15-44 had ever cohabited compared with 41 percent of women in the 1995 survey; the percentage of women currently cohabiting also increased, from 7 to 9 percent between 1995 and 2002.
Key Words: Adolescent, Adult, Data Collection, Family Planning Services/*statistics & numerical data, Female, *Fertility, Humans, Male, Reproductive Medicine/*statistics & numerical data, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.
Study Synopsis: A study of Chinese women finds no association between serum DDE levels and menstrual cycle characteristics. High DDE concentrations were associated with a non-statistically significant lengthening of the menstrual cycle. This conflicts with previous studies in Laotian women who were found to have decreased menstrual cycle length with increased levels of DDT and DDE. These conflicting results may be due to differences in study design or the study population.
Scientific abstract:
High DDE and DDT concentrations were found to be associated with shortened menstrual cycle length in Laotian immigrants to the United States. We examined this issue in a sample of young Chinese women. A total of 60 women aged 20-24 years were enrolled in three maternal and child health clinics (20 from urban, 20 from suburban, 20 from rural) in Shanghai, China, and vicinity, in 1998. Of these women, 47 who did not use hormonal contraceptives and had valid menstrual cycle characteristics were included in the analysis for associations among serum DDE and DDT concentration and menstrual cycle length, duration of menses, and heaviness of menstrual flow. In univariate analysis, higher p,p'-DDE concentration was associated with longer menstrual cycle length (0.66 day per 10 microg/L, 95% confidence interval [CI]: 0.21, 1.11 day). With adjustment for age, body mass index, education, occupation, and resident location, the estimate was 0.42 day (95% CI: -0.35, 1.19 day). p,p'-DDE was not associated with duration of menses or heaviness of menstrual flow. Neither p,p'-DDT nor o,p'-DDT were associated with menstrual cycle length, duration of menses or heaviness of menstrual flow. The study largely suggests no association between DDE and DDT concentrations and menstrual cycle characteristics in young Chinese women, though the weak-to-no correlation of DDE with menstrual cycle length merits further study.
Key Words: Adult, Body Mass Index, China, DDT/*blood/*poisoning, Environmental Exposure, Female, Humans, Insecticides/*blood/*poisoning, Menstruation/*drug effects, Menstruation Disturbances/chemically induced
In a recently completed US case-control study (Children's Oncology Group, 1993-2001) with 253 cases and 394 controls, the authors investigated the association between parental occupational exposure to pesticides and risk of childhood germ-cell tumors. Information on occupational pesticide exposure was collected using job-specific module questionnaires and assessed by an experienced industrial hygienist. Odds ratios for childhood germ-cell tumors associated with maternal exposures before pregnancy, during pregnancy, and after the birth of the index child were 1.0 (95% confidence interval (CI): 0.8, 1.4), 1.1 (95% CI: 0.7, 1.6), and 1.3 (95% CI: 0.9, 1.8), respectively. Paternal exposures before pregnancy, during pregnancy, and after the birth of the index child were not related to germ-cell tumors (odds ratios (ORs) were 0.9 (95% CI: 0.7, 1.2), 0.8 (95% CI: 0.5, 1.2), and 0.8 (95% CI: 0.5, 1.3), respectively). When both parents had ever been occupationally exposed to pesticides before the index pregnancy, the odds ratio was 0.8 (95% CI: 0.4, 1.3). Subgroup analyses showed a positive association between maternal exposure to herbicides during the postnatal period and risk of germ-cell tumors in girls (OR = 2.3, 95% CI: 1.0, 5.2) and an inverse association between paternal exposure to pesticides during the index pregnancy and germ-cell tumors in boys (OR = 0.2, 95% CI: 0.1, 1.0). This study did not provide strong evidence supporting a relation between parental pesticide exposure in the workplace and risk of germ-cell tumors among offspring.
Key Words: Adolescent, Age Factors, Case-Control Studies, Child, Child, Preschool, Environmental Exposure/adverse effects/*statistics & numerical data, Female, Humans, Infant, Male, Neoplasms, Germ Cell and Embryonal/chemically induced/*epidemiology, Odds Ratio, *Pesticides/toxicity, Pregnancy, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S., Risk Assessment, United States/epidemiology
Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumor-suppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an early-life exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to >90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals.
Study Synopsis: New research findings suggest that low-level exposure to PCBs can alter menstrual function. This cohort study from the 1960s found pregnant women with higher blood PCB levels tended to have a history of slightly longer menstrual cycles. The difference in cycle length between women with the highest and lowest PCB levels amounted to less than one day. The findings show that women's menstrual cycles could serve as markers of the potential biological effects of endocrine disruptors. Women with the highest PCB levels were also somewhat more likely to report having irregular periods.
Scientific abstract:
BACKGROUND: Experimental studies in nonhuman primates provide evidence that low-level exposure to persistent organochlorine pollutants such as polychlorinated biphenyls (PCBs) may affect aspects of their menstrual cycle, including cycle length, regularity, and bleeding duration. Few studies have examined these associations in humans. METHODS: We used data from 2314 pregnant women who participated in the Collaborative Perinatal Project, a cohort study that enrolled pregnant women in the 1960s in 12 centers in the United States. Information about usual (prepregnancy) menstrual cycle length, regularity, bleeding duration, and dysmenorrhea was collected at enrollment, and 11 PCBs and p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) were measured in stored blood samples collected during the third trimester of pregnancy. We used multivariate linear and logistic regression to examine the association between organochlorine levels and menstrual cycles, adjusting for demographic factors, cholesterol, and triglycerides. RESULTS: Total PCBs were positively associated with increasing menstrual cycle length (adjusted difference across 5 categories of PCB exposure = 0.7 days, trend-test P value = 0.02). Irregular cycles were slightly more frequent among those in the 2 highest categories of PCB exposure (odds ratio for highest category = 1.5; 95% confidence interval = 0.70-3.3), and there also was some evidence of an association with DDE. The strengths of these associations increased with various exclusions made to decrease potential misclassification of the outcome and the exposures. There was little evidence for associations between DDE or PCBs and bleeding duration, heavy bleeding, or dysmenorrhea. CONCLUSIONS: This study supports experimental studies in monkeys showing an effect of low-dose PCB exposure on menstrual function.
Study Synopsis: Polybrominated biphenyls (PBBs) are synthetic chemicals formerly used as flame retardants. In 1973, the Michigan food supply was contaminated with PBBs when the cattle feed supplement NutriMaster was accidently replaced with the flame retardant FireMaster. More than 4,000 individuals were exposed to PBBs, 337 of which were enrolled in the current study. Researchers estimated maternal exposure to PBBs based on blood measurements. They found no association between PBB exposure and menstrual cycle characteristics (cycle or bleed length).
Scientific abstract:
BACKGROUND: Alteration in menstrual cycle function is suggested among rhesus monkeys and humans exposed to polybrominated biphenyls (PBBs) and structurally similar polychlorinated biphenyls (PCBs). The feedback system for menstrual cycle function potentially allows multiple pathways for disruption directly through the hypothalamic-pituitary-ovarian axis and indirectly through alternative neuroendocrine axes. METHODS: The Michigan Female Health Study was conducted during 1997-1998 among women in a cohort exposed to PBBs in 1973. This study included 337 women with self-reported menstrual cycles of 20-35 days (age range: 24-56 years). Current PBB levels were estimated by exponential decay modeling of serum PBB levels collected from 1976-1987 during enrollment in the Michigan PBB cohort. Linear regression models for menstrual cycle length and the logarithm of bleed length used estimated current PBB exposure or enrollment PBB exposure categorized in tertiles, and for the upper decile. All models were adjusted for serum PCB levels, age, body mass index, history of at least 10% weight loss in the past year, physical activity, smoking, education, and household income. RESULTS: Higher levels of physical activity were associated with shorter bleed length, and increasing age was associated with shorter cycle length. Although no overall association was found between PBB exposure and menstrual cycle characteristics, a significant interaction between PBB exposures with past year weight loss was found. Longer bleed length and shorter cycle length were associated with higher PBB exposure among women with past year weight loss. CONCLUSION: This study suggests that PBB exposure may impact ovarian function as indicated by menstrual cycle length and bleed length. However, these associations were found among the small number of women with recent weight loss suggesting either a chance finding or that mobilization of PBBs from lipid stores may be important. These results should be replicated with larger numbers of women exposed to similar lipophilic compounds.
Study Synopsis: Polybrominated biphenyls (PBBs) are synthetic chemicals formerly used as flame retardants. In 1973, the Michigan food supply was contaminated with PBBs when the cattle feed supplement NutriMaster was accidently replaced with the flame retardant FireMaster. More than 4,000 individuals were exposed to PBBs, 337 of which were enrolled in the current study. Researchers estimated maternal exposure to PBBs based on blood measurements. They found no association between PBB exposure and menstrual cycle characteristics (cycle or bleed length).
Scientific abstract:
BACKGROUND: Alteration in menstrual cycle function is suggested among rhesus monkeys and humans exposed to polybrominated biphenyls (PBBs) and structurally similar polychlorinated biphenyls (PCBs). The feedback system for menstrual cycle function potentially allows multiple pathways for disruption directly through the hypothalamic-pituitary-ovarian axis and indirectly through alternative neuroendocrine axes. METHODS: The Michigan Female Health Study was conducted during 1997-1998 among women in a cohort exposed to PBBs in 1973. This study included 337 women with self-reported menstrual cycles of 20-35 days (age range: 24-56 years). Current PBB levels were estimated by exponential decay modeling of serum PBB levels collected from 1976-1987 during enrollment in the Michigan PBB cohort. Linear regression models for menstrual cycle length and the logarithm of bleed length used estimated current PBB exposure or enrollment PBB exposure categorized in tertiles, and for the upper decile. All models were adjusted for serum PCB levels, age, body mass index, history of at least 10% weight loss in the past year, physical activity, smoking, education, and household income. RESULTS: Higher levels of physical activity were associated with shorter bleed length, and increasing age was associated with shorter cycle length. Although no overall association was found between PBB exposure and menstrual cycle characteristics, a significant interaction between PBB exposures with past year weight loss was found. Longer bleed length and shorter cycle length were associated with higher PBB exposure among women with past year weight loss. CONCLUSION: This study suggests that PBB exposure may impact ovarian function as indicated by menstrual cycle length and bleed length. However, these associations were found among the small number of women with recent weight loss suggesting either a chance finding or that mobilization of PBBs from lipid stores may be important. These results should be replicated with larger numbers of women exposed to similar lipophilic compounds.
Study Synopsis: Chromosomal abnormalities in the fetus are much more likely when the mother smokes. The types of abnormalities observed have been linked to leukemia. The scientists reporting this result suggest that smoking during pregnancy may put children exposed in the womb at risk of developing cancer later in life.
Scientific abstract:
CONTEXT: Tobacco increases the risk of systemic diseases, and it has adverse effects on pregnancy. However, only indirect data have been published on a possible genotoxic effect on pregnancy in humans. OBJECTIVES: To determine whether maternal smoking has a genotoxic effect on amniotic cells, expressed as an increased chromosomal instability, and to analyze whether any chromosomal regions are especially affected by exposure to tobacco. DESIGN, SETTING, AND PATIENTS: In this prospective study, amniocytes were obtained by routine amniocentesis for prenatal diagnosis from 25 controls and 25 women who smoke (> or =10 cigarettes/d for > or =10 years), who were asked to fill out a smoking questionnaire concerning their smoking habits. Chromosomal instability was analyzed in blinded fashion by 2 independent observers in routine chromosome spreads. Breakpoints implicated in chromosomal abnormalities were identified by G-banding. MAIN OUTCOME MEASURES: Association between maternal smoking and increased chromosomal instability in amniotic fluid cells, expressed as chromosomal lesions (gaps and breaks) and structural chromosomal abnormalities. RESULTS: Comparison of cytogenetic data between smokers and nonsmokers (controls) showed important differences for the proportion of structural chromosomal abnormalities (smokers: 12.1% [96/793]; controls: 3.5% [26/752]; P = .002) and to a lesser degree for the proportion of metaphases with chromosomal instability (smokers: 10.5% [262/2492]; controls: 8.0% [210/2637]; P = .04), and for the proportion of chromosomal lesions (smokers: 15.7% [391/2492]; controls: 10.1% [267/2637]; P = .045). Statistical analysis of the 689 breakpoints detected showed that band 11q23, which is a band commonly implicated in hematopoietic malignancies, was the chromosomal region most affected by tobacco. CONCLUSIONS: Our findings show that smoking 10 or more cigarettes per day for at least 10 years and during pregnancy is associated with increased chromosomal instability in amniocytes. Band 11q23, known to be involved in leukemogenesis, seems especially sensitive to genotoxic compounds contained in tobacco.
Study Synopsis: Akwesasne Mohawk Nation girls living near a Superfund site contaminated with multiple chemicals, have an altered age of puberty. Although the study analyzed multiple chemicals including PCBs, DDT, HCB, mirex, lead and mercury, only PCBs and lead were associated with altered puberty onset. In girls with high lead levels, puberty was delayed whereas girls with high levels of estrogenic-PCBs reached puberty at an earlier age. These findings are consistent with previous studies.
Scientific abstract:
BACKGROUND: Children are commonly exposed at background levels to several ubiquitous environmental pollutants, such as lead and persistent organic pollutants, that have been linked to neurologic and endocrine effects. These effects have prompted concern about alterations in human reproductive development. Few studies have examined the effects of these toxicants on human sexual maturation at levels commonly found in the general population, and none has been able to examine multiple toxicant exposures. The aim of the current investigation was to examine the relationship between attainment of menarche and levels of 6 environmental pollutants to which children are commonly exposed at low levels, ie, dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), polychlorinated biphenyls (PCBs), mirex, lead, and mercury. METHODS: This study was conducted with residents of the Akwesasne Mohawk Nation, a sovereign territory that spans the St Lawrence River and the boundaries of New York State and Ontario and Quebec, Canada. Since the 1950s, the St Lawrence River has been a site of substantial industrial development, and the Nation is currently adjacent to a US National Priority Superfund site. PCB, p,p'-DDE, HCB, and mirex levels exceeding the US Food and Drug Administration recommended tolerance limits for human consumption have been found in local animal species. The present analysis included 138 Akwesasne Mohawk Nation girls 10 to 16.9 years of age. Blood samples and sociodemographic data were collected by Akwesasne community members, without prior knowledge of participants' exposure status. Attainment of menses (menarche) was assessed as present or absent at the time of the interview. Congener-specific PCB analysis was available, and all 16 PCB congeners detected in >50% of the sample were included in analyses (International Union of Pure and Applied Chemistry numbers 52, 70, 74, 84, 87, 95, 99, 101 [+90], 105, 110, 118, 138 [+163 and 164], 149 [+123], 153, 180, and 187). Probit analysis was used to determine the median age at menarche for the sample. Binary logistic regression analysis was used to determine predictors of menarcheal status. Six toxicants (p,p'-DDE, HCB, PCBs, mirex, lead, and mercury) were entered into the logistic regression model. Age, socioeconomic status (SES), and BMI were tested as potential cofounders and were included in the model at P < .05. Interactions among toxicants were also evaluated. RESULTS: Toxicant levels were measured in blood for this sample and were consistent with long-term exposure to a variety of toxicants in multiple media. Mercury levels were at or below background levels, all lead levels were well below the Centers for Disease Control and Prevention action limit of 10 microg/dL, and PCB levels were consistent with a cumulative, continuing exposure pattern. The median age at menarche for the total sample was 12.2 years. The predicted age at menarche for girls with lead levels above the median (1.2 microg/dL) was 10.5 months later than that for girls with lead levels below the median. In the logistic regression analysis, age was the strongest predictor of menarcheal status and SES was also a significant predictor but BMI was not. The logistic regression analysis that corrected for age, SES, and other pollutants (p,p'-DDE, HCB, mirex, and mercury) indicated that, at their respective geometric means, lead (geometric mean: 0.49 microg/dL) was associated with a significantly lower probability of having reached menarche (beta = -1.29) and a group of 4 potentially estrogenic PCB congeners (E-PCB) (geometric mean: 0.12 ppb; International Union of Pure and Applied Chemistry numbers 52, 70, 101 [+90], and 187) was associated with a significantly greater probability of having reached menarche (beta = 2.13). Predicted probabilities at different levels of lead and PCBs were calculated on the basis of the logistic regression model. At the respective means of all toxicants and SES, 69% of 12-year-old girls were predicted to have reached menarche. However, at the 75th percentile of lead levels, only 10% of 12-year-old Mohawk girls were predicted to have reached menarche; at the 75th percentile of E-PCB levels, 86% of 12-year-old Mohawk girls were predicted to have reached menarche. No association was observed between mirex, p,p'-DDE, or HCB and menarcheal status. Although BMI was not a significant predictor, we tested BMI in the logistic regression model; it had little effect on the relationships between menarcheal status and either lead or E-PCB. In models testing toxicant interactions, age, SES, lead levels, and PCB levels continued to be significant predictors of menarcheal status. When each toxicant was tested in a logistic regression model correcting only for age and SES, we observed little change in the effects of lead or E-PCB on menarcheal status. CONCLUSIONS: The analysis of multichemical exposure among Akwesasne Mohawk Nation adolescent girls suggests that the attainment of menarche may be sensitive to relatively low levels of lead and certain PCB congeners. This study is distinguished by the ability to test many toxicants simultaneously and thus to exclude effects from unmeasured but coexisting exposures. By testing several PCB congener groupings, we were able to determine that specifically a group of potentially estrogenic PCB congeners affected the odds of reaching menarche. The lead and PCB findings are consistent with the literature and are biologically plausible. The sample size, cross-sectional study design, and possible occurrence of confounders beyond those tested suggest that results should be interpreted cautiously. Additional investigation to determine whether such low toxicant levels may affect reproduction and disorders of the reproductive system is warranted.
Key Words: Adolescent, Child, Cross-Sectional Studies, Dichlorodiphenyl Dichloroethylene/blood, Environmental Exposure, Environmental Pollutants/blood/*pharmacology, Female, Hexachlorobenzene/blood/pharmacology, Humans, Hydrocarbons, Chlorinated/blood/*pharmacology, Indians, North American, Lead/blood/*pharmacology, Logistic Models, Menarche/*drug effects, Mercury/blood/pharmacology, Mirex/blood/pharmacology, Polychlorinated Biphenyls/blood/pharmacology, Research Support, U.S. Gov't, P.H.S., Social Class
Phthalates are multifunctional chemicals used in a variety of applications, including personal care products. The present study explored the relationship between patterns of personal care product use and urinary levels of several phthalate metabolites. Subjects include 406 men who participated in an ongoing semen quality study at the Massachusetts General Hospital Andrology Laboratory between January 2000 and February 2003. A nurse-administered questionnaire was used to determine use of personal care products, including cologne, aftershave, lotions, hair products, and deodorants. Phthalate monoester concentrations were measured in a single spot urine sample by isotope dilution-high-performance liquid chromatography coupled to tandem mass spectrometry. Men who used cologne or aftershave within 48 hr before urine collection had higher median levels of monoethyl phthalate (MEP) (265 and 266 ng/mL, respectively) than those who did not use cologne or aftershave (108 and 133 ng/mL, respectively). For each additional type of product used, MEP increased 33% (95% confidence interval, 14-53%). The use of lotion was associated with lower urinary levels of monobutyl phthalate (MBP) (14.9 ng/mL), monobenzyl phthalate (MBzP) (6.1 ng/mL), and mono(2-ethylhexyl) phthalate (MEHP) (4.4 ng/mL) compared with men who did not use lotion (MBP, 16.8 ng/mL; MBzP, 8.6 ng/mL; MEHP, 7.2 ng/mL). The identification of personal care products as contributors to phthalate body burden is an important step in exposure characterization. Further work in this area is needed to identify other predictors of phthalate exposure.
Key Words: Adult, *Cosmetics, Environmental Monitoring, Humans, Male, Middle Aged, Phthalic Acids/*urine, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S., Time Factors
Study Synopsis: Study of US men finds changes in reproductive hormones associated with phthalate exposure. Increasing concentrations of monobenzyl phthalate (MBzP) were associated with a decrease in FSH and monobutyl phthalate (MBP) exposure was associated with an increase in inhibin B. Although associations were found, they were not in the expected direction and it is unclear whether these associations represent physiologically relevant alterations in these hormones, or whether they represent associations found as a result of conducting multiple comparisons.
Scientific abstract:
BACKGROUND: Phthalates are used in personal and consumer products, food packaging materials, and polyvinyl chloride plastics and have been measured in the majority of the general population of the USA. Consistent experimental evidence shows that some phthalates are developmental and reproductive toxicants in animals. This study explored the association between environmental levels of phthalates and altered reproductive hormone levels in adult men. METHODS: Between 1999 and 2003, 295 men were recruited from Massachusetts General Hospital. Selected phthalate metabolites were measured in urine. Linear regression models explored the relationship between specific gravity-adjusted urinary phthalate monoester concentrations and serum levels of reproductive hormones, including FSH, LH, sex hormone-binding globulin, testosterone, and inhibin B. RESULTS: An interquartile range (IQR) change in monobenzyl phthalate (MBzP) exposure was significantly associated with a 10% [95% confidence interval (CI): -16, -4.0] decrease in FSH concentration. Additionally, an IQR change in monobutyl phthalate (MBP) exposure was associated with a 4.8% (95% CI: 0, 10) increase in inhibin B but this was of borderline significance. CONCLUSIONS: Although we found associations between MBP and MBzP urinary concentrations and altered levels of inhibin B and FSH, the hormone concentrations did not change in the expected patterns. Therefore, it is unclear whether these associations represent physiologically relevant alterations in these hormones, or whether they represent associations found as a result of conducting multiple comparisons.
Eskenazi B, Warner M, Marks AR, Samuels S, Gerthoux PM, Vercellini P, Olive DL, Needham L, Patterson D, Mocarelli P. Serum dioxin concentrations and age at menopause. Environ Health Perspect. 2005 Jul;113(7):858-62.
Study Synopsis: Data from a study of women exposed to dioxin by the Seveso, Italy, accident in 1976 suggest a non-monotonic relationship between dioxin levels and premature menopause. The trend across the first four quintiles of exposure showed a statistically significant increase in risk of early menopause, up to about 100 ppt dioxin.
Scientific abstract:
2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD), a halogenated compound that binds the aryl hydrocarbon receptor, is a by-product of numerous industrial processes including waste incineration. Studies in rats and monkeys suggest that TCDD may affect ovarian function. We examined the relationship of TCDD and age at menopause in a population of women residing near Seveso, Italy, in 1976, at the time of a chemical plant explosion. We included 616 of the women who participated 20 years later in the Seveso Women's Health Study. All women were premenopausal at the time of the explosion, had TCDD levels measured in serum collected soon after the explosion, and were > or = 35 years of age at interview. Using proportional hazards modeling, we found a 6% nonsignificant increase in risk of early menopause with a 10-fold increase in serum TCDD. When TCDD levels were categorized, compared with women in the lowest quintile (< 20.4 ppt), women in quintile 2 (20.4-34.2 ppt) had a hazard ratio (HR) of 1.1 (p = 0.77), quintile 3 (34.3-54.1 ppt) had an HR of 1.4 (p = 0.14), quintile 4 (54.2-118 ppt) had an HR of 1.6 (p = 0.10), and quintile 5 (> 118 ppt) had an HR of 1.1 (p = 0.82) for risk of earlier menopause. The trend toward earlier menopause across the first four quintiles is statistically significant (p = 0.04). These results suggest a nonmonotonic dose-related association with increasing risk of earlier menopause up to about 100 ppt TCDD, but not above.
Key Words: Adolescent, Adult, Age Factors, Chemical Industry, Child, Child, Preschool, Dose-Response Relationship, Drug, Environmental Pollutants/*blood, Explosions, Female, Humans, Infant, Italy/epidemiology, Menopause, Premature/*blood, Middle Aged, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Retrospective Studies, Tetrachlorodibenzodioxin/*blood
Farhang L, Weintraub JM, Petreas M, Eskenazi B, Bhatia R. Association of DDT and DDE with birth weight and length of gestation in the Child Health and Development Studies, 1959-1967. Am J Epidemiol. 2005 Oct;162(8):717-25.
Study Synopsis: DDT is an insecticide that was banned by the U.S. Environmental Protection Agency (EPA) in the 1970s due to concerns about its persistence in the environment and toxic effects on wildlife and humans. DDT was banned internationally by the Stockholm Convention on Persistent Organic Pollutants, except to control insects that carry diseases such as malaria. Researchers used data from the Child Health and Development Studies which enrolled 20,754 pregnant women and their children in the San Francisco Bay Area from 1959 to 1967. DDT, and its breakdown product DDE, were measured in the blood of pregnant women and 420 male infants were examined. No relationships were found between exposure to DDT or DDE and premature birth, size-for-gestational age (a measure of fetal growth) and birth weight.
Scientific abstract:
The pesticide p,p'-dichlorodiphenyltrichloroethane (DDT) and its persistent metabolite p,p'-dichlorodiphenyldichloroethylene (DDE) are associated with negative reproductive outcomes in animals. In humans, however, the findings are inconsistent. Using data from the Child Health and Development Studies, a longitudinal study of 20,754 pregnancies among San Francisco Bay Area women from 1959 to 1967, the authors examined the effects of maternal serum DDT and DDE concentrations on preterm birth, small-for-gestational-age birth, birth weight, and gestational age in 420 male subjects. Data were analyzed using multivariate logistic regression for preterm and small-for-gestational-age birth and linear regression for birth weight and gestational age. Median serum concentrations of DDE were 43 mug/liter (interquartile range: 32-57; range: 7-153) and of DDT were 11 mug/liter (interquartile range: 8-16; range: 3-72), several times higher than current US concentrations. The adjusted odds ratio for preterm birth was 1.28 (95% confidence interval (CI): 0.73, 2.23) for DDE and 0.94 (95% CI: 0.50, 1.78) for DDT. For small-for-gestational-age birth, the adjusted odds ratio was 0.75 (95% CI: 0.44, 1.26) for DDE and 0.69 (95% CI: 0.73, 1.27) for DDT; none of the study results achieved statistical significance. Given the persistence of DDT in the environment and its continuing role in malaria control, studies using more robust data should continue to assess this relation.
Study Synopsis: Ethoxychlor (common organochlorine pesticide) has a lasting effect in mice on the _expression of a gene important for repro tract development and function, resulting in part in diminishment of the uterine desidual cell response necessary to support embryo implantation.
Scientific abstract:
Methoxychlor (MXC) is a pesticide that has adverse effects on reproductive capability in mice. MXC and its metabolites bind the estrogen receptor and function as endocrine disruptors. MXC diminishes the uterine decidual cell response, necessary for the support of pregnancy. Hoxa10 is an estrogen-regulated gene that is an essential mediator of the decidual response and necessary for pregnancy. Here we demonstrate that a mechanism by which MXC disrupts uterine function is by suppressing Hoxa10 expression. MXC treatment of mice produced a mild uterotropic response as measured by increased uterine weight and epithelial height. MXC treatment of uterine Ishikawa cells in vitro induced Hoxa10 expression. Estrogen receptor (ER) binding to the HOXA10 estrogen response element (ERE) was promoted by treatment with estradiol (E2); however, MXC disrupted E2/ER/ERE complex formation and gel shift. MXC alone allowed weak ER/ERE binding. In vivo MXC blocked the effect of E2 on Hoxa10 expression. Neonatal MXC treatment resulted in an immediate suppression and cellular restriction of Hoxa10 expression as well as a permanent generalized decrease in expression that persisted in the adult. MXC inhibited the expression of Hoxa10, a gene necessary for uterine development and function. One common mechanism by which endocrine disrupting chemicals produce lasting reproductive tract defects is through permanent alteration of developmental gene expression.
Key Words: Animals, Animals, Newborn, Cells, Cultured, Epithelial Cells/drug effects, Female, Gene Expression Regulation/*drug effects, Genes, Homeobox, Homeodomain Proteins/genetics, Insecticides/*toxicity, Methoxychlor/*toxicity, Mice, Organ Size/drug effects, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S., Uterus/anatomy; histology/drug effects/*physiology
Study Synopsis: Modest consumption of farmed salmon raises human exposure levels to dioxin-like contaminants above the safety threshold set by the World Health Organization. As few as 4 salmon meals per month for salmon from farms in northern Europe pose elevated risks. In contrast, most wild salmon sampled can be eaten at least twice per day. Proper preparation can significantly reduce the risks, but surveys indicate that most consumers are unaware of this option.
Scientific abstract:
We reported recently that several organic contaminants occurred at elevated concentrations in farmed Atlantic salmon compared with concentrations of the same contaminants in wild Pacific salmon [Hites et al. Science 303: 226-229 (2004)]. We also found that polychlorinated biphenyls (PCBs), toxaphene, dieldrin, dioxins, and polybrominated diphenyl ethers occurred at higher concentrations in European farm-raised salmon than in farmed salmon from North and South America. Health risks (based on a quantitative cancer risk assessment) associated with consumption of farmed salmon contaminated with PCBs, toxaphene, and dieldrin were higher than risks associated with exposure to the same contaminants in wild salmon. Here we present information on cancer and noncancer health risks of exposure to dioxins in farmed and wild salmon. The analysis is based on a tolerable intake level for dioxin-like compounds established by the World Health Organization and on risk estimates for human exposure to dioxins developed by the U.S. Environmental Protection Agency. Consumption of farmed salmon at relatively low frequencies results in elevated exposure to dioxins and dioxin-like compounds with commensurate elevation in estimates of health risk.
Study Synopsis: Experiments with pregnant rats reveal that windows of vulnerability during fetal development for specific impacts can be extremely narrow. For example, exposures to an anti-androgen cause hypospadias in over 50% of fetuses exposed on gestational day 17 but in none on day 16 and fewer than 10% on day 18. Similar patterns were seen for different health effects. Current human epidemiology would have difficulty detecting these strong effects.
Scientific abstract:
Previous studies have indicated that the androgen receptor antagonist, flutamide, can produce a suite of reproductive malformations in the male rat when orally administered daily on gestation days (GD) 12-21. The objective of this study was to investigate the gestation time dependence for the induction of these malformations to establish a robust animal model for future studies of gene expression related to specific malformations. Groups of timed-pregnant Sprague-Dawley rats (GD 0 = day of mating) were administered flutamide as a single gavage dose (50 mg/kg) on GD 16, 17, 18, or 19 with 10 dams per group. Control animals (5 dams per time per group) were administered corn oil vehicle (2 ml/kg). Dams were allowed to litter, and their adult male offspring were killed at postnatal day (PND) 100 +/- 10. Anogenital distance was measured at PND 1 and 100. Areolae were scored at PND 13, and permanent nipples evaluated at PND 100. No reproductive tract malformations were found in control male offspring. In the treated groups, malformations were noted following exposure at every GD, although the incidence of specific malformations varied by GD. At GD 16, the highest incidence was noted for permanent nipples (46% pups, 60% litters), epispadias (12% pups, 30% litters), and missing epididymal components (5% pups, 20% litters). The highest incidences for hypospadias (58% pups, 80% litters), vaginal pouch (49% pups, 70% litters), cleft prepuce (29% pups, 60% litters), and missing prostate lobes (12% pups, 60% litters) were noted at GD 17. At GD 18 the highest incidence of malformations noted were epispadias (5% pups, 30% litters), reduced prostate size (32% pups, 90% litters), and abnormal kidneys (3% pups, 30% litters) and bladders (7% pups, 30% litters), while on GD 19 70% of the litters had animals with abnormal seminal vesicles. Testicular and epididymal morphological changes were noted at all GDs and were consistent with the gross observations and peaked in incidence and severity on GD17. The major discrepancy between this study and previous multiple-dose studies was in the very few numbers of animals presenting with cryptorchidism (only one each on GDs 16 and 17), suggesting that exposure over multiple days may be required to induce this malformation. Thus, a single gestational exposure of flutamide induced numerous reproductive tract malformations consistent with previously reports following multiple exposures, with the timing of the exposure producing marked tissue selectivity in the response noted in adult offspring.
Study Synopsis: While testicular cancer is rare, it is the most common malignancy among young men, and it has been increasing since the middle of the 20th century in many western countries. Most known risk factors are related to early life events, including cryptorchidism and in utero exposure to estrogens. Lifestyle and occupational exposures later in life may play a role in promoting the disease, but are not likely to initiate it.
Scientific abstract:
Testicular cancer is a rare disease, accounting for 1.1% of all malignant neoplasms in Canadian males. Despite the low overall incidence of testicular cancer, it is the most common malignancy among young men. The incidence rate of testicular cancer has been increasing since the middle of the 20th century in many western countries. However, the etiology of testicular cancer is not well understood. A search of the peer-reviewed literature was conducted to identify important articles for review and inclusion in this overview of the epidemiology of testicular cancer. Most of the established risk factors are related to early life events, including cryptorchidism, carcinoma in situ and in utero exposure to estrogens. Occupational, lifestyle, socioeconomic and other risk factors have demonstrated mixed associations with testicular cancer. Although there are few established risk factors for testicular cancer, some appear to be related to hormonal balance at various life stages. Lifestyle and occupational exposures occurring later in life may play a role in promoting the disease, although they are not likely involved in cancer initiation. In addition to summarizing the current epidemiologic evidence on risk factors for testicular cancer, we suggest future research directions that may elucidate the etiology of testicular cancer.
Study Synopsis: The definitions of subfertility and infertility are not standardized in many situations and make calculations of prevalence difficult. Subfertility generally describes any form of reduced fertility with prolonged time of unwanted non-conception. Infertility may be used synonymously with sterility with only sporadically occurring spontaneous pregnancies.Under appropriate circumstances a basic infertility work-up after six unsuccessful cycles with fertility-focused intercourse will identify couples with significant infertility problems to avoid both infertility under- and over-treatment, regardless of age.
Scientific abstract:
A common definition of sub- and infertility is very important for the appropriate management of infertility. Subfertility generally describes any form of reduced fertility with prolonged time of unwanted non-conception. Infertility may be used synonymously with sterility with only sporadically occurring spontaneous pregnancies. The major factor affecting the individual spontaneous pregnancy prospect is the time of unwanted non-conception which determines the grading of subfertility. Most of the pregnancies occur in the first six cycles with intercourse in the fertile phase (80%). After that, serious subfertility must be assumed in every second couple (10%) although--after 12 unsuccessful cycles--untreated live birth rates among them will reach nearly 55% in the next 36 months. Thereafter (48 months), approximately 5% of the couples are definitive infertile with a nearly zero chance of becoming spontaneously pregnant in the future. With age, cumulative probabilities of conception decline because heterogeneity in fecundity increases due to a higher proportion of infertile couples. In truly fertile couples cumulative probabilities of conception are probably age independent. Under appropriate circumstances a basic infertility work-up after six unsuccessful cycles with fertility-focused intercourse will identify couples with significant infertility problems to avoid both infertility under- and over-treatment, regardless of age: Couples with a reasonably good prognosis (e.g. unexplained infertility) may be encouraged to wait because even with treatment they do not have a better chance of conceiving. The others may benefit from an early resort to assisted reproduction treatment.
Study Synopsis: Infants in a hospital that has continued use of phthalate containing plastics in equipment used in neonatal intensive care units have higher phthalate metabolites in their urine than one that switched to other materials. Infants most exposed to DEHP had five times the level of a metabolite as those least exposed.
OBJECTIVE: Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in medical products made with polyvinyl chloride (PVC) plastic and may be toxic to humans. DEHP is lipophilic and binds noncovalently to PVC, allowing it to leach from these products. Medical devices containing DEHP are used extensively in neonatal intensive care units (NICUs). Among neonates in NICUs, we studied exposure to DEHP-containing medical devices in relation to urinary levels of mono(2-ethylhexyl) phthalate (MEHP), a metabolite of DEHP. DESIGN: We used a cross-sectional design for this study. PARTICIPANTS: We studied 54 neonates admitted to either of two level III hospital NICUs for at least 3 days between 1 March and 30 April 2003. MEASUREMENTS: A priori, we classified the infants' exposures to DEHP based on medical products used: The low-DEHP exposure group included infants receiving primarily bottle and/or gavage feedings; the medium exposure group included infants receiving enteral feedings, intravenous hyperalimentation, and/or nasal continuous positive airway pressure; and the high exposure group included infants receiving umbilical vessel catheterization, endotracheal intubation, intravenous hyperalimentation, and indwelling gavage tube. We measured MEHP in the infants' urine using automated solid-phase extraction/isotope dilution/high-performance liquid chromatography/tandem mass spectrometry. RESULTS: Urinary MEHP levels increased monotonically with DEHP exposure. For the low-, medium-, and high-DEHP exposure groups, median (interquartile range) MEHP levels were 4 (18), 28 (58), and 86 ng/mL (150), respectively (p = 0.004). After adjustment for institution and sex, urinary MEHP levels among infants in the high exposure group were 5.1 times those among infants in the low exposure group (p = 0.03). CONCLUSION: Intensive use of DEHP-containing medical devices in NICU infants results in higher exposure to DEHP as reflected by elevated urinary levels of MEHP.
Key Words: Biological Markers/urine, Diethylhexyl Phthalate/*analogs & derivatives/*metabolism/urine, Environmental Monitoring, *Equipment and Supplies, Humans, Infant, Newborn, *Intensive Care Units, Neonatal, Plasticizers/*metabolism, Polyvinyl Chloride, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.
Previously, we reported evidence of inverse associations between exposure to some polychlorinated biphenyls (PCBs) and some phthalate monoesters in relation to semen parameters, specifically sperm motility. Because humans are exposed to both phthalates and PCBs and because experimental studies suggest that PCBs may interact with glucuronidative enzymes that are responsible for phthalate metabolism, we explored the potential interaction between phthalates and PCBs in relation to human semen quality. We studied 303 men who were partners in subfertile couples seeking infertility diagnosis from the andrology laboratory at Massachusetts General Hospital. Semen parameters were dichotomized based on World Health Organization reference values, and phthalate and PCB levels were dichotomized at their respective medians. After adjusting for age and abstinence time, for below reference sperm motility there was a greater than additive interaction between monobenzyl phthalate and PCB-153 [relative excess risk due to interaction (RERI) = 1.40; 95% confidence interval (CI), 0.41-3.22], sum of PCBs (RERI = 1.24; 95% CI, 0.15-2.94), and cytochrome P450 (CYP450)-inducing PCBs (RERI = 1.30; 95% CI, 0.21-3.06). For below-reference sperm motility, there was also a greater than additive interaction between monobutyl phthalate (MBP) and PCB-153 (RERI = 1.42; 95% CI, 0.09-3.76) and CYP450-inducing PCBs (RERI = 1.87; 95% CI, 0.56-4.52) and a suggestive interaction between MBP and sum of PCBs (RERI = 1.35; 95% CI, -0.11 to 3.48). In conclusion, because there are important risk assessment and public health implications of interactions between these two ubiquitous classes of compounds, further studies need to be conducted to confirm these results and identify potential mechanisms of interactions.
Study Synopsis: A study from the NIH finds that women with endometriosis tend to be tall and thin. Women diagnosed with endometriosis were found to have a lower BMI (leaner body habitus), both at the time of diagnosis and historically. The women in this study also tended to have their first menstrual period at a later age (>14 yo). That women diagnosed with endometriosis may have a consistently lean physique during adolescence and young adulthood lends support to the suggestion of there being an in utero or early childhood origin for endometriosis.
Scientific abstract:
OBJECTIVE: To determine whether body size and perceived figure, both current and historical, are associated with a diagnosis of endometriosis on laparoscopy. DESIGN: Cohort study of consecutively identified patients undergoing laparoscopy for tubal sterilization or as a diagnostic procedure. SETTING: Two university-affiliated hospitals. PATIENT(S): A cohort of 84 women aged 18-40 years. Endometriosis was visualized in 32 cases; 52 women (controls) had no visualized endometriosis, including 22 undergoing tubal sterilization and 30 with other gynecologic pathology. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Body mass index (BMI, kg/m2) from self-report and perception of body figure were compared for their ability to predict case status (diagnosed endometriosis), using logistic regression models. Longitudinal trends in BMI based on perceived figure at 5-year intervals from age 15 years were compared using mixed linear models. RESULT(S): Based on self-report, women diagnosed with endometriosis were taller, thinner, and had a significantly lower BMI. In this series, cases were more likely to be late maturers (menarche at > or = 14 y) and late to initiate sexual activity (> or = 21 y), and they were less likely to be gravid, parous, and a current smoker. Adjusting for age (in years), being tall (height > or = 68 in), and parity (yes vs. no), a higher current BMI was statistically protective for a diagnosis of endometriosis, regardless of whether BMI was determined by self-report (adjusted odds ratio [AOR] = 0.88, 95% confidence interval [CI] 0.79-0.99) or from perceived figure (AOR = 0.86, 95% CI 0.75-0.99). For every unit increase in BMI (kg/m2), there was an approximate 12%-14% decrease in the likelihood of being diagnosed with endometriosis. In an adjusted repeated measures model, BMI was 21.3 +/- 0.6 kg/m2 (estimate +/- SE) for women with endometriosis, compared with 23.2 +/- 0.4 kg/m2 for the controls, a difference over all ages of -1.9 +/- 0.8 kg/m2. This is a consistent difference of about 10 lb at every age, assuming an average height of about 64.5 in. CONCLUSION(S): In a laparoscopy cohort, women diagnosed with endometriosis were found to have a lower BMI (leaner body habitus), both at the time of diagnosis and historically. That women diagnosed with endometriosis may have a consistently lean physique during adolescence and young adulthood lends support to the suggestion of there being an in utero or early childhood origin for endometriosis.
Study Synopsis: A case-control study of women in Belgium finds an association between increased PCDD/PCDF and PCB body burden and endometriosis. Serum concentrations of dioxin (PCDD), furan (PCDF) and dioxin-like PCBs were measured and standardized to toxic equivalent factors. Women with endometriosis had higher mean TEQ levels than controls. The risk of endometriosis increased 3 fold for each 10 pg increase in TEQ levels/g lipids.
Scientific abstract:
OBJECTIVE: To investigate the possible association between the body burden of dioxin-like compounds and endometriotic disease. DESIGN: Case-control study. SETTING: Gynecology ward in a university hospital. PATIENT(S): Seventy-one women with peritoneal endometriosis (n = 25) or deep endometriotic (adenomyotic) nodules (n = 25) and controls (n = 21). INTERVENTION(S): Collection of 200 mL of blood (fasted) and face-to-face interview. MAIN OUTCOME MEASURE(S): Assessment of dioxin (PCDD), furan (PCDF), and dioxin-like PCB serum concentrations (picograms toxic equivalent [TEQ]/g lipids). RESULT(S): Age and body mass index were traced by linear multiple regression as determinants of total TEQ levels. After standardization for these variables (30 years and 22.5 kg/m2), the mean TEQ levels were 24.21 (controls), 30.62 (peritoneal endometriosis), and 37.60 (deep endometriotic [adenomyotic] nodules) pg TEQ/g lipids. Logistic regression analysis indicated a significantly increased risk of deep endometriotic (adenomyotic) nodules (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.4-7.6) for an increment of 10 pg in total TEQ levels/g lipids. An increased risk was also found for peritoneal endometriosis (OR, 1.9; 95% CI, 0.9-3.8) for total TEQ levels and for dioxins alone (OR, 3.2; 95% CI, 1.0-9.9). CONCLUSION(S): The results provide the first epidemiological evidence of an association between increased PCDD/PCDF and PCB body burden and endometriosis.
Study Synopsis: An analysis of serum collected from women pregnant in the 1960s finds that exposure to PCBs may be detrimental to fetal growth. Boys born to mothers with higher PCB levels were more likely to have reduced birth weight, smaller head circumference and to be small for their gestational age. These effects did not persist as the boys grew.
Scientific abstract:
BACKGROUND: Polychlorinated biphenyls (PCBs) are industrial chemicals that were used widely for approximately 50 years. Now banned, they are still ubiquitous because of their persistence in the environment, the food chain, and human fatty tissue. High in utero exposures cause developmental deficits accompanied by growth retardation. Studies examining intrauterine growth at lower exposures have been inconsistent, with most such investigations having relied on surrogate exposure indicators such as consumption of fish from contaminated bodies of water. METHODS: In the 1960s, serum specimens were collected from pregnant women participating in the Child Health and Development Study in the San Francisco Bay Area. The women were interviewed and their serum samples stored at -20 degrees C. At 5 years of age, detailed anthropometric measurements were made on children born in the years 1964-1967. We measured PCBs in specimens from 399 mothers using gas chromatography/electron capture detection. We conducted multiple linear regression to examine the relationship between these organochlorine concentrations and both intrauterine and 5-year growth, with adjustment for medical, lifestyle, sociodemographic, and specimen characteristics. RESULTS: In male infants, higher total in utero PCB exposure was associated with reduced birth weight, head circumference, and weight-for-gestational age. An increase from the 10th to 90th percentile in total PCBs was related to 290 g lower birth weight, a 0.7-cm decrease in head circumference, and for weight for gestational age, a reduction in z-score of 0.6. In girls, smaller head circumference and shorter gestations were observed. In contrast, prenatal PCBs were associated with greater growth in 5-year-old girls, with no apparent effect in 5-year-old boys. CONCLUSIONS: Maternally mediated exposure to PCBs may be detrimental to fetal growth, particularly in boys. These effects apparently are not persistent. Interpretation of greater childhood growth of girls is unclear.
Key Words: Adult, Child Development/*drug effects, Child, Preschool, Confounding Factors (Epidemiology), Environmental Exposure/*adverse effects, Female, Fetal Development/*drug effects, Humans, Infant, Newborn, Linear Models, Male, Maternal Exposure, Polychlorinated Biphenyls/blood/*toxicity, Pregnancy, Pregnancy Outcome, *Prenatal Exposure Delayed Effects, Prospective Studies, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S., San Francisco/epidemiology
Polychlorinated biphenyls (PCBs) and dibenzofurans (PCDFs) are persistent environmental pollutants shown to adversely interact with several functions of the endocrine system. In 1978-1979, over 2000 Taiwanese people ingested rice oil accidentally contaminated with PCBs and PCDFs. This is one of the major toxic exposure episodes that occurred globally and was later called Yucheng (oil disease in Chinese). The children born to exposed Yucheng women were therefore exposed in utero to high doses of PCBs/PCDFs. In 1995, 60 Yucheng and 61 control boys participated in physical examination, and serum hormones were measured by radioimmunoassay (RIA). Age, body weight, body height, Tanner status, testicular size, serum luteinizing hormone (LH), prolactin (PRL), thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) levels were not statistically different between Yucheng and control boys in the subgroups of before and at the age of puberty. However, the serum estradiol (E2) levels were significant higher in Yucheng boys at the age of puberty. Yucheng and control boys were further divided into two subgroups, those before (age <13 yr) and those at the age of puberty (age > or = 13 yr). There was a decrease of serum testosterone (TT) levels and increase of serum follicle-stimulating hormone (FSH) levels in Yucheng boys at the age of puberty as compared with controls. There was a significant decrease of the square root of TT/E2 and TT/FSH; however, the square root of E2/FSH was increased in Yucheng boys at the age of puberty as compared with controls. Data indicated that prenatal exposure to PCBs and PCDFs may have implications for boys' sex hormone homeostasis at puberty. Further studies are needed to identify the congeners of PCBs/PCDFs responsible for disruption of the endocrine system, as well as the mechanisms of such disruption.
Key Words: Adolescent, Benzofurans/*toxicity, Child, Cohort Studies, Comparative Study, Estradiol/blood, Female, Gonadal Steroid Hormones/*blood, Gonadotropins, Pituitary/*blood, Homeostasis/drug effects, Humans, Male, Maternal Exposure, Polychlorinated Biphenyls/*toxicity, Pregnancy, *Prenatal Exposure Delayed Effects, Puberty/blood, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Taiwan, Testosterone/blood, Thyroid Hormones/*blood
2-Bromopropane was used as an alternative to chlorofluorocarbons in a Korean electronics factory and caused reproductive and hematopoietic disorders in male and female workers. This causality was revealed by animal studies, and target cells were identified in subsequent studies. After identification of 2-bromopropane toxicity, 1-bromopropane was introduced to the workplace as a new alternative to ozone-depleting solvents. 1-Bromopropane was considered less mutagenic than 2-bromopropane, but, in contrast, animal experiments revealed that 1-bromopropane is a potent neurotoxic compound compared with 2-bromopropane. It was also revealed that 1-bromopropane has reproductive toxicity, but the target cells are different from those of 2-bromopropane. Exposure to 1-bromopropane inhibits spermiation in male rats and disrupts the development of follicles in female rats, in contrast to 2-bromopropane, which targets spermatogonia and oocytes in primordial follicles. After the first animal study describing the neurotoxicity of 1-bromopropane, human cases were reported. Those cases showed decreased sensation of vibration and perception, paresthesia in the lower extremities, decreased sensation in the ventral aspects of the thighs and gluteal regions, stumbling and headache, as well as mucosal irritation, as the initial symptoms. The dose-response of bromopropanes in humans and mechanism(s) underlying the differences in the toxic effects of the two bromopropanes remain to be determined.
Study Synopsis: In a study of Columbian women, work in flower production and tobacco exposure are associated with lower fertility rates. Pregnancy rates were 25% lower in women who smoked or who had worked in floriculture for more than 2 years. Presumably, flower production workers are expose to a number of different kinds of pesticides.
Scientific abstract:
OBJECTIVES: This study explores several factors potentially associated with reduced fecundability among women working in cut flowers production. METHODS: A cross-sectional study of first pregnancies was undertaken in 47 Colombian floriculture companies. Two thousand and eighty-five women were interviewed regarding potential reproductive, lifestyle and work history predictors of time-to-pregnancy (TTP), measured in months. Fecundability odds ratios (fOR) were estimated using a discrete time analogue of Cox's proportional hazard model. RESULTS: Associated with longer TTP were: irregular relationships with her partner (fOR 0.82, 95% CI 0.73-0.91), illness in the year prior to pregnancy (fOR 0.78, 95% CI 0.62-0.98), smoking tobacco (fOR 0.71, 95% CI 0.59-0.85), and work in flower production, less than 24 months (fOR 0.86 95% CI 0.75-0.98) or 2 years or more (fOR 0.73, 95% CI 0.63-0.84). CONCLUSIONS: Work in flower production, irregular relationship, illness and tobacco exposure would be associated with impaired fecundability.
Study Synopsis: A study of normal Swedish men finds no association between phthalate levels and semen quality. Mono ethyl phthalate (MEP), mono ethylhexyl phthaltale (MEHP), mono benzyl phthalate (MBzP), mono butyl phthalate (MBP), and phthalic acid were not found to significantly affect semen quality or hormone levels. These findings are in contrast to studies in the US which did find associations.
Scientific abstract:
BACKGROUND: High exposure to phthalates, which are ubiquitous contaminants, has been shown in animal studies to produce detrimental effects on male reproductive functions. A recent study in humans reported dose-response relations between low phthalate levels in urine and human semen parameters, which raises the question whether humans are more sensitive to phthalate exposure than animals. METHODS: Urine, serum, and semen samples were collected from 234 young Swedish men at the time of their medical conscript examination. Semen volume, sperm concentration, and motility were measured, together with sperm chromatin integrity (sperm chromatin structure assay) and biochemical markers of epididymal and prostatic function. We analyzed reproductive hormones in serum, and mono ethyl phthalate (MEP), mono ethylhexyl phthaltale (MEHP), mono benzyl phthalate (MBzP), mono butyl phthalate (MBP), and phthalic acid in urine. RESULTS: For MBP, MBzP, and MEHP, no clear pattern of associations were observed with any of the reproductive biomarkers. Subjects within the highest quartile for MEP had fewer motile sperm (mean difference = 8.8%; 95% confidence interval = 0.8-17), more immotile sperms (8.9%; 0.3-18), and lower luteinizing hormone values (0.7 IU/L; 0.1-1.2), but there was no suggestion of harmful effects for most other endpoints. Phthalic acid actually was associated with improved function, as measured by several markers. CONCLUSIONS: The observed weak associations between 1 phthalate biomarker and impairment of a few aspects of reproductive function biomarkers were not consistent with results from a recent U.S. study. It is not yet possible to conclude whether phthalate exposure may reflect a hazard for human male reproduction.
Key Words: Adolescent, Adult, Biological Markers/urine, Environmental Exposure/*adverse effects, Gonadal Hormones/blood, Humans, Linear Models, Male, Military Personnel, Phthalic Acids/blood/*toxicity/*urine, Reproduction/*drug effects, Research Support, Non-U.S. Gov't, Semen, Sperm Motility/*drug effects, Spermatozoa/*drug effects, Sweden
Study Synopsis: Among newborn boys in Finland there is a seasonal variation in the incidence of undescended testicles. The incidence of cryptorchidism was significantly higher in spring (FebruaryApril) (3.0%) than in summer (MayJuly) (1.7%). The underlying reason for cyclicity affects similarly both preterm and term boys and indicates an influence by environmental factors.
Scientific abstract:
Conflicting data on circannual variation in birth rates of urogenital malformations have been reported previously. To assess risk factors of cryptorchidism we studied the seasonal variation of cryptorchidism in Finland. We performed a prospective cryptorchidism study in Turku, Finland, from 1997 to 2001 to evaluate the incidence of cryptorchidism. Clinical examinations were performed at birth and at 3 months. Of 9511 liveborn boys (1471 preterm boys) 216 (53 preterm boys) were cryptorchid at birth and 106 (19 preterm boys) at 3 months. The incidence of cryptorchidism was significantly higher in spring (February-April) (3.0%) than in summer (May-July) (1.7%) (OR 1.79; 95% CI: 1.23-2.63). This seasonal difference was observed both among preterm and term boys. We conclude that a circannual fluctuation in the incidence of cryptorchidism exists, which indicates an influence by environmental factors. The underlying reason for cyclicity affects similarly both preterm and term boys.
Study Synopsis: Work with human ovarian cancer cells indicates that silencing of a tumor suppressing gene by DNA methylation is likely to be an early event in the development of human ovarian cancer. When the ZAC gene is suppressed, tumor growth is promoted. Aberrant DNA methlyation is a common feature of cancers, including in a majority of ovarian cancer samples analyzed in this study. Forcing the gene to turn on reduced proliferation and increased apoptotic cell death, two trends that would impede tumor growth.
Scientific abstract:
ZAC is a paternally expressed, imprinted gene located on chromosome 6q24, within a region known to harbor a tumor suppressor gene for several types of neoplasia, including human ovarian cancer (HOC). We have failed to identify genetic mutations in the ZAC gene in tumor material. Many imprinted genes contain differentially allele-specific-methylated regions (DMR) and harbor promoter activity that is regulated by the DNA methylation. Aberrant DNA methylation is a common feature of neoplasia and changes in DNA methylation at the ZAC locus have been reported in some cases of HOC. We investigated the DNA methylation and ZAC mRNA expression levels in a larger sample of primary HOC material, obtained by laser capture microdissection. ZAC mRNA expression was reduced in the majority of samples and this correlated with hypermethylation of the ZAC-DMR. Treatment of hypermethylated cells lines with a demethylating agent restored ZAC expression. Our studies indicate that transcriptional silencing of ZAC is likely to be caused by DNA methylation in HOC. Forced expression of ZAC resulted in a reduction in proliferation and marked induction of apoptotic cell death. The ZAC-mediated apoptosis signal is p53-independent and eliminated by inhibitors of caspase 3, 8 and 9. Reduced expression of ZAC would therefore favor tumor progression. As there were no significant differences in either DNA methylation or expression of ZAC mRNA between localized and advanced tumors, our data indicates that loss of ZAC is a relatively early event in HOC. (Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.)
Study Synopsis: Rats exposed in the womb to a single low dose of a widespread brominated flame retardant become hyperactive and have decreased sperm counts. The effects are observed at an exposure level within the range of PBDE contamination that has been found in samples of breast milk from US mothers.
In utero exposure to a single low dose of 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) disrupts neurobehavioral development and causes permanent effects on the rat male reproductive system apparent in adulthood. PBDEs, a class of flame retardants, are widely used in every sector of modern life to prevent fire. They are persistent in the environment, and increasing levels of PBDEs have been found in biota and human breast milk. In the present study we assessed the effects of developmental exposure to one of the most persistent PBDE congeners (PBDE-99) on juvenile basal motor activity levels and adult male reproductive health. Wistar rat dams were treated by gavage on gestation day 6 with a single low dose of 60 or 300 microg PBDE-99/kg body weight (bw). In offspring, basal locomotor activity was evaluated on postnatal days 36 and 71, and reproductive performance was assessed in males at adulthood. The exposure to low-dose PBDE-99 during development caused hyperactivity in the offspring at both time points and permanently impaired spermatogenesis by the means of reduced sperm and spermatid counts. The doses used in this study (60 and 300 microg/kg bw) are relevant to human exposure levels, being approximately 6 and 29 times, respectively, higher than the highest level reported in human breast adipose tissue. This is the lowest dose of PBDE reported to date to have an in vivo toxic effect in rodents and supports the premise that low-dose studies should be encouraged for hazard identification of persistent environmental pollutants.
Key Words: Development, endocrine active compounds, in utero exposure, low-dose effects, male fertility, neurobehavior, PBDE-99.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers exposed pregnant rats to a single dose of the PBDE congener BDE-99 by gavage. They found that PBDEs caused hyperactivity in offspring 36 and 71 days after birth and resulted in reduced sperm counts. These results suggest that prenatal exposure to BDE-99 affects behavior and semen quality in male rats.
Scientific abstract:
In utero exposure to a single low dose of 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) disrupts neurobehavioral development and causes permanent effects on the rat male reproductive system apparent in adulthood. PBDEs, a class of flame retardants, are widely used in every sector of modern life to prevent fire. They are persistent in the environment, and increasing levels of PBDEs have been found in biota and human breast milk. In the present study we assessed the effects of developmental exposure to one of the most persistent PBDE congeners (PBDE-99) on juvenile basal motor activity levels and adult male reproductive health. Wistar rat dams were treated by gavage on gestation day 6 with a single low dose of 60 or 300 microg PBDE-99/kg body weight (bw). In offspring, basal locomotor activity was evaluated on postnatal days 36 and 71, and reproductive performance was assessed in males at adulthood. The exposure to low-dose PBDE-99 during development caused hyperactivity in the offspring at both time points and permanently impaired spermatogenesis by the means of reduced sperm and spermatid counts. The doses used in this study (60 and 300 microg/kg bw) are relevant to human exposure levels, being approximately 6 and 29 times, respectively, higher than the highest level reported in human breast adipose tissue. This is the lowest dose of PBDE reported to date to have an in vivo toxic effect in rodents and supports the premise that low-dose studies should be encouraged for hazard identification of persistent environmental pollutants.
Study Synopsis: The consequences of exposure to many other chemicals or mixtures of chemicals, such as insecticides—chemicals oftentimes specifically designed to be toxic—are largely unknown. Many of these chemicals or their metabolites are routinely found in the blood and body fluids of pregnant women and children. Exposures to environmental toxins have been linked with higher rates of mental retardation, intellectual impairment, and behavioral problems, as well as preterm birth, low birth weight and spontaneous abortion.
Scientific abstract:
The consequences of exposure to many other chemicals or mixtures of chemicals, such as insecticides and chemicals often times specifically designed to be toxic are largely unknown. Many of these chemicals or their metabolites are routinely found in the blood and body fluids of pregnant women and children. Exposures to environmental toxins have been linked with higher rates of mental retardation, intellectual impairment, and behavioral problems, as well as preterm birth, low birth weight and spontaneous abortion.
Study Synopsis: A new theory proposes that pre-natal exposure to phthalates cause inflammation in the womb and leads to preterm delivery. In animal studies, phthalate exposure initiates a cascade of cellular events culminating in the release of inflammatory factors. This inflammation could, in turn, result in preterm delivery. Experimental studies need to be done to confirm this hypothesis.
Study Synopsis: Exposure to PCBs and DDT found to be weakly associated with impaired fertility. In a study of women from the 1960s, a time when PCB and DDT levels were historically high, elevated levels of PCBs (> 5 ppb) and DDE (>60 ppb) were associated with an increased time to pregnancy. Although animal studies have found similar effects, the results in this study did not reach statistical significance.
Scientific abstract:
Polychlorinated biphenyls (PCBs), once used widely in transformers and other applications, and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the main metabolite of the pesticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), are hormonally active agents. Changes in menstrual cycle functioning associated with PCBs and DDE, and increased odds of spontaneous abortion associated with DDE, suggest that these compounds could affect fertility. The authors investigated the association between PCB and DDE exposure and time to pregnancy by using serum levels measured in 390 pregnant women in the Collaborative Perinatal Project enrolled at 12 study centers in the United States from 1959 to 1965. They estimated adjusted fecundability odds ratios by using Cox proportional hazards modeling for discrete time data. Compared with time to pregnancy for women in the lowest exposure category (PCBs < 1.24 microg/liter, DDE < 14 microg/liter), time to pregnancy increased for women in the highest exposure category in terms of both PCBs (fecundability odds ratio for PCBs > or = 5.00 microg/liter = 0.65, 95% confidence interval: 0.36, 1.18) and DDE (fecundability odds ratio for DDE > or = 60 microg/liter = 0.65, 95% confidence interval: 0.32, 1.31). Overall, time to pregnancy increased with increasing serum PCB levels but was less suggestive of an association with DDE. Both trends were imprecise and attenuated when expressed on a lipid basis. Overall, evidence of an association between PCB or DDE exposure and time to pregnancy was weak and inconclusive.
Key Words: Adult, Dichlorodiphenyl Dichloroethylene/*blood, Female, Fertility/*physiology, Follow-Up Studies, Humans, *Maternal Exposure, Polychlorinated Biphenyls/*blood, Pregnancy, Pregnancy Trimester, Third/*blood, Prospective Studies, Time Factors, United States
BACKGROUND: We investigated the separate and combined effects of smoking and body mass index (BMI) on the success rate of IVF for couples with different causes of subfertility. METHODS: The success rate of IVF was examined in 8457 women. Detailed information on reproduction and lifestyle factors was combined with medical record data on IVF treatment. All IVF clinics in The Netherlands participated in this study. The main outcome measures were live birth rate per first cycle of IVF differentiated for the major predictive factors. RESULTS: For male subfertility the delivery rate per cycle was significantly lower than unexplained subfertility, OR of 0.70 (95% CI 0.57-0.86); for tubal pathology, the delivery rate was slightly lower, OR = 0.86 (95% CI 0.70-1.01). Smoking was associated with a significantly lower delivery rate was slightly lower; for OR = 0.72 (95% CI 0.61-0.84) and a significantly higher abortion rate compared to non-smoking delivery rates of 21.4% and 16.4%, respectively (P=0.02). Women with a BMI of > or = 27 kg/m2 had a significantly lower delivery rate, with an OR of 0.67 (95% CI 0.48-0.94), compared with normal weight women (BMI > or = 20 and <27 kg/m2). CONCLUSIONS: Both smoking and overweight unfavourably affect the live birth rate after IVF. The devastating impact of smoking on the live birth rate in IVF treatment is comparable with an increase in female age of >10 years from age 20 to 30 years. Subfertile couples may improve the outcome of IVF treatment by lifestyle changes.
Key Words: Abortion, Spontaneous/etiology, Adult, Body Mass Index, *Body Weight, Female, *Fertilization in Vitro, Humans, Infant, Newborn, Infertility/*etiology/*therapy, Male, Netherlands, Obesity/complications, Pregnancy, Pregnancy Outcome, Research Support, Non-U.S. Gov't, Smoking/*adverse effects
Study Synopsis: A study of serum stored since the 1960s reveals no relationship between PCB levels and preterm birth or birth weight. The data suggested that babies born to mothers with higher PCB levels were small for their gestational age, but the results were inconclusive.
Scientific abstract:
BACKGROUND: In developed countries, polychlorinated biphenyls (PCBs) are ubiquitous contaminants of the environment, including foods. Within the range of the resulting low-level exposure, associations of PCBs with lower birth weight have been observed in several studies. METHODS: To examine further the association of PCBs with birth outcomes, we measured serum levels in 1034 pregnant women who were enrolled in the U.S. Collaborative Perinatal Project in 1959 to 1965 before PCB manufacturing was banned. RESULTS: The multivariate-adjusted odds ratio for preterm birth among those with PCB levels of >/=4 microg/L of total PCBs, compared with those with <2 microg/L, was 1.1 (95% confidence interval = 0.6-2.2); for the same exposure contrast, the odds ratio for delivering an infant who was small-for-gestational-age at birth was 1.6 (0.7-3.7). Birth weight and length of gestation were essentially unrelated to PCB level. CONCLUSIONS: In these data, maternal levels of PCBs during pregnancy were essentially unrelated to preterm birth, birth weight, or length of gestation. An association of PCBs with small-for-gestational-age birth was observed, but the results were inconclusive and occurred in the absence of an overall decrease in birth weight.
Study Synopsis: A study of women exposed to historically high levels of DDT have higher incidence of pregnancy loss. Women exposed to DDT between 1959 and 1965 were found to have an increased risk of spontaneous abortion with increasing blood levels of DDE. Up to 60 ppm there was a dose-response effect. These results are consistent with other studies on DDE and pregnancy loss.
Scientific abstract:
Use of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) continues in about 25 countries. This use has been justified partly by the belief that it has no adverse consequences on human health. Evidence has been increasing, however, for adverse reproductive effects of DDT, but additional data are needed. Pregnant women who enrolled in the Collaborative Perinatal Project (United States, 1959-1965) were asked about their previous pregnancy history; blood samples were drawn and the serum frozen. In 1997-1999, the sera of 1717 of these women who had previous pregnancies were analyzed for 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the major breakdown product of DDT. The odds of previous fetal loss was examined in relation to DDE level in logistic regression models. Compared with women whose DDE level was <15 microg/L, the adjusted odds ratios of fetal loss according to category of DDE were as follows: 15-29 microg/L, 1.1; 30-44 microg/L, 1.4; 45-59 microg/L, 1.6; and 60+ microg/L, 1.2. The adjusted odds ratio per 60 microg/L increase was 1.4 (95% confidence interval 1.1-1.6). The results were consistent with an adverse effect of DDE on fetal loss, but were inconclusive owing to the possibility that previous pregnancies ending in fetal loss decreased serum DDE levels less than did those carried to term.
Study Synopsis: A study of US women finds exposure to PCBs is associated with a diagnosis of endometriosis. Women in the highest tertile of anti-estrogenic PCBs had a 3-fold increase in risk of endometriosis. There was no association between serum levels of estrogenic PCBs and endometriosis in this study.
Scientific abstract:
BACKGROUND: Hormonally active environmental agents have recently been associated with the development of endometriosis. METHODS: We undertook a study to assess the relationship between endometriosis, an estrogen-dependent gynaecological disease, and 62 individual polychlorinated biphenyl (PCBs) congeners. We enrolled 84 eligible women aged 18-40 years undergoing laparoscopy for study, which included an interview and blood specimen (n=79; 94%). Thirty-two women had visually confirmed endometriosis at laparoscopy while 52 did not. Blood specimens were run in batches of 14 including four quality control samples for toxicological analysis. Each PCB congener was adjusted for recovery; batch-specific reagent blanks were subtracted. All PCB concentrations were log transformed and expressed in ng/g serum first as a sum and then as tertiles by purported estrogenic or anti-estrogenic activity of PCB congeners. RESULTS: Using unconditional logistic regression analysis, a significantly elevated odds ratio (OR) was observed for women in the third tertile of anti-estrogenic PCBs [OR 3.77; 95% confidence interval (CI) 1.12-12.68]. Risk remained elevated after controlling for gravidity, current cigarette smoking and serum lipids (OR 3.30; 95% CI 0.87-12.46). CONCLUSIONS: These data suggest that anti-estrogenic PCBs may be associated with the development of endometriosis.
Key Words: Adolescent, Adult, Cohort Studies, Endometriosis/*blood/*etiology, Environmental Pollutants/*blood/*toxicity, Estrogen Receptor Modulators/*blood/chemistry/*toxicity, Female, Humans, Odds Ratio, Polychlorinated Biphenyls/*blood/chemistry/*toxicity, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S., Risk Factors
Luebker DJ, Case MT, York RG, Moore JA, Hansen KJ, Butenhoff JL. Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats. Toxicology. 2005 Nov;215(2-Jan):126-48.
Study Synopsis: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA and PFOS. The current study focused on the potential reproductive and developmental effects of PFOS by conducting a study over two generations of rats. Daily doses of PFOS were administered to males and female rats for six weeks prior to mating, during mating and, for females, through gestation and lactation. Reduction in body weight and food consumption were observed in both males and females who were directly exposed but not in their offspring. PFOS did not affect fertility but reduced the duration of gestation and caused stillbirth. Developmental outcomes, such as eye opening, were also delayed. The study also determined that prenatal, rather than postnatal, exposure to PFOS was responsible for these effects
Scientific abstract:
Perfluorooctanesulfonate (PFOS) is a persistent acid found widely distributed in wildlife and humans. To understand the potential reproductive and developmental effects of PFOS, a two-generation reproduction study was conducted in rats. Male and female rats were dosed via oral gavage at dose levels of 0, 0.1, 0.4, 1.6, and 3.2 mg/(kg day) for 6 weeks prior to mating, during mating, and, for females, through gestation and lactation, across two generations. Due to substantial F1 neonatal toxicity observed in the 1.6 and 3.2 mg/(kg day) groups, continuation into the second generation was limited to F1 pups from the 0, 0.1, and 0.4 mg/(kg day) groups. No adverse effects were observed in F0 females or their fetuses upon caesarean sectioning at gestation day 10. Statistically significant reductions in body-weight gain and feed consumption were observed in F0 generation males and females at dose levels of 0.4 mg/(kg day) and higher, but not in F1 adults. PFOS did not affect reproductive performance (mating, estrous cycling, and fertility); however, reproductive outcome, as demonstrated by decreased length of gestation, number of implantation sites, and increased numbers of dams with stillborn pups or with all pups dying on lactation days 1-4, was affected at 3.2 mg/(kg day) in F0 dams. These effects were not observed in F1 dams at the highest dose tested, 0.4 mg/(kg day). Neonatal toxicity in F1 pups, as demonstrated by reduced survival and body-weight gain through the end of lactation, occurred at a maternal dose of 1.6 mg/(kg day) and higher while not at dose levels of 0.1 or 0.4 mg/(kg day) or in F2 pups at the 0.1 or 0.4 mg/(kg day) dose levels tested. In addition to these adverse effects, slight yet statistically significant developmental delays occurred at 0.4 (eye opening) and 1.6 mg/(kg day) (eye opening, air righting, surface righting, and pinna unfolding) in F1 pups. Based on these data, the NOAELs were as follows: reproductive function: F0> or =3.2 and F1> or =0.4 mg/(kg day); reproductive outcome: F0=1.6 and F1> or =0.4 mg/(kg day); overall parental effects: F0=0.1 and F1> or =0.4 mg/(kg day); offspring effects: F0=0.4 and F1> or =0.4 mg/(kg day). To distinguish between maternal and pup influences contributing to the perinatal mortality observed in the two-generation study, a follow-up cross-foster study was performed. Results of this study indicated that in utero exposure to PFOS causally contributed to post-natal pup mortality, and that pre-natal and post-natal exposure to PFOS was additive with respect to the toxic effects observed in pups.
Luebker DJ, Case MT, York RG, Moore JA, Hansen KJ, Butenhoff JL. Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats. Toxicology. 2005 Nov;215(1-2):126-48.
Study Synopsis: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are highly persistent water and oil repellents used in products such as Teflon, Scotchguard and Gore-Tex. They are used in stain resistant carpets, furniture, microwaveable popcorn bags and clothing. Studies report that virtually all U.S. residents have detectable blood levels of PFOA and PFOS. The current study focused on the potential reproductive and developmental effects of PFOS by conducting a study over two generations of rats. Daily doses of PFOS were administered to males and female rats for six weeks prior to mating, during mating and, for females, through gestation and lactation. Reduction in body weight and food consumption were observed in both males and females who were directly exposed but not in their offspring. PFOS did not affect fertility but reduced the duration of gestation and caused stillbirth. Developmental outcomes, such as eye opening, were also delayed. The study also determined that prenatal, rather than postnatal, exposure to PFOS was responsible for these effects
Scientific abstract:
Perfluorooctanesulfonate (PFOS) is a persistent acid found widely distributed in wildlife and humans. To understand the potential reproductive and developmental effects of PFOS, a two-generation reproduction study was conducted in rats. Male and female rats were dosed via oral gavage at dose levels of 0, 0.1, 0.4, 1.6, and 3.2 mg/(kg day) for 6 weeks prior to mating, during mating, and, for females, through gestation and lactation, across two generations. Due to substantial F1 neonatal toxicity observed in the 1.6 and 3.2 mg/(kg day) groups, continuation into the second generation was limited to F1 pups from the 0, 0.1, and 0.4 mg/(kg day) groups. No adverse effects were observed in F0 females or their fetuses upon caesarean sectioning at gestation day 10. Statistically significant reductions in body-weight gain and feed consumption were observed in F0 generation males and females at dose levels of 0.4 mg/(kg day) and higher, but not in F1 adults. PFOS did not affect reproductive performance (mating, estrous cycling, and fertility); however, reproductive outcome, as demonstrated by decreased length of gestation, number of implantation sites, and increased numbers of dams with stillborn pups or with all pups dying on lactation days 1-4, was affected at 3.2 mg/(kg day) in F0 dams. These effects were not observed in F1 dams at the highest dose tested, 0.4 mg/(kg day). Neonatal toxicity in F1 pups, as demonstrated by reduced survival and body-weight gain through the end of lactation, occurred at a maternal dose of 1.6 mg/(kg day) and higher while not at dose levels of 0.1 or 0.4 mg/(kg day) or in F2 pups at the 0.1 or 0.4 mg/(kg day) dose levels tested. In addition to these adverse effects, slight yet statistically significant developmental delays occurred at 0.4 (eye opening) and 1.6 mg/(kg day) (eye opening, air righting, surface righting, and pinna unfolding) in F1 pups. Based on these data, the NOAELs were as follows: reproductive function: F0> or =3.2 and F1> or =0.4 mg/(kg day); reproductive outcome: F0=1.6 and F1> or =0.4 mg/(kg day); overall parental effects: F0=0.1 and F1> or =0.4 mg/(kg day); offspring effects: F0=0.4 and F1> or =0.4 mg/(kg day). To distinguish between maternal and pup influences contributing to the perinatal mortality observed in the two-generation study, a follow-up cross-foster study was performed. Results of this study indicated that in utero exposure to PFOS causally contributed to post-natal pup mortality, and that pre-natal and post-natal exposure to PFOS was additive with respect to the toxic effects observed in pups.
Study Synopsis: The sex ratio in a First Nation community near Sarnia, Ontario has dropped to fewer than 35% boys, significantly below normal. Prior to 1993, the sex ratio appeared to be normal and stable. Since that time, it has declined significantly, with the strongest decline in the last 5 years. The community lives in close proximity to a large petrochemical complex. Researchers propose that chemical exposures may be contributing to the decline. This would be consistent with some but not all related studies.
Members of the Aamjiwnaang First Nation community near Sarnia, Ontario, Canada, voiced concerns that there appeared to be fewer male children in their community in recent years. In response to these concerns, we assessed the sex ratio (proportion of male births) of the Aamjiwnaang First Nation over the period 1984-2003 as part of a community-based participatory research project. The trend in the proportion of male live births of the Aamjiwnaang First Nation has been declining continuously from the early 1990s to 2003, from an apparently stable sex ratio prior to this time. The proportion of male births (m) showed a statistically significant decline over the most recent 10-year period (1994-2003) (m = 0.412, p = 0.008) with the most pronounced decrease observed during the most recent 5 years (1999-2003) (m = 0.348, p = 0.006). Numerous factors have been associated with a decrease in the proportion of male births in a population, including a number of environmental and occupational chemical exposures. This community is located within the Great Lakes St. Clair River Area of Concern and is situated immediately adjacent to several large petrochemical, polymer, and chemical industrial plants. Although there are several potential factors that could be contributing to the observed decrease in sex ratio of the Aamjiwnaang First Nation, the close proximity of this community to a large aggregation of industries and potential exposures to compounds that may influence sex ratios warrants further assessment into the types of chemical exposures for this population. A community health survey is currently under way to gather more information about the health of the Aamjiwnaang community and to provide additional information about the factors that could be contributing to the observed decrease in the proportion of male births in recent years.
Key Words: Animals, Animals-Wild, Female, Humans, *Indians, North American, Male, Ontario/epidemiology, Pregnancy, Pregnancy Outcome, Research Support, Non-U.S. Gov't, *Sex Ratio
Study Synopsis: Experiments with mice show that exposure during pregnancy to 25 parts per trillion of bisphenol A causes changes in the genital tract of female offspring that are revealed during adulthood. The dose levels used are well within the range to which many people are exposed because of BPA's use in food and beverage containers and as a dental sealant.
Scientific abstract:
Developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. Humans are routinely exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials and plastic food and beverage containers. The aim of the present study was to determine the effects of in utero exposure to low, environmentally relevant doses of BPA on the development of female reproductive tissues in CD-1 mice. In previous publications, we have shown that this treatment alters the morphology of the mammary gland and affects estrous cyclicity. Here we report that in utero exposure to 25 and 250 ng BPA/ kg of body weight per day via osmotic pumps implanted into pregnant dams at Gestational Day 9 induces alterations in the genital tract of female offspring that are revealed during adulthood. They include decreased wet weight of the vagina, decreased volume of the endometrial lamina propria, increased incorporation of bromodeoxyuridine into the DNA of endometrial gland epithelial cells, and increased expression of estrogen receptor-alpha (ERalpha) and progesterone receptor in the luminal epithelium of the endometrium and subepithelial stroma. Because ERalpha is known to be expressed in these estrogen-target organs at the time of BPA exposure, it is plausible that BPA may directly affect the expression of ER-controlled genes involved in the morphogenesis of these organs. In addition, BPA-induced alterations that specifically affect hypothalamic-pituitary-gonadal axis function may further contribute to the anomalies observed at 3 mo of age, long after the cessation of BPA exposure.
Study Synopsis: Research from the US EPA finds women who eat contaminated sport fish during pregnancy are more likely to have a male baby with a birth defect. For New York women who at 2 or more meals per month of sport caught fish there was a non-significant increase in the rate of a major birth defects. However, when analyzed by sex, the risk was significantly elevated 3-fold for male compared to female newborns. Exposure to endocrine disruptors or other environmental contaminants may explain these sex differences.
Scientific abstract:
Contaminated sport fish consumption may result in exposure to various reproductive and developmental toxicants, including pesticides and other suspected endocrine disruptors. We investigated the relation between maternal sport fish meals and risk of major birth defects among infants born to members of the New York State (NYS) Angler Cohort between 1986 and 1991 (n=2237 births). Birth defects (n=125 cases) were ascertained from both newborn medical records and the NYS Congenital Malformations Registry. For sport fish meals eaten during pregnancy, the odds ratio (OR) for all major malformations combined was slightly elevated for < or =1 meal/month (OR=1.26, 95% confidence interval (CI): 0.84, 1.89) and > or =2 meals/month (OR=1.51, CI=0.74, 3.09), with no meals during pregnancy as the reference category. Higher ORs were consistently observed among male offspring compared with females. For > or =2 meals/month, the risk for males was significantly elevated (males: OR=3.01, CI: 1.2, 7.5; females: OR=0.73, CI: 0.2, 2.4). Exposure during pregnancy and effect modification by infants sex could be important considerations for future studies of birth outcomes associated with endocrine disruptors.
Key Words: Abnormalities, Drug-Induced/*epidemiology/etiology, Adolescent, Adult, Animals, Environmental Pollutants/*adverse effects, Female, *Fishes, *Food Contamination, Humans, Infant, Infant, Newborn, Male, *Maternal Exposure, Medical Records, New York/epidemiology, Pregnancy, Questionnaires, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Retrospective Studies, Risk Factors, Sports
Developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. Humans are exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials and plastic food and beverage containers. The aim of the present study was to determine the effects of perinatal exposure to low, environmentally relevant doses of BPA [25 and 250 ng BPA/kg body weight (bw).d] on the peripubertal development of the mammary gland. BPA exposure enhanced the mammary glands' sensitivity to estradiol in ovariectomized CD-1 mice. In their intact 30-d-old littermates, the area and numbers of terminal end buds relative to the gland ductal area increased whereas their apoptotic activity decreased. There was a positive correlation between ductal length and the age at first proestrus; that was reduced as the BPA dose increased, suggesting that BPA exposure slows down ductal invasion of the stroma. There was also a significant increase of progesterone receptor-positive ductal epithelial cells that were localized in clusters, suggesting future branching points. Indeed, lateral branching was significantly enhanced at 4 months of age in mice exposed to 25 ng BPA /kg bw.d. In conclusion, perinatal exposure to environmentally relevant BPA doses results in persistent alterations in mammary gland morphogenesis. Of special concern is the increased terminal end bud density at puberty as well as the increased number of terminal ends reported previously in adult animals, as these two structures are the sites at which cancer arises in humans and rodents.
Study Synopsis: Exposure to active or secondhand smoke increases the risk of failure in fertility treatments. Despite similar embryo quality, women undergoing in vitro fertilization with exposure to tobacco smoke have one-half the rate of implantation as women not exposed to smoke. Pregnancy rates were 40% lower in smoke-exposed compared to non-exposed.
Scientific abstract:
BACKGROUND: Cigarette smoking (CS) is a widely recognized health hazard, yet it remains prevalent in society and the effects of environmental tobacco smoke exposure on fertility are unknown. Our objective was to measure the effects of CS on the fertility of mainstream (MS) or sidestream (SS) smoke-exposed women compared to their non-smoking (NS) counterparts. METHODS: This retrospective study investigated 225 female patients undergoing IVF (n = 97) or ICSI (n = 128). Patients were grouped based on their smoking status for comparison. This included: 39 MS (18 IVF and 21 ICSI); 40 SS (16 IVF and 24 ICSI); and 146 NS (63 IVF and 83 ICSI) women. Fertility treatment outcomes including embryo quality, implantation and pregnancy rate were measured. RESULTS: No difference in embryo quality between the three groups was observed. However, there was a significant difference in implantation rate (MS = 12.0%, SS = 12.6%, and NS = 25.0%) and pregnancy rate (MS = 19.4%, SS = 20.0%, and NS = 48.3%) per embryo transfer. CONCLUSIONS: Despite similar embryo quality there was a striking difference in implantation and pregnancy rates of MS and SS smokers when compared with NS. Our data demonstrate that the effects of SS smoking are equally as damaging as MS smoke on fertility.
Study Synopsis: A study of newly married Chinese textile workers reveals that women who reached puberty earlier had higher levels of DDT in their blood. The age of menarche was 1.1 years younger in women in the highest exposure group compared to women with the lowest levels of serum DDT. Menstrual cycle lengths were also shorter.
Scientific abstract:
BACKGROUND: Although dichlorodiphenyl trichloroethane (DDT) exposure is known to affect human endocrine function, few previous studies have investigated the effects of DDT exposure on age at menarche or menstrual cycle length. METHODS: A cross sectional study was conducted to study the effects of DDT exposure on age at menarche and menstrual cycle length among 466 newly married, nulliparous female Chinese textile workers aged 20-34 years enrolled between 1996 and 1998. Serum was analysed for DDT and its major metabolites. Multivariate linear regression was used to estimate DDT exposure effects on age at menarche and multivariate logistic regression was used to estimate DDT exposure effects on odds of experiencing short or long cycles. RESULTS: Relative to those in the lowest DDT quartile, the adjusted mean age at menarche was younger in those in the fourth quartile (-1.11 years). Modeled as a continuous variable, a 10 ng/g increase in serum DDT concentration was associated with an adjusted reduction in age at menarche of 0.20 years. Relative to those in the lowest DDT quartile, odds of any short cycle (<21 days) in the previous year were higher for those in the fourth quartile (odds ratio = 2.78; 95% CI 1.07 to 7.14). There were no associations between serum DDT concentrations and odds of experiencing a long cycle (>40 days). CONCLUSION: Results suggest that DDT exposure was associated with earlier age at menarche and increased risk of experiencing a shortened menstrual cycle.
Under physiological conditions, factors affecting the genetic control of hypothalamic functions are predominant in determining the individual variations in timing of pubertal onset. In pathological conditions, however, these variations can involve different genetic susceptibility and the interaction of environmental factors. The high incidence of precocious puberty in foreign children migrating to Belgium and the detection in their plasma of a long-lasting 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (DDT) residue suggest the potential role of environmental endocrine disrupting chemicals in the early onset of puberty. This hypothesis was confirmed by experimental data showing that temporary exposure of immature female rats to DDT in vivo results in early onset of puberty. We compared the gene expression profile of hypothalamic hamartoma associated or not with precocious puberty in order to identify gene networks responsible for both hamartoma-dependent sexual precocity and the onset of normal human puberty. In conclusion, pathological variations in the timing of puberty may provide unique information about the interactions of either environmental conditions or genetic susceptibility with the hypothalamic mechanism controlling the onset of sexual maturation, as shown by examples of precocious puberty following exposure to endocrine disrupters or due to hypothalamic hamartoma.
Study Synopsis: Minnows exposed before hatching to extremely low concentrations of a synthetic estrogen used in birth control pills and excreted into wastewater were more likely to be female. They also showed decreased egg fertilization. These effects were observed at the lowest exposure levels tested. Exposed male minnows were demasculinized at slightly higher levels. The concentrations for these effects were similar to or lower than those detected in many municipal wastewater effluents.
Scientific abstract:
Forty-eight hours after fertilization, fathead minnow (Pimephales promelas) eggs were exposed to the synthetic estrogen 17alpha-ethinylestradiol (EE2) at nominal concentrations of 0.32 and 0.96 ng/L and measured concentrations of 3.5, 9.6, and 23 ng/L. The fish were observed through the larval, juvenile, and adult stages. Growth, secondary sex characteristics, the liver somatic index, the gonadosomatic index, and fecundity were examined after several lengths of exposure. No significant changes were seen in fry or juvenile growth from 8 to 30 days posthatch (dph). An increase in the ovipositor index (a female secondary sex characteristic) was the most sensitive early response at 60 dph and was seen in fish exposed to EE2 concentrations > or = 3.5 ng/L. Continuation of the EE2 exposure until 150 dph, through maturation and reproduction, allowed measurement of two sensitive end points: decreased egg fertilization and sex ratio (skewed toward females), both of which were significantly affected at the lowest EE2 concentration tested, 0.32 ng/L. The next most sensitive end point was demasculinization (decreased male secondary sex characteristic index) of males exposed to an EE2 concentration of 0.96 ng/L. The effects of low concentrations of EE2 (0.32 and 0.96 ng/L) were manifested in male fish (decreased male sex characteristics and reduced egg fertilization success), whereas female fish showed no changes in the gonadosomatic index. Exposure to higher EE2 concentrations negatively affected females, as shown by a reduced gonadosomatic index at 150 dph in fish exposed to > or =3.5 ng/L EE2. Although there were some end points that showed changes at 60 dph, the reproductive end points and external sex characteristics measured in mature fish at 150 dph were more sensitive, with response thresholds of EE2 ranging from 0.32 to 0.96 ng/L. The concentrations of EE2 that negatively affected fathead minnows were similar to or lower than those detected in many municipal wastewater effluents. In conclusion, life-cycle exposure of fathead minnows proved to be a very sensitive bioassay, and responses were seen at concentrations of less than 1 ng/L, which are environmentally relevant concentrations of EE2.
Acid/base transporters play a key role in establishing an acidic luminal environment for sperm maturation and storage in the male reproductive tract. Impairment of the acidification capacity of the epididymis, via either genetic mutations or exposure to environmental factors, may have profound consequences on male fertility.
Key Words: Acid-Base Equilibrium, Acids/*metabolism, Animals, Genitalia, Male/*metabolism, Humans, Infertility, Male/*etiology, Male, Membrane Transport Proteins/*physiology, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Study Synopsis: Experiments with sheep demonstrate that male offspring born to females feeding on pastures treated with sewage sludge showed abnormal testicular development and hormonal function. The treatment had no effect on the body on the body weight of the ewes, but did reduce fetal weight. Male testicular weight was reduced, as were the numbers of cells crucial for sperm production.
Scientific abstract:
The purpose of this study was to evaluate whether experimental exposure of pregnant sheep to a mixture of environmental chemicals added to pasture as sewage sludge (n = 9 treated animals) exerted effects on fetal testis development or function; application of sewage sludge was undertaken so as to maximize exposure of the ewes to its contents. Control ewes (n = 9) were reared on pasture treated with an equivalent amount of inorganic nitrogenous fertilizer. Treatment had no effect on body weight of ewes, but it reduced body weight by 12-15% in male (n = 12) and female (n = 8) fetuses on gestation day 110. In treated male fetuses (n = 11), testis weight was significantly reduced (32%), as were the numbers of Sertoli cells (34% reduction), Leydig cells (37% reduction), and gonocytes (44% reduction), compared with control fetuses (n = 8). Fetal blood levels of testosterone and inhibin A were also reduced (36% and 38%, respectively) in treated compared with control fetuses, whereas blood levels of luteinizing hormone and follicle-stimulating hormone were unchanged. Based on immunoexpression of anti-Mullerian hormone, cytochrome P450 side chain cleavage enzyme, and Leydig cell cytoplasmic volume, we conclude that the hormone changes in treated male fetuses probably result from the reduction in somatic cell numbers. This reduction could result from fetal growth restriction in male fetuses and/or from the lowered testosterone action; reduced immunoexpression of alpha-smooth muscle actin in peritubular cells and of androgen receptor in testes of treated animals supports the latter possibility. These findings indicate that exposure of the developing male sheep fetus to real-world mixtures of environmental chemicals can result in major attenuation of testicular development and hormonal function, which may have consequences in adulthood.
Study Synopsis: A prospective cohort study of a multi-ethnic population in northern Manhattan finds exposures to environmental contaminants interferes with fetal growth. Pregnant women exposed to secondhand smoke had smaller babies with lower birth weight and decreased head circumferences. Cord blood levels of the pesticide, chlorpyrifos, was associated with decreased birth weight and body length.
Scientific abstract:
Inner-city minority populations are high-risk groups for adverse birth outcomes and also more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), benzo[a]pyrene B[a]P, other ambient polycyclic aromatic hydrocarbons (global PAHs), and residential pesticides. The Columbia Center for Children's Environmental Health (CCCEH) is conducting a prospective cohort study of 700 northern Manhattan pregnant women and newborns to examine the effects of prenatal exposure to these common toxicants on fetal growth, early neurodevelopment, and respiratory health. This paper summarizes results of three published studies demonstrating the effects of prenatal ETS, PAH, and pesticides on birth outcomes and/or neurocognitive development [Perera FP, Rauh V, Whyatt RM, Tsai WY, Bernert JT, Tu YH, et al. Molecular evidence of an interaction between prenatal environment exposures on birth outcomes in a multiethnic population. Environ Health Perspect 2004;12:630-62; Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, et al. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicol Teratol 2004;26:373-85; Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R, et al. Prenatal insecticide exposures, birth weight and length among an urban minority cohort. Environ Health Perspect, in press]. To evaluate the effects of prenatal exposure to ETS, PAHs, and pesticides, researchers analyzed questionnaire data, cord blood plasma (including biomarkers of ETS and pesticide exposure), and B[a]P-DNA adducts (a molecular dosimeter of PAHs). Self-reported ETS was associated with decreased head circumference (P = 0.04), and there was a significant interaction between ETS and adducts such that combined exposure had a significant multiplicative effect on birth weight (P = 0.04) and head circumference (P = 0.01) after adjusting for confounders. A second analysis examined the neurotoxic effects of prenatal ETS exposure and postpartum material hardship (unmet basic needs in the areas of food, housing, and clothing) on 2-year cognitive development. Both exposures depressed cognitive development (P < 0.05), and there was a significant interaction such that children with exposure to both ETS and material hardship exhibited the greatest cognitive deficit (7.1 points). A third analysis found that cord chlorpyrifos, and a combined measure of cord chlorpyrifos, diazinon, and propoxur-metabolite, were inversely associated with birth weight and/or length (P < 0.05). These results underscore the importance of policies that reduce exposure to ETS, air pollution, and pesticides with potentially adverse effects on fetal growth and child neurodevelopment.
Key Words: Child, Child Development/*drug effects, Child, Preschool, Cohort Studies, Environmental Pollutants/*adverse effects, Female, Fetal Development/drug effects, Humans, Infant, Infant, Newborn, Pesticides/*adverse effects, Pregnancy, Pregnancy Outcome/*epidemiology, Prenatal Exposure Delayed Effects, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Tobacco Smoke Pollution/*adverse effects, p-Aminohippuric Acid/*adverse effects
Study Synopsis: A combination of environmental tobacco smoke and polycyclic aromatic hydrocarbons increases the risk of low birth weight babies. Women closer to the World Trade Center explosion on 9/11 had higher levels of PAHs than those farther away. Those with higher levels and, simultaneously, exposure to ETS were more likely to give birth to babies with low birth weight and reduced head circumference. No effects of PAH exposure or ETS alone were observed.
Scientific abstract:
Polycyclic aromatic hydrocarbons (PAHs) are toxic pollutants released by the World Trade Center (WTC) fires and various urban combustion sources. Benzo[a]pyrene (BaP) is a representative member of the class of PAHs. PAH-DNA adducts, or BaP-DNA adducts as their proxy, provide a measure of chemical-specific genetic damage that has been associated with increased risk of adverse birth outcomes and cancer. To learn whether PAHs from the WTC disaster increased levels of genetic damage in pregnant women and their newborns, we analyzed BaP-DNA adducts in maternal (n = 170) and umbilical cord blood (n = 203) obtained at delivery from nonsmoking women who were pregnant on 11 September 2001 and were enrolled at delivery at three downtown Manhattan hospitals. The mean adduct levels in cord and maternal blood were highest among newborns and mothers who resided within 1 mi of the WTC site during the month after 11 September, intermediate among those who worked but did not live within this area, and lowest in those who neither worked nor lived within 1 mi (reference group). Among newborns of mothers living within 1 mi of the WTC site during this period, levels of cord blood adducts were inversely correlated with linear distance from the WTC site (p = 0.02). To learn whether PAHs from the WTC disaster may have affected birth outcomes, we analyzed the relationship between these outcomes and DNA adducts in umbilical cord blood, excluding preterm births to reduce variability. There were no independent fetal growth effects of either PAH-DNA adducts or environmental tobacco smoke (ETS), but adducts in combination with in utero exposure to ETS were associated with decreased fetal growth. Specifically, a doubling of adducts among ETS-exposed subjects corresponded to an estimated average 276-g (8%) reduction in birth weight (p = 0.03) and a 1.3-cm (3%) reduction in head circumference (p = 0.04). The findings suggest that exposure to elevated levels of PAHs, indicated by PAH-DNA adducts in cord blood, may have contributed to reduced fetal growth in women exposed to the WTC event.
Key Words: Adolescent, Adult, Air Pollutants, Environmental/toxicity, Benzo(a)pyrene, Birth Weight/*drug effects, DNA/analysis, DNA Adducts/*blood, Female, Fetal Blood/chemistry, Fetal Development, Head/*growth & development, Humans, Maternal Exposure, New York, Polycyclic Hydrocarbons, Aromatic/*toxicity, Pregnancy, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., *September 11 Terrorist Attacks, Tobacco Smoke Pollution/adverse effects
Study Synopsis: Preterm birth is linked to air pollution in the Los Angeles basin. Mothers living in neighborhoods with concentrated poverty, unemployment and dependence on public assistance are at disproportionately high risk. Winter season increased susceptibility further.
Scientific abstract:
Preterm birth may be affected by the interaction of residential air pollution with neighborhood economic hardship. The authors examined variations in traffic-related pollution exposure--measured by distance-weighted traffic density--using a framework reflecting the social and physical environments. An adverse social environment was conceptualized as low socioeconomic status (SES) neighborhoods--census tracts with concentrated poverty, unemployment, and dependence on public assistance. An adverse physical environment was depicted by the winter season, when thermal inversions trap motor vehicle pollutants, thereby increasing traffic-related air pollution. Los Angeles County, California, birth records from 1994 to 1996 were linked to traffic counts, census data, and ambient air pollution measures. The authors fit multivariate logistic models of preterm birth, stratified by neighborhood SES and third pregnancy trimester season. Traffic-related air pollution exposure disproportionately affected low SES neighborhoods in the winter. Further, in these poorer neighborhoods, the winter season evidenced increased susceptibility among women with known risk factors. Health insurance was most beneficial to women residing in neighborhoods exposed to economic hardship and an adverse physical environment. Reducing preterm births warrants a concerted effort of social, economic, and environmental policies, focused on not only individual risk factors but also the reduction of localized air pollution, expansion of health-care coverage, and improvement of neighborhood resources.
Key Words: Adolescent, Adult, Environmental Pollutants/*adverse effects, Ethnic Groups, Female, Humans, Insurance Coverage/economics, Insurance, Health/economics, Los Angeles/epidemiology, Maternal Age, Maternal Exposure/*adverse effects, *Motor Vehicles, Multivariate Analysis, *Poverty Areas, Pregnancy, Pregnancy Outcome/epidemiology, Pregnancy Trimester, Third, Premature Birth/*epidemiology/ethnology/etiology, Public Assistance, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S., Risk, Seasons, Unemployment
Study Synopsis: Men who are undergoing treatment for infertility are 20 times more likely than men in the general population to be diagnosed with testicular cancer, a new study shows. The finding underscores the importance of urological screening for any man with infertility, Dr. Marc Goldstein said, especially because this evaluation is often not a part of infertility treatment. The findings show that it would be necessary to screen only 500 infertile men to identify one case of testicular cancer, compared with breast cancer screening of 1,500 women to pick up a single case.
Scientific abstract:
PURPOSE: We determined the standardized incidence ratio of testicular cancer in infertile men presenting with an abnormal semen analysis compared to the general population. MATERIALS AND METHODS: The charts from more than 3,800 men presenting with infertility and abnormal semen analysis during a 10-year period were retrospectively reviewed. The incidence of testicular tumors diagnosed in this group was compared to that of race and age matched controls during the same period from the general population (as reported by the Surveillance, Epidemiology and End Results [SEER] database). RESULTS: Of 3,847 men 10 (0.3%) with infertility and abnormal semen analysis were diagnosed with testicular tumors. Mean patient age was 32.6 years (range 25 to 52) and all 10 men were diagnosed with a seminomatous germ cell tumor. Two men had a history of cryptorchidism while the remaining 8 had no identifiable risk factors for testicular cancer. The SEER database reported an incidence of 10.6 cases of testicular cancer (95% CI 10.3-10.8) per 100,000 men of similar age group and racial composition during the same period. The standardized incidence ratio of testicular cancer was 22.9 (95% CI 22.4-23.5) when comparing our infertile group to the control population. Exclusion from analysis of the 2 patients with a history of cryptorchidism decreased the standardized incidence ratio to 18.3 (95% CI 18.0-18.8). CONCLUSIONS: Infertile men with abnormal semen analyses have a 20-fold greater incidence of testicular cancer compared to the general population. Patients and physicians should be aware that one of the causes of infertility could be cancer, particularly testicular cancer.
Organophosphorous pesticides (OPs) are suspected of altering reproductive function by reducing brain acetylcholinesterase activity and monoamine levels, thus impairing hypothalamic and/or pituitary endocrine functions and gonadal processes. Our objective was to evaluate in a longitudinal study the association between OP exposure and serum levels of pituitary and sex hormones. Urinary OP metabolite levels were measured by gas-liquid chromatography, and serum pituitary and sex hormone levels by enzymatic immunoassay and radioimmunoassay in 64 men. A total of 147 urine and blood samples were analyzed for each parameter. More than 80% of the participants had at least one OP metabolite in their urine samples. The most frequent metabolite found was diethylthiophosphate (DETP; 55%), followed by diethylphosphate (DEP; 46%), dimethylthiophosphate (DMTP; 32%), and dimethyldithiophosphate (DMDTP; 31%). However, the metabolites detected at higher concentrations were DMTP, DEP, DMDTP, and dimethylphosphate. There was a high proportion of individuals with follicle-stimulating hormone (FSH) concentrations outside the range of normality (48%). The average FSH serum levels were higher during the heavy pesticide spraying season. However, a multivariate analysis of data collected in all periods showed that serum FSH levels were negatively associated with urinary concentrations of both DMTP and DMDTP, whereas luteinizing hormone (LH) was negatively associated with DMTP. We observed no significant associations between estradiol or testosterone serum levels with OP metabolites. The hormonal disruption in agricultural workers presented here, together with results from experimental animal studies, suggests that OP exposure disrupts the hypothalamic-pituitary endocrine function and also indicates that FSH and LH are the hormones most affected.
Key Words: Adolescent, Adult, Agriculture, Air Pollutants, Occupational/adverse effects/urine, Environmental Monitoring, Follicle Stimulating Hormone/*blood, Humans, Luteinizing Hormone/*blood, Male, Mexico, Middle Aged, *Occupational Exposure, Organothiophosphorus Compounds/*adverse effects/urine, Pesticides/*adverse effects/urine, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.
Study Synopsis: Intersex frogs became common in Illinois during the period, mid-20th century, when DDT and PCBs were in highest use. Very few intersex frogs were detected prior to widespread use of these chemicals. The highest porportion was observed in animals from the heavily industrialized and urbanized NE portion of Illinois. The frequency of intersex has declined since DDT's heyday. Contaminants causing intersex are likely to have contributed to the decline of the cricket frog in Illinois.
Scientific abstract:
Exposure to anthropogenic endocrine disruptors has been listed as one of several potential causes of amphibian declines in recent years. We examined gonads of 814 cricket frogs (Acris crepitans) collected in Illinois and deposited in museum collections to elucidate relationships between the decline of this species in Illinois and the spatial and temporal distribution of individuals with intersex gonads. Compared with the preorganochlorine era studied (1852-1929), the percentage of intersex cricket frogs increased during the period of industrial growth and initial uses of polychlorinated biphenyls (PCBs) (1930-1945), was highest during the greatest manufacture and use of p,p-dichlorodiphenyltrichloroethane (DDT) and PCBs (1946-1959), began declining with the increase in public concern and environmental regulations that reduced and then prevented sales of DDT in the United States (1960-1979), and continued to decline through the period of gradual reductions in environmental residues of organochlorine pesticides and PCBs in the midwestern United States (1980-2001). The proportion of intersex individuals among those frogs was highest in the heavily industrialized and urbanized northeastern portion of Illinois, intermediate in the intensively farmed central and northwestern areas, and lowest in the less intensively managed and ecologically more diverse southern part of the state. Records of deposits of cricket frog specimens into museum collections indicate a marked reduction in numbers from northeastern Illinois in recent decades. These findings are consistent with the hypothesis that endocrine disruption contributed to the decline of cricket frogs in Illinois.
Key Words: Animals, Female, Geography, Hermaphroditism/*history/*veterinary, History, 19th Century, History, 20th Century, Illinois, Male, Museums, Population Dynamics, Ranidae/*growth & development/physiology, Research Support, Non-U.S. Gov't, Water Pollutants, Chemical/*poisoning
Roundup is a glyphosate-based herbicide used worldwide, including on most genetically modified plants that have been designed to tolerate it. Its residues may thus enter the food chain, and glyphosate is found as a contaminant in rivers. Some agricultural workers using glyphosate have pregnancy problems, but its mechanism of action in mammals is questioned. Here we show that glyphosate is toxic to human placental JEG3 cells within 18 hr with concentrations lower than those found with agricultural use, and this effect increases with concentration and time or in the presence of Roundup adjuvants. Surprisingly, Roundup is always more toxic than its active ingredient. We tested the effects of glyphosate and Roundup at lower nontoxic concentrations on aromatase, the enzyme responsible for estrogen synthesis. The glyphosate-based herbicide disrupts aromatase activity and mRNA levels and interacts with the active site of the purified enzyme, but the effects of glyphosate are facilitated by the Roundup formulation in microsomes or in cell culture. We conclude that endocrine and toxic effects of Roundup, not just glyphosate, can be observed in mammals. We suggest that the presence of Roundup adjuvants enhances glyphosate bioavailability and/or bioaccumulation.
Study Synopsis: Although DDT is generally not toxic to human beings, research has shown that exposure to DDT at amounts that would be needed in malaria control might cause preterm birth and early weaning. Other risks, such as neurological and reproductive effects in spraying staff, might also apply. Decisions to use DDT for malaria control should balance the benefits and risks.
Scientific abstract:
DDT (bis[4-chlorophenyl]-1,1,1-trichloroethane) is a persistent insecticide that was used worldwide from the mid 1940s until its ban in the USA and other countries in the 1970s. When a global ban on DDT was proposed in 2001, several countries in sub-Saharan Africa claimed that DDT was still needed as a cheap and effective means for vector control. Although DDT is generally not toxic to human beings and was banned mainly for ecological reasons, subsequent research has shown that exposure to DDT at amounts that would be needed in malaria control might cause preterm birth and early weaning, abrogating the benefit of reducing infant mortality from malaria. Historically, DDT has had mixed success in Africa; only the countries that are able to find and devote substantial resources towards malaria control have made major advances. DDT might be useful in controlling malaria, but the evidence of its adverse effects on human health needs appropriate research on whether it achieves a favourable balance of risk versus benefit.
Key Words: Africa South of the Sahara, Animals, DDT/*adverse effects/pharmacokinetics, Environmental Exposure, Humans, Insecticides/*adverse effects/pharmacokinetics, Malaria/*prevention & control, *Mosquito Control
Research notes: Comment in Lancet. 2005 Nov 19;366(9499):1771-2; author reply 1772.
Study Synopsis: Men in the Czech Republic who were exposed to high air pollution levels were likely to have more fragmented DNA in their sperm. Other aspects of sperm quality were not associated with air quality. Pollution levels were at or above the upper limit of US air quality standards. The analysis suggests that exposure to air pollution may increase rates of male-mediated infertility.
Scientific abstract:
BACKGROUND: This study examined potential associations between exposure to episodes of air pollution and alterations in semen quality. The air pollution, resulting from combustion of coal for industry and home heating in the Teplice district of the Czech Republic, was much higher during the winter than at other times of year with peaks exceeding US air quality standards. METHODS: Young men from Teplice were sampled up to seven times over 2 years allowing evaluation of semen quality after periods of exposure to both low and high air pollution. Routine semen analysis (sperm concentration, motility and morphology) and tests for sperm aneuploidy and chromatin integrity were performed, comparing measurements within each subject. Exposure was classified as high or low based on data from ambient air pollution monitoring. RESULTS: Using repeated measures analysis, a significant association was found between exposure to periods of high air pollution (at or above the upper limit of US air quality standards) and the percentage of sperm with DNA fragmentation according to sperm chromatin structure assay (SCSA). Other semen measures were not associated with air pollution. CONCLUSION: Exposure to intermittent air pollution may result in sperm DNA damage and thereby increase the rates of male-mediated infertility, miscarriage, and other adverse reproductive outcomes.
Study Synopsis: There is no evidence that a genetic mutation in the enzyme that synthesizes estrogens (aromatase) is the cause of polycystic ovarian syndrome (PCOS). Previous theories have proposed that a mutation in the aromatase enzyme could cause PCOS. These results do not preclude the possibility that an aromatase disorder could be an important cause of endometriosis.
Scientific abstract:
BACKGROUND: Etiology and inheritance pattern in polycystic ovary syndrome (PCOS) remain uncertain. Granulosa cells from follicles of women with PCOS have little, if any, aromatase (encoded by the CYP19 gene) activity; follicles contain low levels of estradiol, P450arom mRNA and aromatase stimulating bioactivity. Mice with targeted disruption of the CYP19 gene present cystic follicles. It has been proposed that chronic exposure to high levels of LH, because of aromatase deficiency, determines the development of ovarian cysts. Herein, we investigated if mutations in the CYP19 gene and/or its ovary promoter are causal in patients with PCOS. METHODS: Twenty-five patients with PCOS and 50 control women were studied. PCR analysis of genomic DNA and complete sequence of all exons of the aromatase gene and its ovary promoter were performed. RESULTS: No heterozygous or homozygous mutant alleles were present in any of the patients studied. CONCLUSIONS: In the population studied, mutations of the P450arom gene or its promoter are not the cause of PCOS. However, these findings do not preclude the possible importance of an aromatase disorder in PCOS etiology. Variations in aromatase complex function could play a role in PCOS etiology, but the determinants of such variations might be located in other genes.
Key Words: Adolescent, Adult, Aromatase/*genetics, Female, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Mutation, Polycystic Ovary Syndrome/*genetics, Promoter Regions (Genetics), Research Support, Non-U.S. Gov't
Study Synopsis: Scientists studying trends of fertility over past 50 years conclude it is impossible to identify declines because of changes in social factors that affect the rate and fate of unintended pregnancies. These biases may explain the conflicting reports in the literature. Except in rare settings in which the factors affecting reproductive choices have not changed, it is probably impossible to identify biologic changes in fertility over recent decades.
Scientific abstract:
BACKGROUND: Reports of decreased semen quality over time have raised concerns about possible reductions in human fertility. Studies of couple fertility have produced conflicting results. We evaluate how changes in the availability and use of effective contraception and induced abortion might bias the direct study of time trends in couple fertility. METHODS: We assess the potential for bias in the context of 2 common study designs: (1) a study of time-to-pregnancy that estimates fecundability (excluding unintended pregnancies) and (2) a study of infertility rates that categorizes couples as fertile or infertile (including couples with unintended pregnancies as fertile). RESULTS: In time-to-pregnancy studies, bias alone could produce more than a 2-fold apparent increase in fecundability over recent decades. In studies of infertility rates, the bias works in the opposite direction: a 30% underestimation of infertility during earlier decades could produce an apparent decrease in fertility over time. CONCLUSIONS: Over the past 5 decades, changes in social factors that affect the rate and fate of unintended pregnancies could substantially bias time trends in fertility. These biases may explain the conflicting reports in the literature. Except in rare settings in which the factors affecting reproductive choices have not changed, it is probably impossible to identify biologic changes in fertility over recent decades.
Study Synopsis: Scientists studying trends of fertility over past 50 years conclude it is impossible to identify declines because of changes in social factors that affect the rate and fate of unintended pregnancies. These biases may explain the conflicting reports in the literature. Except in rare settings in which the factors affecting reproductive choices have not changed, it is probably impossible to identify biologic changes in fertility over recent decades.
Scientific abstract:
Environmental risk factors (defined as those agents and stresses that are generally the responsibility of environmental agencies) are often tangible indicators of economic and social disparity in the United States. Many site-specific analyses have reported that communities of color and poverty are exposed more often and more intensively to such environmental hazards as lead, air pollution, agrochemicals, incinerator emissions, and releases from hazardous waste sites. Thus, exposures to these toxicants may explain part of the socioeconomic disparity that is observed in terms of risks of adverse pregnancy outcomes. The purpose of this study was to describe the associations between certain environmental exposures and reproductive outcomes through a discussion of both epidemiologic and animal model studies. In addition, we list potential sources of exposure data and describe physiologic changes in pregnancy that may increase the likelihood of both external exposures and increased internal dose. Several models for further study of environmental risk factors are suggested to increase our understanding of gene-environment interactions toward the goal of indentifying preventable risk factors to improve reproductive outcomes of particular concern to disadvantaged populations.
Study Synopsis: Pregnant women with partners older than age 35 have a greater risk of miscarriage. In women less than 30 years of age, there was a 56% increase in the rate of first trimester miscarriage when the father was older than 35. This likely occurs because of chromosomal anomalies in sperm from older men.
Scientific abstract:
The frequency of chromosomal anomalies in spermatozoa appears to increase with male age. Because these anomalies play a role in the etiology of spontaneous abortion, an influence of paternal age on risk of spontaneous abortion is plausible but not established. The aim was to characterize this influence in a prospective study among 5,121 California women, who as members of a prepaid health plan were interviewed in 1990 or 1991 when they were less than 13 weeks' pregnant and who were followed until the end of pregnancy. The risk of spontaneous abortion between weeks 6 and 20 of pregnancy was studied using a Cox model adjusted for maternal age. The adjusted hazard ratio of spontaneous abortion associated with paternal age of 35 years or more, compared with less than 35 years, was 1.27 (95% confidence interval: 1.00, 1.61), with no modification by maternal age. Among women aged less than 30 years, the hazard ratio of spontaneous abortion associated with paternal age of 35 years or more was 1.56 for first trimester spontaneous abortion and 0.87 for early second trimester spontaneous abortion (test of interaction, p = 0.25). In conclusion, the risk of spontaneous abortion increased with increasing paternal age, with a suggestion that the association is stronger for first trimester losses.
Study Synopsis: European men with higher levels of a persistent bioaccumulative contaminant, the PCB CB-153, are more likely to have sperm chromatin damage. A study of over 700 men found a strong relationship between higher PCB levels and increased chromatin fragmentation. No association was seen in 193 Inuits from Greenland, nor was an association detected with DDE levels in any of the exposure groups.
Scientific abstract:
BACKGROUND: Persistent organochlorine pollutants (POP), such as polychlorinated biphenyls (PCB) and dichlorodiphenyldichloroethylene (p, p'-DDE), are widely found in the environment and considered potential endocrine-disrupting compounds (EDC). Their impact on male fertility is still unknown. METHODS: To explore the hypothesis that POP is associated with altered sperm chromatin integrity, a cross-sectional study involving 707 adult males (193 Inuits from Greenland, 178 Swedish fishermen, 141 men from Warsaw, Poland, and 195 men from Kharkiv, Ukraine) was carried out. Serum levels of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153), as a proxy of the total PCB burden, and of p,p'-DDE were determined. Sperm chromatin structure assay (SCSA) was used to assess sperm DNA/chromatin integrity. RESULTS: We found a strong and monotonically increasing DNA fragmentation index with increasing serum levels of CB-153 among European but not Inuit men, reaching a 60% higher average level in the highest exposure group. No significant associations were found between SCSA-derived parameters and p, p'-DDE serum concentrations. CONCLUSION: These results suggest that human dietary PCB exposure might have a negative impact on the sperm chromatin integrity of adult males but additional issues, including differences in the genetic background and lifestyle habits, still need to be elucidated.
Study Synopsis: In laboratory studies, male rats exposed to a commonly used flame retardant have adverse reproductive effects. Exposure to the polybrominated diphenyl ether mixture, DE-71, delays the onset of puberty and inhibits the growth of the prostate and seminal vesicles. PBDE congeners in the mixture inhibit natural androgens from binding to their receptor and ultimately inhibit gene expression. This study is important because levels of PBDEs have been rapidly increasing in wildlife and human tissues.
Scientific abstract:
PBDEs have been synthesized in large quantities as flame retardants for commercial products, such as electronic equipment and textiles. The rising in levels of PBDEs in tissues in wildlife species and in human milk and plasma samples over the past several years have raised concerns about possible health effects. Recently, we showed that the PBDE mixture, DE-71, delayed puberty and suppressed the growth of androgen-dependent tissues in male Wistar rat following a peri-pubertal exposure. These effects suggested that DE-71 may be either inducing steroid hormone metabolism or acting as an androgen receptor (AR) antagonist. To elucidate the potential anti-androgenic effects of this mixture, we evaluated DE-71 in several in vivo assays, which are responsive to alterations in androgen activity. In a pubertal exposure study designed to further evaluate the delay in preputial separation (PPS), we observed a dose-dependent delay in PPS with 60 and 120 mg/kg/day of DE-71 (4 and 5 days) and a corresponding suppression of ventral prostate (VP) and seminal vesicle growth at both doses. Adult males exposed to 60 mg/kg DE-71 for 3 days resulted in a significant increase in luteinizing hormone and a non-significant increase in testosterone, androstenedione and estrone. DE-71 also tested positive for anti-androgenic activity in an immature rat Hershberger assay, with decreases in mean VP and seminal vesicle weight following doses of 30-240 mg/kg. DE-71 and the individual BDE congeners which comprise the mixture (BDE-47, -99, -100, -153, -154) were also evaluated in vitro. First, AR binding was evaluated in a competitive binding assay using rat VP cytosol. In addition, we evaluated gene activation in a transcriptional activation assay using the MDA-kb2 cell line which contains an endogenous human AR and a transfected luciferase reporter. DE-71 and BDE-100 (2, 4, 6-pentaBDE) both inhibited AR binding, with IC50s of approximately 5 muM. In addition, DE-71 and two of the congeners (BDE-100 and BDE-47) inhibited DHT-induced transcriptional activation. The pattern of inhibition shown in the double-reciprocal plot for BDE-100 and the linear slope replot confirmed that the in vitro mechanism is pure competitive inhibition, with a inhibition constant (K(i)) of 1 muM. The delay in puberty in the male rat and decreased growth of androgen-dependent tissues observed previously following exposure to DE-71 were likely due to this inhibition of AR binding by several of the congeners which make up this mixture.
Stoker TE, Cooper RL, Lambright CS, Wilson VS, Furr J, Gray LE. In vivo and in vitro anti-androgenic effects of DE-71, a commercial polybrominated diphenyl ether (PBDE) mixture. Toxicol Appl Pharmacol. 2005 Aug;207(1):78-88.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. In this study, researchers exposed young rats to different doses of the PBDE mixture DE-71. They found a dose-related delay in preputial separation, an indicator of puberty onset in males, and a suppression in the growth of tissues regulated by male hormones (called androgens) such as testosterone. DE-71 as well as some PBDE congeners also inhibited the action of androgens by blocking their access to a specialized receptor called the androgen receptor. Binding of androgens to the androgen receptor is necessary for these hormones to exert their action. Results thus suggest that exposure to DE-71 delays puberty in male rats and that this effect may be due to an interference with the binding of androgens to the androgen receptor.
Scientific abstract:
PBDEs have been synthesized in large quantities as flame retardants for commercial products, such as electronic equipment and textiles. The rising in levels of PBDEs in tissues in wildlife species and in human milk and plasma samples over the past several years have raised concerns about possible health effects. Recently, we showed that the PBDE mixture, DE-71, delayed puberty and suppressed the growth of androgen-dependent tissues in male Wistar rat following a peri-pubertal exposure. These effects suggested that DE-71 may be either inducing steroid hormone metabolism or acting as an androgen receptor (AR) antagonist. To elucidate the potential anti-androgenic effects of this mixture, we evaluated DE-71 in several in vivo assays, which are responsive to alterations in androgen activity. In a pubertal exposure study designed to further evaluate the delay in preputial separation (PPS), we observed a dose-dependent delay in PPS with 60 and 120 mg/kg/day of DE-71 (4 and 5 days) and a corresponding suppression of ventral prostate (VP) and seminal vesicle growth at both doses. Adult males exposed to 60 mg/kg DE-71 for 3 days resulted in a significant increase in luteinizing hormone and a non-significant increase in testosterone, androstenedione and estrone. DE-71 also tested positive for anti-androgenic activity in an immature rat Hershberger assay, with decreases in mean VP and seminal vesicle weight following doses of 30-240 mg/kg. DE-71 and the individual BDE congeners which comprise the mixture (BDE-47, -99, -100, -153, -154) were also evaluated in vitro. First, AR binding was evaluated in a competitive binding assay using rat VP cytosol. In addition, we evaluated gene activation in a transcriptional activation assay using the MDA-kb2 cell line which contains an endogenous human AR and a transfected luciferase reporter. DE-71 and BDE-100 (2, 4, 6-pentaBDE) both inhibited AR binding, with IC50s of approximately 5 microM. In addition, DE-71 and two of the congeners (BDE-100 and BDE-47) inhibited DHT-induced transcriptional activation. The pattern of inhibition shown in the double-reciprocal plot for BDE-100 and the linear slope replot confirmed that the in vitro mechanism is pure competitive inhibition, with a inhibition constant (Ki) of 1 microM. The delay in puberty in the male rat and decreased growth of androgen-dependent tissues observed previously following exposure to DE-71 were likely due to this inhibition of AR binding by several of the congeners which make up this mixture.
Study Synopsis: In a small prospective study, researchers in Japan report that bisphenol A levels are higher in women with a history of repeated spontaneous miscarriages. This research was based on proof that BPA causes meiotic aneuploidy in mice. Meiotic aneuploidy is the commonest known cause of miscarriage in people. The researchers also followed the pregnancies of the women to completion, and found evidence of aneuploidy in several of the miscarried fetuses. Bisphenol A is widely used in consumer product, including polycarbonate water bottles, epoxy linings for food cans and coatings for papers. Almost all Americans carry measureable levels of BPA, at levels within the range known to cause changes in cellular responses.
Scientific abstract:
BACKGROUND: Little is known about the influence of high exposure to bisphenol A on recurrent miscarriage and immunoendocrine abnormalities. METHODS: Serum bisphenol A, antiphospholipid antibodies (aPLs), antinuclear antibodies (ANAs), natural killer cell (NK) activity, prolactin, progesterone, thyroid-stimulating hormone (TSH) and free T4 were examined in 45 patients with a history of three or more (3-11) consecutive first-trimester miscarriages and 32 healthy women with no history of live birth and infertility. Subsequent pregnancy outcome and embryonic karyotype of abortuses were examined prospectively. RESULTS: The mean+/-SD values for bisphenol A in patients were 2.59+/-5.23 ng/ml, significantly higher than the 0.77+/-0.38 ng/ml found for control women (P=0.024). High exposure to bisphenol A was associated with the presence of ANAs but not hypothyroidism, hyperprolactinaemia, luteal phase defects, NK cell activity or aPLs. A high level of bisphenol A in itself did not predict subsequent miscarriage. CONCLUSION: Exposure to bisphenol A is associated with recurrent miscarriage.
Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, Mao CS, Redmon JB, Ternand CL, Sullivan S, Teague JL. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect. 2005 Aug;113(8):1056-61.
Study Synopsis: Phthalates are chemicals used in personal care products (perfume, lotions and cosmetics), medical devices, coating in some drugs, food packaging and vinyl flooring. Human exposure to phthalates is common due to their widespread use. In this study, researchers measured the concentration of nine phthalate residues in urine collected from 134 pregnant women. They found that women with higher urine levels of four phthalate residues, namely monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate (MiBP), had a smaller anogenital index, a marker of antiandrogenic effect. These results support the hypothesis that phthalates may interfere with androgens such as testosterone in humans.
Scientific abstract:
Prenatal phthalate exposure impairs testicular function and shortens anogenital distance (AGD) in male rodents. We present data from the first study to examine AGD and other genital measurements in relation to prenatal phthalate exposure in humans. A standardized measure of AGD was obtained in 134 boys 2-36 months of age. AGD was significantly correlated with penile volume (R = 0.27, p = 0.001) and the proportion of boys with incomplete testicular descent (R = 0.20, p = 0.02). We defined the anogenital index (AGI) as AGD divided by weight at examination [AGI = AGD/weight (mm/kg)] and calculated the age-adjusted AGI by regression analysis. We examined nine phthalate monoester metabolites, measured in prenatal urine samples, as predictors of age-adjusted AGI in regression and categorical analyses that included all participants with prenatal urine samples (n = 85). Urinary concentrations of four phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate (MiBP)] were inversely related to AGI. After adjusting for age at examination, p-values for regression coefficients ranged from 0.007 to 0.097. Comparing boys with prenatal MBP concentration in the highest quartile with those in the lowest quartile, the odds ratio for a shorter than expected AGI was 10.2 (95% confidence interval, 2.5 to 42.2). The corresponding odds ratios for MEP, MBzP, and MiBP were 4.7, 3.8, and 9.1, respectively (all p-values < 0.05). We defined a summary phthalate score to quantify joint exposure to these four phthalate metabolites. The age-adjusted AGI decreased significantly with increasing phthalate score (p-value for slope = 0.009). The associations between male genital development and phthalate exposure seen here are consistent with the phthalate-related syndrome of incomplete virilization that has been reported in prenatally exposed rodents. The median concentrations of phthalate metabolites that are associated with short AGI and incomplete testicular descent are below those found in one-quarter of the female population of the United States, based on a nationwide sample. These data support the hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans.
Study Synopsis: For the first time, researchers have identified an association between pregnant womenĘs exposure to phthalates and adverse effects on genital development in baby boys. The adverse effects are seen at phthalate levels below those found in one-quarter of women in the US, based on CDC data. Boys in the highest exposure group were 90 times more likely to have altered genital development than those in the lowest.
Scientific abstract:
Prenatal phthalate exposure impairs testicular function and shortens anogenital distance (AGD) in male rodents. We present data from the first study to examine AGD and other genital measurements in relation to prenatal phthalate exposure in humans. A standardized measure of AGD was obtained in 134 boys 2-36 months of age. AGD was significantly correlated with penile volume (R = 0.27, p = 0.001) and the proportion of boys with incomplete testicular descent (R = 0.20, p = 0.02). We defined the anogenital index (AGI) as AGD divided by weight at examination [AGI = AGD/weight (mm/kg)] and calculated the age-adjusted AGI by regression analysis. We examined nine phthalate monoester metabolites, measured in prenatal urine samples, as predictors of age-adjusted AGI in regression and categorical analyses that included all participants with prenatal urine samples (n = 85). Urinary concentrations of four phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate (MiBP)] were inversely related to AGI. After adjusting for age at examination, p-values for regression coefficients ranged from 0.007 to 0.097. Comparing boys with prenatal MBP concentration in the highest quartile with those in the lowest quartile, the odds ratio for a shorter than expected AGI was 10.2 (95% confidence interval, 2.5 to 42.2). The corresponding odds ratios for MEP, MBzP, and MiBP were 4.7, 3.8, and 9.1, respectively (all p-values < 0.05). We defined a summary phthalate score to quantify joint exposure to these four phthalate metabolites. The age-adjusted AGI decreased significantly with increasing phthalate score (p-value for slope = 0.009). The associations between male genital development and phthalate exposure seen here are consistent with the phthalate-related syndrome of incomplete virilization that has been reported in prenatally exposed rodents. The median concentrations of phthalate metabolites that are associated with short AGI and incomplete testicular descent are below those found in one-quarter of the female population of the United States, based on a nationwide sample. These data support the hypothesis that prenatal phthalate exposure at environmental levels can adversely affect male reproductive development in humans. Key words: anogenital distance, benzylbutyl phthalate, dibutyl phthalate, diethyl phthalate, monobenzyl phthalate, monoethyl phthalate, monoisobutyl phthalate, mono-n-butyl phthalate, phthalates, prenatal exposure.
The oviduct is an exquisitely designed organ that functions in picking-up ovulated oocytes, transporting gametes in opposite directions to the site of fertilization, providing a suitable environment for fertilization and early development, and transporting preimplantation embryos to the uterus. A variety of biological processes can be studied in oviducts making them an excellent model for toxicological studies. This review considers the role of the oviduct in oocyte pick-up and embryo transport and the evidence that chemicals in both mainstream and sidestream cigarette smoke impair these oviductal functions. Epidemiological data have repeatedly shown that women who smoke are at increased risk for a variety of reproductive problems, including ectopic pregnancy, delay to conception, and infertility. In vivo and in vitro studies indicate the oviduct is targeted by smoke components in a manner that could explain some of the epidemiological data. Comparisons between the toxicity of smoke from different types of cigarettes, including harm reduction cigarettes, are discussed, and the chemicals in smoke that impair oviductal functioning are reviewed.
Polybrominated diphenyl ethers (PBDEs), used as flame retardants in textiles, plastics and electrical appliances, have been shown to interfere with thyroid homeostasis. We evaluated the effects of environmentally relevant concentrations (low doses) of 2,2',4, 4',5-pentabromodiphenyl ether (PBDE-99) on the female reproductive system. A single dose of either 60 microg or 300 microg PBDE-99/kg body weight (BW) was administered on gestation day 6 to gravid Wistar rats. A reference control was treated with 6-n-propyl-2-thiouracil (PTU) on gestation days 7-21. Ultrastructural changes compatible with altered mitochondrial morphology were observed in the ovaries of the F1 offspring. No statistically significant changes in ovarian follicle counts were observed. Mating of the F1 females with untreated males revealed resorption rates in the PBDE groups greater than the limits considered normal for our controls. External and skeletal anomalies were detected in offspring (F2) from two different dams (F1) with early developmental exposure to 300 microg PBDE-99/kg BW. Exposure to PBDE-99 resulted in female reproductive tract changes in the F1 generation which were apparent at adulthood.
Study Synopsis: Polybrominated diphenyl ethers (PBDEs) are synthetic chemicals used as flame retardant in a wide range of consumer products including electronics, furniture, textiles, carpets and construction materials. About 97% of the U.S. population has detectable levels of PBDEs in their blood. Researchers administered a single dose of the PBDE congener BDE-99 to pregnant rats and found structural alterations in the ovaries of female offspring. Female offspring mated with untreated males also had increased rates of resorption (early death of the embryo). Results suggest that prenatal exposure to high doses of BDE-99 adversely affects the female reproductive system in adulthood.
Scientific abstract:
Polybrominated diphenyl ethers (PBDEs), used as flame retardants in textiles, plastics and electrical appliances, have been shown to interfere with thyroid homeostasis. We evaluated the effects of environmentally relevant concentrations (low doses) of 2,2',4, 4',5-pentabromodiphenyl ether (PBDE-99) on the female reproductive system. A single dose of either 60 microg or 300 microg PBDE-99/kg body weight (BW) was administered on gestation day 6 to gravid Wistar rats. A reference control was treated with 6-n-propyl-2-thiouracil (PTU) on gestation days 7-21. Ultrastructural changes compatible with altered mitochondrial morphology were observed in the ovaries of the F1 offspring. No statistically significant changes in ovarian follicle counts were observed. Mating of the F1 females with untreated males revealed resorption rates in the PBDE groups greater than the limits considered normal for our controls. External and skeletal anomalies were detected in offspring (F2) from two different dams (F1) with early developmental exposure to 300 microg PBDE-99/kg BW. Exposure to PBDE-99 resulted in female reproductive tract changes in the F1 generation which were apparent at adulthood.
Study Synopsis: Scientists from government, academic and independent laboratories challenge proposals that 'hormesis' be used to justify weakening public health standards. This dose-response pattern involves low- dose stimulation in contrast to high-dose inhibition. A peer-reviewed commentary in the scientific journal of the National Institute of Environmental Health Sciences concludes that it is irresponsible for proponents of hormesis to portray chemicals with numerous adverse effects as having "benefits" from low-dose stimulation while ignoring their hazards.
Scientific abstract:
Hormesis (defined operationally as low-dose stimulation, high-dose inhibition) is often used to promote the notion that while high-level exposures to toxic chemicals could be detrimental to human health, low-level exposures would be beneficial. Some proponents claim hormesis is an adaptive, generalizable phenomenon and argue that the default assumption for risk assessments should be that toxic chemicals induce stimulatory (i.e., "beneficial") effects at low exposures. In many cases, nonmonotonic dose-response curves are called hormetic responses even in the absence of any mechanistic characterization of that response. Use of the term "hormesis," with its associated descriptors, distracts from the broader and more important questions regarding the frequency and interpretation of nonmonotonic dose responses in biological systems. A better understanding of the biological basis and consequences of nonmonotonic dose-response curves is warranted for evaluating human health risks. The assumption that hormesis is generally adaptive is an oversimplification of complex biological processes. Even if certain low-dose effects were sometimes considered beneficial, this should not influence regulatory decisions to allow increased environmental exposures to toxic and carcinogenic agents, given factors such as interindividual differences in susceptibility and multiplicity in exposures. In this commentary we evaluate the hormesis hypothesis and potential adverse consequences of incorporating low-dose beneficial effects into public health decisions. Key words: biphasic dose response, hormesis, individual susceptibility, low-dose exposures, nonmonotonic dose response, nonlinear dose response, public health, regulation, risk assessment.
Key Words: Decision Making, Organizational, Dose-Response Relationship, Drug, Environmental Exposure, Health Status, Humans, Occupational Exposure, Public Health
Study Synopsis: An epidemiological study of Swedish fishermen reveals that exposure to persistent organic pollutants can increase the portion of sperm bearing the Y chromosome. Two POPs were analysed, a PCB (CB-153) and DDE (a metabolyte of DDT). Y chromosomes were more likely with higher levels of both. Neither age, smoking nor hormone levels showed associations. These data add to the growing body of evidence that exposure to endocrine disruptors may alter the offspring sex ratio.
Scientific abstract:
BACKGROUND: During the last decades, there has been concern that exposure to endocrine disruptors, such as persistent organochlorine pollutants (POPs), may contribute to sex ratio changes in offspring of exposed populations. METHODS: To investigate whether exposure to 2,2'4,4'5,5'-hexachlorobiphenyl (CB-153) and dichlorodiphenyl dichloroethene (p,p'-DDE) affect Y:X chromosome proportion, semen of 149 Swedish fishermen, aged 27-67 years, was investigated. The men provided semen and blood for analysis of hormone, CB-153 and p,p'-DDE levels. The proportion of Y- and X-chromosome bearing sperm in semen samples was determined by two-colour fluorescence in situ hybridization (FISH) analysis. RESULTS: Log transformed CB-153 as well as log transformed p,p'-DDE variables were both significantly positively associated with Y chromosome fractions (P-values = 0.05 and <0.001, respectively). Neither age, smoking nor hormone levels showed any association with Y-chromosome fractions. CONCLUSIONS: This is the first study to indicate that exposure to POPs may increase the proportion of ejaculated Y-bearing spermatozoa. These data add to the growing body of evidence that exposure to POPs may alter the offspring sex ratio.
Study Synopsis: Two estrogenic contaminants cause adverse effects in prostate development in mice at levels to which millions of Americans are exposed each year. The results implicate these compounds, the birth control agent ethinylestradiol and the plastic monomer bisphenol A, in human prostate diseases, including prostate cancer. The study also shows the futility of predicting the developmental consequences of low-dose exposures based on high-dose experiments.
Scientific abstract:
Exposure of human fetuses to man-made estrogenic chemicals can occur through several sources. For example, fetal exposure to ethinylestradiol occurs because each year approximately 3% of women taking oral contraceptives become pregnant. Exposure to the estrogenic chemical bisphenol A occurs through food and beverages because of significant leaching from polycarbonate plastic products and the lining of cans. We fed pregnant CD-1 mice ethinylestradiol (0.1 microg/kg per day) and bisphenol A (10 microg/kg per day), which are doses below the range of exposure by pregnant women. In male mouse fetuses, both ethinylestradiol and bisphenol A produced an increase in the number and size of dorsolateral prostate ducts and an overall increase in prostate duct volume. Histochemical staining of sections with antibodies to proliferating cell nuclear antigen and mouse keratin 5 indicated that these increases were due to a marked increase in proliferation of basal epithelial cells located in the primary ducts. The urethra was malformed in the colliculus region and was significantly constricted where it enters the bladder, which could contribute to urine flow disorders. These effects were identical to those caused by a similar dose (0.1 microg/kg per day) of the estrogenic drug diethylstilbestrol (DES), a known human developmental teratogen and carcinogen. In contrast, a 2,000-fold higher DES dose completely inhibited dorsolateral prostate duct formation, revealing opposite effects of high and low doses of estrogen. Acceleration in the rate of proliferation of prostate epithelium during fetal life by small amounts of estrogenic chemicals could permanently disrupt cellular control systems and predispose the prostate to disease in adulthood.
Study Synopsis: Endocrine-disrupting chemicals probed as potential pathways to illness. Accumulating evidence that some widely used chemicals may have hormonelike effects on the body is heightening concerns about their potential long-term health risks, particularly when developing fetuses and neonates are exposed.
Study Synopsis: In a study of infertile Japanese women, serum levels of organochlorines were not associated with endometriosis. A few animal studies and some human epidemiological studies have found an association between organochlorines and endometriosis. This study did not find an association. Conflicting results may be a result of study design as well as differences in the mechanism of endocrine disruption in different organochlorines.
Scientific abstract:
Endocrine-disrupting chemicals (EDCs) have been proposed as risk factors for endometriosis. Persistent organochlorine compounds, a group of suspected EDCs, are present to some extent in almost all human adipose tissue and blood via the food chain. A few animal studies have confirmed that exposure to these compounds can increase the incidence of endometriosis. In this study, we examined the associations between endometriosis and exposure to selected organochlorine compounds, including 8 polychlorinated dibenzo-p-dioxins (PCDDs), 10 polychlorinated dibenzofurans (PCDFs), 4 coplanar polychlorinated biphenyls (cPCBs), 36 ortho-substituted polychlorinated biphenyls (PCBs), and 13 chlorinated pesticides or their metabolites. The participants were 139 infertile Japanese women who were examined by laparoscopy and diagnosed as either endometriosis cases (Stages II-IV) or controls (Stages 0-I). The serum levels (lipid adjusted) of the targeted organochlorine compounds were in both 58 cases and 81 controls. There were very few differences in the various levels between endometriosis cases and controls. The total serum toxic equivalency (TEQ) value of PCDDs was significantly higher in the controls than in the cases (P=0.02). No other total TEQ values differed between cases and controls. For PCDDs, PCDFs, cPCBs, and PCBs, the multivariate odds ratio was 0.38 [95% confidence interval (CI), 0.12-1.17] and 0.41 (95% CI, 0.14-1.27) for the third and highest quartiles, respectively, compared to the lowest quartile of total TEQ values. A weak, negative dose-response relationship was evident for total TEQs (P for trend of 0.06). The results of this study provide some evidence that serum levels of these organochlorine compounds are not associated with an increased risk of endometriosis in infertile Japanese women.
Study Synopsis: Japanese study finds bisphenol A (BPA) exposure begins early in life. BPA was found in the fluid of developing oocytes at levels similar to those found in blood, as well as in fetal serum and full-term amniotic fluid, confirming passage through the placenta. Serum BPA concentrations were significantly higher in normal men and in women with polycystic ovary syndrome (PCOS) compared with normal women possibly due to differences in the androgen-related metabolism of BPA. The Journal of steroid biochemistry and molecular biology.
Scientific abstract:
There is broad human exposure to estrogenic endocrine-disrupting chemicals (EDCs), but the data sets that exist are primarily for various environmental media such as food and water rather than the most relevant internal exposure. We have detected various kind of EDC contamination in humans including dioxin and bisphenol A (BPA) widely used for the production of plastic products. BPA was present in serum and follicular fluid at approximately 1-2 ng/ml, as well as in fetal serum and full-term amniotic fluid, confirming passage through the placenta. An approximately five-fold higher concentration, 8.3+/-8.7 ng/ml, was revealed in amniotic fluid at 15-18 weeks of gestation, compared to other fluids showing increased exposure at the critical developmental period in humans. Interestingly, serum BPA concentrations were significantly higher in normal men and in women with polycystic ovary syndrome (PCOS) compared with normal women possibly due to differences in the androgen-related metabolism of BPA. These findings may provide some insight into the metabolism of EDCs in human and the pathophysiology of endocrine disorders such as PCOS. Dioxin contamination in relationship to development of endometriosis is also discussed.
Study Synopsis: Women with higher DDT levels are more likely to experience early spontaneous miscarriage. Tracking hormone levels of newly married women in China, the study found that losses occurred before the women knew they were pregnant. Miscarriage later in pregnancy was not associated with DDT levels.
Scientific abstract:
Previous studies of pregnancy losses and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) were limited because they did not include losses prior to clinical detection of pregnancy and because exposures were measured after the pregnancies of interest. The authors examined the association of preconception serum total DDT (sum of DDT isomers and metabolites) concentration and subsequent pregnancy losses in 388 newly married, nonsmoking, female textile workers in China between 1996 and 1998. Upon stopping contraception, subjects provided daily urine specimens and records of vaginal bleeding for up to 1 year or until clinical pregnancy. Daily urinary human chorionic gonadotropin was assayed to detect conception and early pregnancy losses, and pregnancies were followed to detect clinical spontaneous abortions. There were 128 (26%) early pregnancy losses in 500 conceptions and 36 (10%) spontaneous abortions in 372 clinical pregnancies. Subjects were grouped in tertiles by preconception serum total DDT concentration (group 1: 5.5-22.9 ng/g; group 2: 23.0-36.5 ng/g; group 3: 36.6-113.3 ng/g). Compared with group 1, group 2 had adjusted relative odds of early pregnancy losses of 1.23 (95% confidence interval (CI): 0.72, 2.10), and group 3 had adjusted odds of 2.12 (95% CI: 1.26, 3.57). The relative odds of early pregnancy losses associated with a 10-ng/g increase in serum total DDT were 1.17 (95% CI: 1.05, 1.29). The small number of spontaneous abortions following clinical detection of pregnancy were not associated with serum total DDT. In this population, there was a positive, monotonic, exposure-response association between preconception serum total DDT and the risk of subsequent early pregnancy losses.
Study Synopsis: A review and analysis of the literature on the strength of evidence on exposures to environmental estrogens and male reproductive health. This study summarizes the relevant supporting evidence and current knowledge, identifies gaps and limitations in the interpretation of published data, and defines future research directions. The results do not support with certainty the view that environmental estrogens contribute to an increase in male reproductive disorders, neither do they provide sufficient grounds to reject such a hypothesis. The optimal information regarding harmful effects of xenoestrogens in humans should come from longitudinal epidemiologic studies.
Scientific abstract:
In recent years, chemicals with hormone-like properties have become a topic of scientific and public discussion. It has been hypothesized that prenatal exposure of the male fetus to endocrine disruptors may be responsible for a series of outcomes, such as hypospadias and cryptorchidism. The purpose of this study was to review the endocrine disruption hypothesis, to present the relevant supporting evidence, to summarize the current knowledge, to identify gaps and limitations in the interpretation of published data, and to define future directions in research. An update on environmental estrogens was followed by an assessment of the biological plausibility and evidence connecting the environmental chemicalization with adverse reproductive outcomes in males. Subsequently, we carried out a systematic review of human studies attempting to document a direct effect of exogenous estrogens on the male reproductive system. The results do not support with certainty the view that environmental estrogens contribute to an increase in male reproductive disorders, neither do they provide sufficient grounds to reject such a hypothesis.
Study Synopsis: Male rats are feminized by perinatal exposure to prochloraz, a commonly-used fungicide. Effects include reductions in testosterone levels, an increase in nipple retention and heightened activity levels. The effects are probably caused by decreases in hormone production.
Scientific abstract:
Prochloraz is a commonly used fungicide that has shown multiple mechanisms of action in vitro. It antagonizes the androgen and the estrogen receptors, agonizes the Ah receptor, and inhibits aromatase activity. In vivo prochloraz acts antiandrogenically in the Hershberger assay by reducing weights of reproductive organs, affecting androgen-regulated gene expressions, and increasing luteinizing hormone (LH) levels. The purpose of this study was to investigate reproductive toxic effects after exposure during gestation and lactation to prochloraz alone and a mixture of five pesticides (deltamethrin, methiocarb, prochloraz, simazine, and tribenuron-methyl). Prochloraz (30 mg/kg/day) or the mixture (20 mg/kg/day) was dosed to pregnant Wistar dams from gestational day (GD) 7 until postnatal day (PND) 16. Some dams were taken for cesarean section at GD 21, and others were allowed to give birth. Results showed that prochloraz and the mixture significantly reduced plasma and testicular testosterone levels in GD 21 male fetuses, whereas testicular progesterone was increased. Gestational length was increased by prochloraz. Chemical analysis of the rat breast milk showed that prochloraz was transferred to the milk. In males a significant increase of nipple retention was found, and the bulbourethral gland weight was decreased, whereas other reproductive organs were unaffected. In addition cytochrome P450 (CYP)1A activities in livers were induced by prochloraz, possibly as a result of Ah receptor activation. Behavioral studies showed that the activity level and sweet preference of adult males were significantly increased. Overall these results strongly indicate that prochloraz feminizes the male offspring after perinatal exposure, and that these effects are due, at least in part, to diminished fetal steroidogenesis.
Study Synopsis: A review of scientific research on a plastic molecule detectable in 95% of Americans links exposures at very low doses to a wide range of health problems. Lab experiments indicate that Bisphenol A, the basic building block of polycarbonate plastic, alters development of the reproductive tract, the immune system, increases prostate tumor proliferation, changes brain chemistry and structure and affects an array of behaviors, including hyperactivity. Very few human studies have been conducted. Of 11 lab studies of the compound's effects at low doses, none funded by industry reported impacts. In contrast, 94 out of 104 government-funded studies found effects. Includes audio files of an international teleconference about bisphenol A.
Scientific abstract:
Bisphenol A (BPA) is the monomer used to manufacture polycarbonate plastic, the resin lining of cans, and other products, with global capacity in excess of 6.4 billion lb/year. Because the ester bonds in these BPA-based polymers are subject to hydrolysis, leaching of BPA has led to widespread human exposure. A recent report prepared by the Harvard Center for Risk Analysis and funded by the American Plastics Council concluded that evidence for low-dose effects of BPA is weak on the basis of a review of only 19 studies; the report was issued after a delay of 2.5 years. A current comprehensive review of the literature reveals that the opposite is true. As of December 2004, there were 115 published in vivo studies concerning low-dose effects of BPA, and 94 of these report significant effects. In 31 publications with vertebrate and invertebrate animals, significant effects occurred below the predicted "safe" or reference dose of 50 microg/kg/day BPA. An estrogenic mode of action of BPA is confirmed by in vitro experiments, which describe disruption of cell function at 10(-12) M or 0.23 ppt. Nonetheless, chemical manufacturers continue to discount these published findings because no industry-funded studies have reported significant effects of low doses of BPA, although > 90% of government-funded studies have reported significant effects. Some industry-funded studies have ignored the results of positive controls, and many studies reporting no significant effects used a strain of rat that is inappropriate for the study of estrogenic responses. We propose that a new risk assessment for BPA is needed based on a) the extensive new literature reporting adverse effects in animals at doses below the current reference dose; b) the high rate of leaching of BPA from food and beverage containers, leading to widespread human exposure; c) reports that the median BPA level in human blood and tissues, including in human fetal blood, is higher than the level that causes adverse effects in mice; and d) recent epidemiologic evidence that BPA is related to disease in women.
Key Words: Animals, Dose-Response Relationship, Drug, *Environmental Exposure, Environmental Pollutants/toxicity, Estrogens, Non-Steroidal/*toxicity, Humans, Phenols/*toxicity, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S., Risk Assessment
Research notes: Comment in Environ Health Perspect. 2006 Jan;114(1):A16; author reply A16-7.
We discuss the similarities and differences of two types of effects that occur at low but not high doses of chemicals: hormesis and stimulation by oestrogenic endocrine-disrupting chemicals or xenoestrogens. While hormesis is a general phenomenon evoked by many compounds, oestrogenic stimulation occurs for specific chemicals that disrupt actions of endogenous oestrogen. Both types of phenomena can induce an inverted-U dose-response curve, resulting from low-dose stimulation of response, and thus challenge current methods of risk assessment. Hormesis is generally thought to be caused by an over-reaction of detoxification mechanisms, which is considered an adaptive response that should protect an organism from subsequent stress. One view of the hormetic low-dose stimulatory response, i.e., increased performance, is that it is beneficial. In contrast, we propose that for manmade xenoestrogens this is never the case. This is demonstrated with examples for low doses of the oestrogenic environmental chemicals bisphenol A and octylphenol, and the oestrogenic drug diethylstilbestrol. Adverse low-dose effects include oviduct rupture, an enlarged prostate, feminization of males and reduced sperm quality. These adverse stimulatory effects divert energy needed for other processes, resulting in reduced fitness. In conclusion, while there are similarities (inverted-U dose-response), there are also differences, adaptive response for hormesis versus adverse stimulatory response for low doses of manmade xenoestrogens, that have been almost totally ignored in discussions of hormesis. We propose that the risk posed by low doses of manmade xenoestrogens that show inverted-U dose-response curves is underestimated by the current threshold model used in risk assessment, and this is likely to apply to other endocrine-disrupting chemicals.
Key Words: Animals, Caenorhabditis elegans/*drug effects, Diethylstilbestrol/pharmacology, Dose-Response Relationship, Drug, Endocrine Disruptors/*pharmacology/toxicity, Estradiol Congeners/*pharmacology/toxicity, Mice, No-Observed-Adverse-Effect Level, Phenols/pharmacology, Reproduction/*drug effects, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Risk Assessment, Snails/*drug effects, Stimulation, Chemical, Xenobiotics/*pharmacology/toxicity
Study Synopsis: Menstrual cycle length was shorter in SE Asian immigrant women among those with higher DDE levels. For each doubling of DDE concentration, cycle length decreased 1.1 days. Progesterone metabolite levels were consistently decreased with higher DDE concentration. This study indicates that DDE exposure affects ovarian function in women, which may influence fertility, pregnancy and reproductive cancers.
Scientific abstract:
BACKGROUND: Some chemicals appear to have hormonally active properties in animals, but data in humans are sparse. Therefore, we examined ovarian function in relation to organochlorine compound levels. METHODS: During 1997-1999, 50 Southeast Asian immigrant women of reproductive age collected urine samples daily. These samples were assayed for metabolites of estrogen and progesterone, and the women's menstrual cycle parameters were assessed. Organochlorine compounds (including DDT, its metabolite DDE, and 10 polychlorinated biphenyl [PCB] congeners) were measured in serum. RESULTS: All samples had detectable DDT and DDE, with mean levels higher than typical U.S. populations. Mean cycle length was approximately 4 days shorter at the highest quartile concentration of DDT or DDE compared with the lowest. After adjustment for lipid levels, age, parity, and tubal ligation, and exclusion of a particularly long cycle, the decrements were attenuated to less than 1 day, with wide confidence intervals (CIs). The adjusted mean luteal phase length was shorter by approximately 1.5 days at the highest quartile of DDT (95% CI = -2.6 to -0.30) or DDE (-2.6 to -0.20). With each doubling of the DDE level, cycle length decreased 1.1 day (-2.4 to 0.23) and luteal phase length decreased 0.6 days (-1.1 to -0.2). Progesterone metabolite levels during the luteal phase were consistently decreased with higher DDE concentration. PCB levels were not generally associated with cycle length or hormone parameters after adjustment, and they did not alter the DDE associations when included in the same models. CONCLUSIONS: This study indicates a potential effect of DDE on ovarian function, which may influence other end points such as fertility, pregnancy, and reproductive cancers.
Study Synopsis: Measuring steroids and FSH in daily urine samples, we found decreases in luteal phase progesterone metabolite levels, slight increases in baseline (beginning of the cycle) levels of both steroids, and increased in FSH levels during the time of transition between menstrual cycles, indicating potential endocrine disrupting effects of smoking.
Scientific abstract:
Cigarette smoke contains compounds that are suspected to cause reproductive damage and possibly affect hormone activity; therefore, we examined hormone metabolite patterns in relation to validated smoking status. We previously conducted a prospective study of women of reproductive age (n = 403) recruited from a large health maintenance organization, who collected urine daily during an average of three to four menstrual cycles. Data on covariates and daily smoking habits were obtained from a baseline interview and daily diary, and smoking status was validated by cotinine assay.Urinary metabolite levels of estrogen and progesterone were measured daily throughout the cycles. For the present study, we measured urinary levels of the pituitary hormone follicle-stimulating hormone (FSH) in a subset of about 300 menstrual cycles, selected by smoking status, with the time of transition between two cycles being of primary interest. Compared with nonsmokers, moderate to heavy smokers (>/= 10 cigarettes/day) had baseline levels (e.g., early follicular phase) of both steroid metabolites that were 25-35% higher, and heavy smokers (>/= 20 cigarettes/day) had lower luteal-phase progesterone metabolite levels. The mean daily urinary FSH levels around the cycle transition were increased at least 30-35% with moderate smoking, even after adjustment. These patterns suggest that chemicals in tobacco smoke alter endocrine function, perhaps at the level of the ovary, which in turn effects release of the pituitary hormones. This endocrine disruption likely contributes to the reported associations of smoking with adverse reproductive outcomes, including menstrual dysfunction, infertility, and earlier menopause.
Study Synopsis: Several 'weakly' estrogenic compounds including bisphenol A and endosulfan are as powerful as estrogen at provoking cellular responses via a cell membrane estrogen receptor. The changes affect calcium influx into the cell and subsequently prolactin secretion. This powerful new pathway is activated at extremely small exposure levels.
Scientific abstract:
Xenoestrogens (XEs) are widespread in our environment and are known to have deleterious effects in animal (and perhaps human) populations. Acting as inappropriate estrogens, XEs are thought to interfere with endogenous estrogens such as estradiol (E2) to disrupt normal estrogenic signaling. We investigated the effects of E2 versus several XEs representing organochlorine pesticides (dieldrin, endosulfan, o',p'-dichlorodiphenylethylene), plastics manufacturing by-products/detergents (nonylphenol, bisphenol A), a phytoestrogen (coumestrol), and a synthetic estrogen (diethylstilbestrol) on the pituitary tumor cell subline GH3/B6/F10, previously selected for expression of high levels of membrane estrogen receptor-alpha. Picomolar to nanomolar concentrations of both E2 and XEs caused intracellular Ca2+ changes within 30 sec of administration. Each XE produced a unique temporal pattern of Ca2+ elevation. Removing Ca2+ from the extracellular solution abolished both spontaneous and XE-induced intracellular Ca2+ changes, as did 10 microM nifedipine. This suggests that XEs mediate their actions via voltage-dependent L-type Ca2+ channels in the plasma membrane. None of the Ca2+ fluxes came from intracellular Ca2+ stores. E2 and each XE also caused unique time- and concentration-dependent patterns of prolactin (PRL) secretion that were largely complete within 3 min of administration. PRL secretion was also blocked by nifedipine, demonstrating a correlation between Ca2+ influx and PRL secretion. These data indicate that at very low concentrations, XEs mediate membrane-initiated intracellular CCa2+ increases resulting in PRL secretion via a mechanism similar to that for E2, but with distinct patterns and potencies that could explain their abilities to disrupt endocrine functions.
Key Words: Animals, Calcium/*metabolism, Cell Line, Tumor, Comparative Study, Coumestrol/toxicity, Dichlorodiphenyl Dichloroethylene/toxicity, Dieldrin, Diethylstilbestrol/toxicity, Endosulfan/toxicity, Estradiol/toxicity, Estrogen Receptor alpha/*metabolism, Estrogens/*toxicity, Phenols/toxicity, Prolactin/*metabolism, Rats, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S., Signal Transduction/drug effects, Xenobiotics/toxicity
Study Synopsis: In laboratory studies, exposure to the phthalate, DEHP, causes alterations in cellular metabolism in the placenta. Cells isolated from the rat placenta were exposed to DEHP and its metabolites, MEHP and EHA. Exposure caused changes in the expression of genes involved in cell metabolism and differentiation and also caused changes in fatty acid transport. Together these results suggest exposure to DEHP could interfere with placenta function and fetal development.
Scientific abstract:
Di-(2-ethylhexyl)-phthalate (DEHP) is a widely used plasticizer and ubiquitous environmental contaminant. The potential health hazards, including teratogenicity, from exposure to DEHP may be related to the role of DEHP or its metabolites in the trans-activation of peroxisome proliferator-activated receptors (PPARs). Fetal essential fatty acid (EFA) homeostasis is controlled by directional transfer across the placenta through a highly regulated process, including PPAR activation. Using HRP-1 rat trophoblastic cells, the effects of DEHP and two of its metabolites, mono-(2-ethylhexyl)-phthalate (MEHP) and 2-ethylhexanoic acid (EHA), on the mRNA and protein expression of the three known PPAR isoforms (alpha, beta, and gamma), fatty acid transport protein 1 (FATP1), plasma membrane fatty acid binding protein (FABPpm), and the heart cytoplasmic fatty acid binding protein (HFABP) were investigated. This study also investigated the functional effects of exposure on the uptake and transport of six long chain fatty acids (LCFAs): arachidonic acid (AA), docosahexaenoic acid (DHA), linoleic acid (LA), alpha-linolenic acid (ALA), oleic acid (OA), and stearic acid (SA). In the presence of DEHP, MEHP, and EHA, the expression of PPARalpha, PPARgamma, FATP1, and HFABP were up-regulated in a dose- and time- dependent manner, while PPARbeta and FABPpm demonstrated variable expression. The uptake rates of EFAs (AA, DHA, LA, ALA) increased significantly upon exposure, and the transport of AA (omega-6) and DHA (omega-3) were directionally induced. These results suggest that DEHP, MEHP, and EHA can influence EFA transfer across HRP-1 cells, implying that these compounds may alter placental EFA homeostasis and potentially result in abnormal fetal development.
Study Synopsis: Prenatal exposure to PCBs/PCDFs in girls from Taiwan is associated with altered menstrual cycles and abnormal hormone profiles. Exposed girls had a menstrual cycle on average one day shorter than non-exposed and a 40% higher rate of irregular menstrual cycles. Serum levels of estradiol and the pituitary hormone, FSH, were also higher in exposed girls.
Scientific abstract:
BACKGROUND: Polychlorinated biphenyls (PCBs) and related compounds such as polychlorinated dibenzofurans (PCDFs) and polychlorinated dibenzo-dioxins (PCDDs) alter sexual maturation and endocrine function in animals. In 1978-1979, a mass poisoning occurred in central Taiwan from cooking oil contaminated by heat-degraded PCBs and oxidated compounds PCDFs. We tested the hypothesis that in utero exposed to PCBs/PCDFs alter sexual maturation, endocrine, and reproductive function in the human pubescent females. METHODS: In 1997-1999, girls aged 13-19 years, born to mothers exposed to PCBs/PCDFs, was invited to participate in the study. Menstruation characteristic was recorded daily for 84 days and serum levels of estradiol, LH, FSH, and testosterone were measured on the 3rd day of menstruation. RESULTS: A total of 17 exposed girls and controls participated, the exposed girls reported shorter mean duration of bleeding per cycle than 16 unexposed (5.5 vs 6.5 days, P=0.0055). There was a higher rate of irregular menstrual cycle in the exposed girls (40% vs 0%, P=0.018). Serum levels of estradiol (P=0.016) and FSH (P=0.061) were higher in exposed girls as compared to controls. CONCLUSIONS: We conclude that prenatal exposure to PCBs/PCDFs resulted in abnormal menstruation and higher estradiol and FSH levels in follicular phase of menstrual cycle in adolescent girls.
Reproductive function has been shown to be sensitive to changes in the physical, psychosocial and chemical environments. Although reproductive effects of occupational exposure to hazardous chemicals have been well documented in the literature, the potential effects of chemical contaminants at levels representative of contemporary exposures in the general population are much less certain. Evidence for adverse effects of exposure to environmental contaminants is more conclusive among the lower animals than for humans where considerable controversy remains. In addition to potential reproductive hazards of exposure to environmental contaminants, there is also evidence for adverse reproductive effects of the physical and psychosocial environments. In this review we focus on the difficulties involved in linking exposure to putative hazardous substances in environmental and occupational settings to adverse reproductive outcomes, especially success of IVF procedures. We highlight the plausibility of adverse events through animal and cell studies and the application of these results to the interpretation of human data. We consider both the male and female partners since it is essentially their combined contributions of gametes which may be affected by chemicals, which lead to successful outcomes.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. In this study, researchers exposed rats to BPA during pregnancy and lactation. They found that prenatal exposure to BPA caused increases in the blood levels of the thyroid hormone thyroxine (T4) and activated genes regulated by thyroid hormones. Results suggest that exposure to BPA affects thyroid hormone levels and action.
Scientific abstract:
Considering the importance of thyroid hormone (TH) in brain development, it is of potential concern that a wide variety of environmental chemicals can interfere with thyroid function or, perhaps of greater concern, with TH action at its receptor (TR). Recently bisphenol-A (BPA, 4,4' isopropylidenediphenol) was reported to bind to the rat TR and act as an antagonist in vitro. BPA is a high production volume chemical, with more than 800 million kg of BPA produced annually in the United States alone. It is detectable in serum of pregnant women and cord serum taken at birth; is 5-fold higher in amniotic fluid at 15-18 wk gestation, compared with maternal serum; and was found in concentrations of up to 100 ng/g in placenta. Thus, the human population is widely exposed to BPA and it appears to accumulate in the fetus. We now report that dietary exposure to BPA of Sprague Dawley rats during pregnancy and lactation causes an increase in serum total T4 in pups on postnatal d 15, but serum TSH was not different from controls. The expression of the TH-responsive gene RC3/neurogranin, measured by in situ hybridization, was significantly up-regulated by BPA in the dentate gyrus. These findings suggest that BPA acts as a TH antagonist on the beta-TR, which mediates the negative feedback effect of TH on the pituitary gland, but that BPA is less effective at antagonizing TH on the alpha-TR, leaving TRalpha-mediated events to respond to elevated T4.
Aitken RJ, Koopman P, Lewis SE. Seeds of concern. Nature. 2004;432(7013):48-52.
Study Synopsis: Seeds of concern. During the past few decades, worries about environmental threats to human health have centred on the possible induction of cancers. Now risks to the male germ line, both real and potential, are also causing disquiet.
Study Synopsis: A cross-sectional study among Hispanic women finds an association between serum levels of several organochlorine pesticides and earlier age at menopause. Women with the highest exposures to p,p'-DDT, beta-HCH, and trans-nonachlor experienced menopause 5.7, 3.4, and 5.2 year earlier, respectively, than those in the lowest exposure category, though no consistent dose-response was observed. The effect of these pesticides on earlier age at menopause may occur through disruption of the normal hormonal milieu within the ovary and subsequent damage to the ovary.
Scientific abstract:
A cross-sectional study was conducted to evaluate the relationship between exposure to selected organochlorine pesticides (OCP) (p,p'-DDT, p',p'-DDE, dieldrin, hexachlorobenzene, beta-hexachlorocyclohexane [beta-HCH], oxychlordane, trans' nonachlor) and age at natural menopause in a sample of 219 menopausal women participating in the Hispanic Health and Nutrition Examination Survey in 1982-1984. Information on age at menopause, reproductive history, demographic variables, and potential confounding variables was collected via interview. Analysis of variance was employed to compare adjusted mean age at natural menopause among women by category of serum OCP level. Serum levels of p,p'-DDT, p,p'-DDE, beta-HCH, and trans-nonachlor were associated with a younger age at menopause. In particular, women with exposure levels in the highest exposure categories (serum p,p'-DDT > or = 6ppb, beta-HCH > or = 4ppb, or trans-nonachlor > or = 2ppb) had an adjusted mean age at menopause on average 5.7, 3.4, and 5.2 yr earlier, respectively, than women with serum levels of these pesticides below the detection limit. Women with serum p,p'-DDE levels greater than 23.6 ppb (highest quintile) had an adjusted mean age at menopause 1.7 yr earlier than women with serump,p'-DDE levels less than 5.5 ppb (lowest quintile). However, no consistent dose-response effect was apparent across low, medium, and high exposure categories. Interactions were detected for p,p'-DDT in combination with beta-HCH, trans-nonachlor, or oxychlordane, as well as beta-HCH in combination with oxychlordane.
Study Synopsis: Swedish women who consume large amounts of fatty fish from the Baltic Sea have shorter menstrual cycles. Fatty fish are a major exposure route to persistent organochlorine compounds. Compared to women who do not consume these fish, menstrual cycles were an average half day shorter. These results are not conclusive but have similar findings as previous studies. Averaged over a population, these shorter menstrual cycles could result in lower fertility rates.
Scientific abstract:
Dietary exposure to persistent organochlorine compounds (POCs) has been found to affect the menstrual cycle in both animals and humans. In Sweden, the major exposure route for POCs is the consumption of fatty fish from the Baltic Sea. Thus, women who eat relatively large amounts of this fish constitute a suitable study group when investigating a possible association between dietary exposure to POC and menstrual cycle disruption. Questionnaires were sent to the exposed women, as well as to a socioeconomically similar cohort of controls, and information was collected on their menstrual cycles. Since the exposed women tended to smoke more than the controls, all results were adjusted for smoking habits. A cohort comparison found that the exposed women on average had 0.46 (95% confidence interval: 0.03, 0.89) days shorter menstrual cycles than controls. However, within the exposed cohort no effects were found of the proxy variables early life exposure and high consumption of Baltic Sea fatty fish. The results give some support to previous results from studies on women with similar exposure, but are not conclusive with respect to whether there is a causal association between POC exposure and menstrual cycle disruption.
Key Words: Adolescent, Adult, Animals, Cohort Studies, Comparative Study, *Diet, Female, *Fishes, *Food Contamination, Geography, Humans, Insecticides/*toxicity, Life Style, Menstrual Cycle/*drug effects, Oceans and Seas, Polychlorinated Biphenyls/toxicity, Questionnaires, Research Support, Non-U.S. Gov't, Smoking, Sweden, Time Factors
Study Synopsis: A study of Michigan women finds exposure to tobacco smoke, but not PBBs or PCBs is associated with endometriosis. PCB and PBB measurements were taken between 1976-1978, a time with exposure to these chemicals was relatively high. Neither was associated with endometriosis. Consistent with findings from previous studies, woman who were smokers were 2 times more likely to undergo menopause at an earlier age than non-smokers.
Scientific abstract:
OBJECTIVES: Because halogenated biphenyl exposure is suspected to disrupt endocrine function, we assessed time to menopause in women aged 24 years and older who were exposed orally to polybrominated biphenyls (PBBs) and polychlorinated biphenyls (PCBs) (n = 874). We also examined smoking in relation to menopause. METHODS: To define menopausal status, women were interviewed in 1997 and asked whether they had had any menstrual periods in the previous year, why their menstrual periods had stopped (e.g. surgery), and age at their last menstrual period. Serum PBB and PCB taken at enrollment (1976-1978) into the Michigan PBB registry was used as the measure of halogenated biphenyl exposure. Women whose menopause occurred before their PBB exposure were excluded. Proportional hazard modeling was used to analyze the "risk" for menopause in relation to exposure. Premenopausal women contributed person-time until their interview date, at which time they were censored. RESULTS: We did not find an association between either PBB or PCB exposure and time to menopause. Women who were current smokers had a shorter time to menopause than never smokers (menopause ratio 2.02, 95% C.I. 1.21-3.37). Time to menopause was shortest among women who reported started smoking when they were <18 years of age, smoked at least 20 cigarettes per day, or had at least 10 pack-years of smoking.
Study Synopsis: Across the developed world, birth rates are plummeting. Is this just a social phenomenon, or is our biological fertility also declining? Declining birth rates may be in part due to demographic changes with couples choosing to have fewer children, or none at all. But might something more sinister be going on, such as environmental pollution or sexually transmitted diseases causing a decline in male or female fertility? It turns out studying fertility is not an easy task.
Study Synopsis: A case-control study of stillbirths in eastern Canada finds strong association with exposure to chlorination by-products in drinking water. Women with a residential total THM level of 80 or more microg/L had twice the risk of a stillbirth compared with women with no exposure to THMs. A clear dose-reponse relationship was not founds.
Scientific abstract:
BACKGROUND: The chlorine used to disinfect public drinking water supplies reacts with naturally occurring organic matter to form a number of chemical byproducts. Recent studies have implicated exposure to chlorination byproducts in drinking water, trihalomethanes (THMs), in particular, with intrauterine death. METHODS: We conducted a population-based case-control study in Nova Scotia and Eastern Ontario, Canada, to examine the effect of exposure to THMs on stillbirth risk. Cases were women who had a stillborn infant, and controls were a random sample of women with live births. Subjects were interviewed, and women with a public water source provided a residential water sample. Risks were examined according to residential THM level in tap water and to a total exposure metric incorporating tap water ingestion, showering, and bathing. RESULTS: We enrolled 112 stillbirth cases and 398 live birth controls. Women with a residential total THM level of 80 or more microg/L had twice the risk of a stillbirth compared with women with no exposure to THMs (adjusted odds ratio [OR] = 2.2; 95% confidence interval [CI] = 1.1-4.4). The highest quintile of total THM exposure using the total exposure metric was associated with an adjusted odds ratio of 2.4 (95% CI = 1.2-4.6) compared with women not exposed to THMs. Similar results were seen for specific THM compounds. A monotonic dose-response relationship was not seen. CONCLUSIONS: Our results provide evidence for an increased risk of stillbirth associated with exposure to chlorination byproducts through ingestion and showering and bathing, although there was not a clear dose-response relationship.
Key Words: Adult, Case-Control Studies, Chlorine/adverse effects, Educational Status, Female, Humans, Income, Nova Scotia/epidemiology, Ontario/epidemiology, Pregnancy, Pregnancy Outcome/*epidemiology, Research Support, Non-U.S. Gov't, Risk Factors, Trihalomethanes/*adverse effects, Water Purification/*methods
Study Synopsis: Phthalate exposure is linked to DNA damage in human sperm. Duty et al. report a link between phthalate exposure and DNA damage in human sperm. Their finding is important because the damaged sperm were obtained from men living in the Boston area who had not been exposed to unusually high levels of phthalates, suggesting that DNA sperm damage due to phthalates may be widespread in American men. Whether this damage is linked to infertility or to reproductive outcomes is unknown.
Scientific abstract:
The general population is exposed to phthalates through consumer products, diet, and medical devices. The present study explored whether phthalates, reproductive toxins in laboratory animals, were associated with altered sperm movement characteristics in men. Two-hundred twenty subjects provided a semen sample for computer-aided sperm analysis (CASA) and a urine sample for measurement of phthalate monoesters, monoethyl (MEP), monobenzyl (MBzP), mono-n-butyl (MBP), mono-2-ethylhexyl (MEHP), and monomethyl (MMP). Three CASA parameters, straight-line velocity (VSL), curvilinear velocity (VCL), and linearity (LIN), were used as measures of sperm progression, sperm vigor, and swimming pattern, respectively. There were suggestive dose-response relationships (shown as the predicted change in mean sperm motion parameter for the second and third tertiles compared with the first tertile; P value for trend) for MBzP with VSL (-2.36 microm/s, -2.81 microm/s; P =.09) and VCL (-1.67 microm/s, -2.45 microm/s; P =.4). There were suggestive negative associations between MBP and VSL (-3.07 microm/s, -2.87 microm/s; P =.08) and VCL (-3.25 microm/s, -3.46 microm/s; P =.2), and between MEHP with VSL (-1.09 microm/s, -2.73 microm/s; P =.1) and VCL (-0.29 microm/s, -2.93 microm/s; P =.3). In contrast to the other phthalates, MEP was positively associated with VSL and VCL but negatively associated with LIN. No consistent relationship was found for MMP and any sperm motion parameter. Although we did not find statistically significant associations, trends between CASA parameters, sperm velocity, and forward progression, and increased urinary levels of MBP, MBzP, and MEHP warrant further follow-up.
Although pesticide use is widespread, little is known about potential adverse health effects of in utero exposure. We investigated the effects of organophosphate pesticide exposure during pregnancy on fetal growth and gestational duration in a cohort of low-income, Latina women living in an agricultural community in the Salinas Valley, California. We measured nonspecific metabolites of organophosphate pesticides (dimethyl and diethyl phosphates) and metabolites specific to malathion (malathion dicarboxylic acid), chlorpyrifos [O,O-diethyl O-(3,5,6-trichloro-2-pyridinyl) phosphoro-thioate], and parathion (4-nitrophenol) in maternal urine collected twice during pregnancy. We also measured levels of cholinesterase in whole blood and butyryl cholinesterase in plasma in maternal and umbilical cord blood. We failed to demonstrate an adverse relationship between fetal growth and any measure of in utero organophosphate pesticide exposure. In fact, we found increases in body length and head circumference associated with some exposure measures. However, we did find decreases in gestational duration associated with two measures of in utero pesticide exposure: urinary dimethyl phosphate metabolites [beta(adjusted) = -0.41 weeks per log10 unit increase; 95% confidence interval (CI), -0.75 -- -0.02; p = 0.02], which reflect exposure to dimethyl organophosphate compounds such as malathion, and umbilical cord cholinesterase (beta(adjusted) = 0.34 weeks per unit increase; 95% CI, 0.13-0.55; p = 0.001). Shortened gestational duration was most clearly related to increasing exposure levels in the latter part of pregnancy. These associations with gestational age may be biologically plausible given that organophosphate pesticides depress cholinesterase and acetylcholine stimulates contraction of the uterus. However, despite these observed associations, the rate of preterm delivery in this population (6.4%) was lower than in a U.S. reference population.
Key Words: Adolescent, Adult, *Agriculture, *Birth Weight, Body Height, Embryonic and Fetal Development/*drug effects, *Environmental Exposure, Female, Humans, Infant, Newborn, Insecticides/*poisoning, Male, Obstetric Labor, Premature, *Organophosphorus Compounds, Pregnancy, Pregnancy Outcome, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.
Study Synopsis: Pesticide use in women farm workers is associated with changes in menstrual cycles. In this study, women who used pesticides experienced longer periods and were more likey to miss periods than women who never used pesticides. Furthermore, women using pesticides known to mimic hormones were 60-100% more likely to have longer cycles, missed periods, and breakthrough bleeding. These changes are significant because they could result in reduced fertility.
Scientific abstract:
Menstrual cycle characteristics may have implications for women's fecundability and risk of hormonally related diseases. Certain pesticides disrupt the estrous cycle in animals. The authors investigated the cross-sectional association between pesticide use and menstrual function among 3,103 women living on farms in Iowa and North Carolina. Women were aged 21-40 years, premenopausal, not pregnant or breastfeeding, and not taking oral contraceptives. At study enrollment (1993-1997), women completed two self-administered questionnaires on pesticide use and reproductive health. Exposures of interest were lifetime use of any pesticide and hormonally active pesticides. Menstrual cycle characteristics of interest included cycle length, missed periods, and intermenstrual bleeding. The authors used generalized estimating equations to assess the association between pesticide use and menstrual cycle characteristics, controlling for age, body mass index, and current smoking status. Women who used pesticides experienced longer menstrual cycles and increased odds of missed periods (odds ratio = 1.5, 95% confidence interval: 1.2, 1.9) compared with women who never used pesticides. Women who used probable hormonally active pesticides had a 60-100% increased odds of experiencing long cycles, missed periods, and intermenstrual bleeding compared with women who had never used pesticides. Associations remained after control for occupational physical activity.
The amount of research into endocrine disruption has exploded over the past decade and a re-evaluation of the state of research in this area is timely. There are debates about whether human male reproductive health is really declining and whether endocrine disrupting chemicals play any role in the perceived decline. Most data currently conclude that there are wide geographical variations in semen quality and in the incidence of testicular cancer, cryptorchidism and hypospadias. This review aims to give a brief overview of the issues surrounding the perceived decline in human male reproductive health and the importance of the hormonal environment for the development of the testis and reproductive tract. The consequences for the male reproductive tract of abnormal androgen levels or action are discussed with reference to environmental anti-androgenic compounds. The in vivo data on several anti-androgenic compounds that have been administered to pregnant rodents during the period of male reproductive tract development are assessed with attention to the effects on the male offspring. Finally, the data on in utero phthalate administration are discussed in detail to illustrate the similarities between the effects of some phthalate esters and the human male reproductive tract disorders which comprise testicular dysgenesis syndrome (TDS).
Study Synopsis: A recent review highlights emerging mechanisms of endocrine disruption. At least two mechanism of endocrine disruption are not mediated via steroid receptors; firstly, the suppression of fetal testosterone synthesis in rodents by in utero exposure to phthalates; and secondly, the ability of several chemicals to interfere with steroid metabolism by inhibiting estrogen sulfotransferases.
Scientific abstract:
Despite the surge of interest in the endocrine disruption field, there is still no globally accepted definition of the term. There is a great political will to test chemicals to determine whether they have endocrine disrupting potential. This is a huge task and the US Environmental Protection Agency has taken the lead by setting up an Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), which with international co-operation, will ultimately deliver a validated testing strategy to detect endocrine disrupting chemicals (EDCs) in humans and wildlife. One of the major developments will be the use of high throughput pre-screening (HTPS) methods that will detect binding to steroid receptor hormones, although many other testing methods will be employed. This paper describes two mechanisms of EDC action that are not mediated via steroid receptors; firstly, the suppression of fetal testosterone synthesis in rodents by in utero exposure to phthalates; and secondly, the ability of several chemicals to interfere with steroid metabolism by inhibiting estrogen sulfotransferases. These examples will be discussed with reference to pertinent human disorders, which have been associated with exposure to EDCs. Issues and questions about how scientists and regulators can deal with these types of chemicals or potential mechanisms in a risk assessment paradigm are raised.
Study Synopsis: Even at levels considered safe by the U.S. EPA, exposure very early in development to lawn care and farm chemicals resulted in serious developmental injury to mouse embryos. All but one of the 13 chemicals tested individually on pre-implantation mouse embryos impaired normal development. All 6 mixtures created to resemble environmentally- realistic mixtures caused damage.
Scientific abstract:
Occupational exposures to pesticides may increase parental risk of infertility and adverse pregnancy outcomes such as spontaneous abortion, preterm delivery, and congenital anomalies. Less is known about residential use of pesticides and the risks they pose to reproduction and development. In the present study we evaluate environmentally relevant, low-dose exposures to agrochemicals and lawn-care pesticides for their direct effects on mouse preimplantation embryo development, a period corresponding to the first 5-7 days after human conception. Agents tested were those commonly used in the upper midwestern United States, including six herbicides [atrazine, dicamba, metolachlor, 2,4-dichlorophenoxyacetic acid (2,4-D)], pendimethalin, and mecoprop), three insecticides (chlorpyrifos, terbufos, and permethrin), two fungicides (chlorothalonil and mancozeb), a desiccant (diquat), and a fertilizer (ammonium nitrate). Groups of 20-25 embryos were incubated 96 hr in vitro with either individual chemicals or mixtures of chemicals simulating exposures encountered by handling pesticides, inhaling drift, or ingesting contaminated groundwater. Incubating embryos with individual pesticides increased the percentage of apoptosis (cell death) for 11 of 13 chemicals (p Key Words: Agriculture, Animals, Apoptosis, Blastocyst/*drug effects, Dose-Response Relationship, Drug, Drug Interactions, Embryonic and Fetal Development/*drug effects, *Environmental Exposure, Female, Fertilizers, Fungicides, Industrial/*toxicity, Herbicides/*toxicity, Humans, Insecticides/*toxicity, Mice, Models, Animal, *Occupational Exposure, Pregnancy, Research Support, Non-U.S. Gov't
Yucheng ("oil-disease") victims were Taiwanese people exposed to polychlorinated biphenyls (PCBs) and their heat-degradation products, mainly polychlorinated dibenzofurans (PCDFs), from the ingestion of contaminated rice oil in 1978-1979. Serial studies in Yucheng offspring born between 1978 and 1992 are summarized. Children of the exposed women were born with retarded growth, with dysmorphic physical findings, and, during development, with delayed cognitive development, increased otitis media, and more behavioral problems than unexposed children. Recently, examination of the reproductive system has suggested that prenatal exposure exerts late effects on semen parameters in young men after puberty. Results of the investigation in Yucheng children will provide important information about the human health effects and toxicology of PCB/PCDF exposure. Prenatal exposure to these environmental chemicals causes the fetus to be sensitive to the toxic effects of persistent organic pollutants.
Study Synopsis: A review of the scientific evidence demonstrates that employment in agriculture is associated with a number of adverse reproductive event. The epidemiological studies presented in this paper refer to the association between agricultural occupation of parents and the incidence of infertility, congenital malformations, miscarriage, low birthweight, small-for-gestational-age (SGA) birth, preterm delivery and stillbirth.The literature review suggests a great need to increase awareness of workers who are occupationally exposed to pesticides about their potential negative influence on fertility and pregnancy outcome.
Scientific abstract:
The epidemiological studies presented in this paper refer to the association between agricultural occupation of parents and the incidence of infertility, congenital malformations, miscarriage, low birthweight, small-for-gestational-age (SGA) birth, preterm delivery and stillbirth. The results of the analyses showed that employment in agriculture increases the risk of specific morphological abnormalities in sperm, including the decreased sperm count per ejaculate and declined percentage of viable sperm. In general, no effect of exposure to pesticides on sexual hormones was observed. The data on the effect of employment in agriculture on the time to pregnancy are unequivocal, but most of them suggest that there is a relationship between the decreased fecundability ratio and pesticide exposure. Nor does the research on the sex ratio of offspring provide explicit results. The analyses indicate that parental employment in agriculture could increase the risk of congenital malformations in the offsprings, particularly such as orofacial cleft, birthmarks in the form of hemangioma as well as musculoskeletal and nervous system defects. The data on the effect of occupational exposure to pesticides on birthweight are inconsistent. Although most of epidemiological studies do not reveal a significantly increased risk of SGA, a slower pace of fetal development corresponding to SGA in the population of women exposed to pyrethroids has been recently reported. There are also some indications that exposure to pesticides may contribute to stillbirth and female infertility. The literature review suggests a great need to increase awareness of workers who are occupationally exposed to pesticides about their potential negative influence on fertility and pregnancy outcome. In the light of existing although still limited evidence of adverse effects of pesticide exposure on fertility during the preconceptual period, it is necessary to reduce the exposure to pesticides.
Study Synopsis: A review of industry-funded studies used to challenge findings that atrazine at extremely low levels causes hermaphroditism in frogs reveals flawed experiments and misleading representation of the results. Controls in experiments were contaminated. Positive results were summarized as negative. Poor animal husbandry caused high mortality rates. A statistical analysis of relevant studies finds that industry funding and specific labs are strongly associated with reporting negative results.
Scientific abstract:
Recent studies from my laboratory, showing the chemical castration (demasculinization) and feminization of amphibians by low but ecologically relevant concentrations of atrazine in the laboratory and in the wild, prompted a critical response from atrazine's manufacturer, Syngenta Crop Protection, and Syngenta-funded scientists. A careful analysis of the published data funded by Syngenta, and of several studies submitted to the US Environmental Protection Agency (EPA) by the Syngenta-funded panel for data evaluation, indicates that the data presented in these studies are not in disagreement with my laboratory's peer-reviewed, published data. Further, the published and unpublished data presented to the EPA by the Syngenta-funded panel (and touted in the popular press) suffer from contaminated laboratory controls; high mortality; inappropriate measurements of hormone levels in stressed, sexually immature animals during nonreproductive seasons; and contaminated reference sites. The confounding factors in the industry-funded studies severely limit any conclusions about the adverse effects of atrazine on amphibians and prevent meaningful comparisons with my laboratory's published data.
Key Words: ATRAZINE, AMPHIBIAN, ENDOCRINE DISRUPTOR, CHEMICAL CASTRATION, Feminization/*chemically induced
Cadmium (Cd(2+)) is a common environmental pollutant and a major constituent of tobacco smoke. Exposure to this heavy metal, which has no known beneficial physiological role, has been linked to a wide range of detrimental effects on mammalian reproduction. Intriguingly, depending on the identity of the steroidogenic tissue involved and the dosage used, it has been reported to either enhance or inhibit the biosynthesis of progesterone, a hormone that is inexorably linked to both normal ovarian cyclicity and the maintenance of pregnancy. Thus, Cd(2+) has been shown to exert significant effects on ovarian and reproductive tract morphology, with extremely low dosages reported to stimulate ovarian luteal progesterone biosynthesis and high dosages inhibiting it. In addition, Cd(2+) exposure during human pregnancy has been linked to decreased birth weights and premature birth, with the enhanced levels of placental Cd(2+) resulting from maternal exposure to industrial wastes or tobacco smoke being associated with decreased progesterone biosynthesis by the placental trophoblast. The stimulatory effects of Cd(2+) on ovarian progesterone synthesis, as revealed by the results of studies using stable porcine granulosa cells, appear centered on the enhanced conversion of cholesterol to pregnenolone by the cytochrome P450 side chain cleavage (P450scc). However, in the placenta, the Cd(2+)-induced decline in progesterone synthesis is commensurate with a decrease in P450scc. Additionally, placental low-density lipoprotein receptor (LDL-R) mRNA declines in response to Cd(2+) exposure, suggesting an inhibition in the pathway that provides cholesterol precursor from the maternal peripheral circulation. Potential mechanisms by which Cd(2+) may affect steroidogenesis include interference with the DNA binding zinc (Zn(2+))-finger motif through the substitution of Cd(2+) for Zn(2+) or by taking on the role of an endocrine disrupting chemical (EDC) that could mimic or inhibit the actions of endogenous estrogens. Divergent, tissue-specific (ovary vs. placenta) effects of Cd(2+) also cannot be ruled out. Therefore, in consideration of the data currently available and in light of the potentially serious consequences of environmental Cd(2+) exposure to human reproduction, we propose that priority should be given to studies dedicated to further elucidating the mechanisms involved.
It has been proposed that a global decline in sperm counts, semen quality, and several male reproductive disorders are associated with exposure to environmental chemicals. Thus, the present study examined the effects of two estrogenic chemicals, octylphenol (OP) and bisphenol A (BPA), on epididymal sperm counts and sperm motility, luteinizing hormone (LH)-releasing hormone (LHRH)-stimulated plasma LH and steroid hormones, insulin-like growth factor I (IGF-I), and accessory reproductive organs in pubertal male Wistar rats. Fifty-day-old rats in the OP group (n=11) and BPA group (n=11) received daily sc injections of the respective chemical at a dose of 3 mg/kg bw dissolved in 0.2 mL DMSO. Rats in the control group (DMSO group; n=10) received 0.2 mL DMSO alone. After 2 wk of treatment, a jugular blood sample was taken, and, on the next day, a second blood sample was taken 1 h after an sc injection of LHRH (250 ng). After 5 wk of treatment, rats were deeply anesthetized and heart blood was collected. Epididymal sperm motility and sperm head counts were determined. LHRH increased plasma LH to higher levels in all groups, but the increases were significant (p<0.01) in the BPA and OP groups. However, despite higher LH levels after LHRH injection, the incremental responses of testosterone and pro-gesterone in the OP and BPA groups were small compared to those in the DMSO group, which showed a small LH response. After 5 wk of treatment, plasma testosterone levels were significantly (p<0.01) reduced in the OP and BPA groups and this was accompanied by reduced (p<0.05) epididymal sperm counts. However, the chemical-treated groups had high basal progesterone levels. No significant effects of chemicals on sperm motility parameters were noted. The chemical-induced increases (p<0.05) of the weight of ventral prostate gland were coincided with elevated plasma IGF-I levels in the BPA (p<0.05) and OP (p<0.01) groups. The present results demonstrated that OP and BPA can reduce sperm counts resulting from lowered plasma testosterone in male rats just after puberty. The enlarged ventral prostate gland may possibly be associated with increased plasma IGF-I, raising the possibility of a link between these chemicals and prostate diseases because IGF-I has been implicated in the pathogenesis of human prostate cancers.
Prenatal exposure to environmental chemicals that interfere with the androgen signaling pathway can cause permanent adverse effects on reproductive development in male rats. The objectives of this study were to 1) determine whether a documented antiandrogen butyl benzyl phthalate (BBP) and/or linuron (an androgen receptor antagonist) would decrease fetal testosterone (T) production, 2) describe reproductive developmental effects of linuron and BBP in the male, 3) examine the potential cumulative effects of linuron and BBP, and 4) investigate whether treatment-induced changes to neonatal anogenital distance (AGD) and juvenile areola number were predictive of adult reproductive alterations. Pregnant rats were treated with either corn oil, 75 mg/kg/day of linuron, 500 mg/kg/day of BBP, or a combination of 75 mg/kg/day linuron and 500 mg/kg/day BBP from gestational Day 14 to 18. A cohort of fetuses was removed to assess male testicular T and progesterone production, testicular T concentrations, and whole-body T concentrations. Male offspring from the remaining litters were assessed for AGD and number of areolae and then examined for alterations as young adults. Prenatal exposure to either linuron or BBP or BBP + linuron decreased T production and caused alterations to androgen-organized tissues in a dose-additive manner. Furthermore, treatment-related changes to neonatal AGD and infant areolae significantly correlated with adult AGD, nipple retention, reproductive malformations, and reproductive organ and tissue weights. In general, consideration of the dose-response curves for the antiandrogenic effects suggests that these responses were dose additive rather than synergistic responses. Taken together, these data provide additional evidence of cumulative effects of antiandrogen mixtures on male reproductive development.
In utero and lactational exposure to estrogenic agents has been shown to influence morphological and functional development of reproductive tissues. Thus, consumption of dietary phytoestrogens, such as isoflavones, during pregnancy and lactation could influence important periods of development, when the fetus and neonate are more sensitive to estrogen exposure. In this study, reproductive outcomes after developmental exposure to isoflavones were examined in Long-Evans rats maternally exposed to isoflavones via a commercial soy beverage or as the isolated isoflavone, genistein. Most reproductive endpoints examined at birth, weaning, and 2 months of age were not significantly modified in pups of either sex after lactational exposure to soy milk (provided to the dams in place of drinking water) from birth until weaning. However, soy milk exposure induced a significant increase in progesterone receptor (PR) in the uterine glandular epithelium of the 2-month-old pups. In pregnant dams treated with genistein (GEN; 15 mg/kg body weight) by gavage, from Gestational Day 14 through weaning, PR expression in the uterine glandular epithelium from 2-month-old GEN-treated females (postexposure) was also significantly increased. Diethylstilbesterol (DES) also stimulated uterine PR expression only in the glandular but not luminal epithelial cells. However, unlike DES, in utero/lactational exposure to GEN did not increase expression of the proliferation marker, proliferating cell nuclear antigen (PCNA), in the luminal epithelial cells of the 2-month-old rat uteri. These experiments demonstrate that developmental exposure to dietary isoflavones, at levels comparable to the ranges of human exposure, modify expression of the estrogen-regulated PR in the uterus of sexually mature rats weeks after exposure ended. Since the PR is essential for regulating key female reproductive processes, such as uterine proliferation, implantation, and maintenance of pregnancy, its increased expression suggests that soy phytoestrogen exposure during reproductive development may have long-term reproductive health consequences.
To determine the relationship between abnormal pregnancy in humans and methylmercury contamination, a retrospective study was conducted on women in two heavily contaminated areas, Modo (area M) and Akasaki (area A). Abnormal pregnancy was defined as fetal death, i.e., stillbirth and spontaneous abortion. In area M, prior to 1956, the incidence of abnormal pregnancy among the respondents was 7.0%. The incidence increased to 18.1% in the period between 1956 and 1968, when the pollution become serious. In area A, the incidence increased from 5.4% before 1956 to 14.2% between 1956 and 1968. In each area, the difference in the incidence between two periods, i.e., before and during the severe contamination, was statistically significant (area M, p<0.01; area A, p<0.001). Women living in Ikitsuki Island (area I) were selected as the control group. The incidence of the abnormal pregnancy in the three areas was compared by the birth years of mothers. Among women born between 1931 and 1940, the incidences were 26%, 15.1% and 13.5% in areas M, A and I, respectively. These women reached their reproductive age during the period of severe contamination in the two areas. The differences in the incidence between areas M and A and between areas M and I were statistically significant (areas M and A, p<0.05; areas M and I, p<0.01). These suggest that there is a relationship between methylmercury contamination and the increase in abnormal pregnancy in humans.
Key Words: Abortion, Spontaneous/epidemiology, Data Collection, *Environmental Exposure, Environmental Pollutants/*toxicity, Female, Fetal Death/epidemiology, Humans, Incidence, Japan/epidemiology, Life Tables, Mercury Poisoning, Nervous System/epidemiology, Methylmercury Compounds/*toxicity, Middle Aged, Oceans and Seas, Pregnancy, Pregnancy Complications/*epidemiology, Pregnancy Outcome/epidemiology, Retrospective Studies, Risk, Time Factors
Between 1996 and 1999, the authors invited all young men from five European countries who were undergoing compulsory medical examination for possible military service to participate in a study on male reproductive health. The participation rate was 19% in two cities in Denmark (n = 889), 17% in Oslo, Norway (n = 221), 13% in Turku, Finland (n = 313), 14% in Kaunas, Lithuania (n = 157), and 19% in Tartu, Estonia (n = 190). Each man provided a semen sample, was examined by a physician, and, in collaboration with his mother, completed a questionnaire about general and reproductive health, current smoking habits, and exposure to smoking in utero. After adjustment for confounding factors, men exposed to smoking in utero had a reduction in sperm concentration of 20.1% (95% confidence interval (CI): 6.8, 33.5) and a reduction in total sperm count of 24.5% (95% CI: 9.5, 39.5) in comparison with unexposed men. Percentages of motile and morphologically normal sperm cells were 1.85 (95% CI: 0.46, 3.23) and 0.64 (95% CI: -0.02, 1.30) percentage points lower, respectively, among men exposed in utero, and exposed men had a 1.15-ml (95% CI: 0.66, 1.64) smaller testis size. The associations were present when data from the study centers were analyzed separately (though not in Lithuania, where only 1% of mothers smoked during pregnancy), although the strength of the association varied. Maternal smoking may have long-term implications for the reproductive health of the offspring. This is another good reason to advise pregnant women to avoid smoking.
In 123 Croatian men with no occupational exposure to metals, the influence of cadmium on reproductive parameters was examined after adjusting for age, smoking, alcohol, and biomarkers of lead, copper, zinc, and selenium. The following variables were measured: blood cadmium (BCd), blood lead (BPb), activity of delta-aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin, serum copper (SCu), serum zinc (SZn), serum selenium (SSe), activity of glutathione peroxidase (GPx) in blood, testis size, semen quality (including sperm concentration, motility, viability, and morphology), indicators in seminal fluid (the lactate dehydrogenase isoenzyme LDH-C4, fructose, zinc, acid phosphatase, and citric acid), and hormones in serum (follicle-stimulating hormone--FSH, luteinizing hormone, prolactin, testosterone, and estradiol). The median and range BCd values were 2.94 (0.49-11.93) microg/L in 61 smokers and 0.59 (0.20-3.71) microg/L in 62 nonsmokers (p < 0.0001). Smoking habits (cigarettes/day) highly significantly correlated with BCd (p < 0.0001). After adjusting for potential confounding variables by multiple regression, BCd was significantly associated with a decrease in testis size (p < 0.03) and an increase in serum estradiol (p < 0.005), FSH (p < 0.03), and testosterone (p < 0.04). Smoking was significantly associated with a decrease in serum prolactin (p < 0.006) and LDH-C4 in seminal fluid (p < 0.03). Several reproductive parameters were significantly associated with BPb and ALAD, biomarkers of lead, and/or with SCu, SZn, SSe, and GPx. The necessity of controlling for various metals, and other potential confounders when assessing the influence of a particular metal on reproductive function in men, is emphasized.
BACKGROUND: Recent reviews conclude that environmental tobacco smoke (ETS) leads to diminished birth weight. However, the threshold and magnitude of that effect is uncertain. We aimed to determine the magnitude and shape of the relations between ETS and various adverse pregnancy outcomes using a highly sensitive biochemical assay. METHODS: Maternal serum specimens were collected from more than 3000 women enrolled in California's prenatal screening program in 1992 and analyzed for cotinine. Information on pregnancy outcomes was obtained from live birth/fetal death records and hospital questionnaires. We conducted analyses on 2777 woman-live birth pairs and 19 woman-fetal death pairs in which the mother was presumed to be a nonsmoker (midtrimester cotinine levels < or =10 ng/mL). RESULTS: In multiple logistic regression analyses, the odds ratios of fetal death, preterm delivery, and term-low birth weight were 3.4, 1.8, and 1.8, respectively, in the highest cotinine quintile (0.236-10 ng/mL), compared with the lowest quintile (<0.026 ng/mL). In adjusted linear models, there was a linear dose-dependent effect of log cotinine on mean birth weight (-109 g) and mean infant length (-0.84 cm) over the range of cotinine values. Linear relations were not found with respect to infant head circumference or the ratio of brain weight to body weight. Infant's body mass index declined with exposures above approximately 0.5 ng/mL cotinine. We estimated that ETS levels at or above 0.05 ng/mL (experienced by 62% of the study population) accounted for 12% of all adverse outcomes. CONCLUSIONS: ETS exposure in pregnant women adversely affects pregnancy by increasing fetal mortality and preterm delivery at higher exposure levels and slowing fetal growth across all levels of ETS exposure.
Since the 1930s, plasticizers have been used to impart flexibility to an otherwise rigid polyvinylchloride (PVC). Di-(2-ethylhexyl)-phthalate (DEHP) is the most widely used plasticizer in PVC formulations. However, DEHP leaks out from PVC items with time and use and consequently it is an ubiquitous environmental contaminant. To date, very little is known about the actual extent of DEHP exposure in infants, who are believed to be the most sensitive population, as they may be exposed to several different sources (breast milk, infant formula, baby food, indoor air, and by dermal and oral exposure via indoor dust containing DEHP) since early in life and since differences in DEHP pharmacokinetics and metabolism between children and adults have been well documented. Little information exists on DEHP dietary exposure, believed to represent a major source and orally administered DEHP is converted more rapidly to MEHP than other routes of exposure. Although DEHP has been shown to induce toxicity in experimental animals, a limited but suggestive human exposure data causes a serious concern that an early in life DEHP exposure may adversely affect male reproductive tract development. Here, we report a review on dietary phthalate exposure in babies.
Agent Orange is a phenoxy herbicide that was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We studied pregnancy outcomes among wives of male chemical workers who were highly exposed to chemicals contaminated with TCDD and among wives of nonexposed neighborhood referents. For exposed pregnancies, we estimated serum TCDD concentration at the time of conception using a pharmacokinetic model. The mean TCDD concentration for workers' births was 254 pg/g lipid (range, 3-16,340 pg/g). The mean referent concentration of 6 pg/g was assigned to pregnancies fathered by workers before exposure. A total of 1,117 live singleton births of 217 referent wives and 176 worker wives were included. Only full-term births were included in the birth weight analysis (greater than or equal to 37 weeks of gestation). Mean birth weight among full-term babies was similar among referents' babies (n = 604), preexposure workers' babies (n = 221), and exposed workers' babies (n = 292) (3,420, 3,347, and 3,442 g, respectively). Neither continuous nor categorical TCDD concentration had an effect on birth weight for term infants after adjustment for infant sex, mother's education, parity, prenatal cigarette smoking, and gestation length. An analysis to estimate potential direct exposure of the wives during periods of workers' exposure yielded a nonstatistically significant increase in infant birth weight of 130 g in the highest exposure group (TCDD concentration > 254 pg/g) compared with referents (p = 0.09). Mothers' reports of preterm delivery showed a somewhat protective association with paternal TCDD (log) concentration (odds ratio = 0.8; 95% confidence interval, 0.6-1.1). We also include descriptive information on reported birth defects. Because the estimated TCDD concentrations in this population were much higher than in other studies, the results indicate that TCDD is unlikely to increase the risk of low birth weight or preterm delivery through a paternal mechanism. Key words: birth defects, birth weight, congenital anomalies, dioxin, occupation, paternal exposure, preterm birth, TCDD.
Study Synopsis: Babies born to pregnant mothers living near the WTC on 9/11 were more likely to have lower birth weight and shorter birth length. If in the first trimester on 9/11 they also were more likely to be born early and with a smaller head circumference. Stress or pollutants could be involved.
Scientific abstract:
The effects of prenatal exposure to pollutants from the World Trade Center (WTC) disaster on fetal growth and subsequent health and development of exposed children remain a source of concern. We assessed the impact of gestational timing of the disaster and distance from the WTC in the 4 weeks after 11 September on the birth outcomes of 300 nonsmoking women who were pregnant at the time of the event. They were recruited at delivery between December 2001 and June 2002 from three hospitals close to the WTC site. Residential and work addresses of all participants for each of the 4 weeks after 11 September 2001 were geocoded for classification by place and timing of exposure. Average daily hours spent at each location were based on the women's reports for each week. Biomedical pregnancy and delivery data extracted from the medical records of each mother and newborn included medical complications, type of delivery, length of gestation, birth weight, birth length, and head circumference. Term infants born to women who were pregnant on 11 September 2001 and who were living within a 2-mile radius of the WTC during the month after the event showed significant decrements in term birth weight (-149 g) and birth length (-0.82 cm), compared with infants born to the other pregnant women studied, after controlling for sociodemographic and biomedical risk factors. The decrements remained significant with adjustment for gestational duration (-122 g and -0.74 cm, respectively). Women in the first trimester of pregnancy at the time of the WTC event delivered infants with significantly shorter gestation (-3.6 days) and a smaller head circumference (-0.48 cm), compared with women at later stages of pregnancy, regardless of the distance of their residence or work sites from the WTC. The observed adverse effects suggest an impact of pollutants and/or stress related to the WTC disaster and have implications for the health and development of exposed children.
Key Words: Adolescent, Adult, Aircraft, Birth Weight, Body Height, Cohort Studies, Environmental Pollutants/*poisoning, Female, Geography, Gestational Age, Humans, Infant, Newborn, Male, New York City, Pregnancy, *Pregnancy Outcome, Pregnancy Trimester, First, Pregnancy Trimester, Second, Pregnancy Trimester, Third, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., *September 11 Terrorist Attacks, Stress, Psychological, Urban Population
Study Synopsis: At exposure levels within the range experienced by the general public, the phthalate DBP reduces expression of genes necessary for testosterone synthesis in fetal rats. The effective dose is equivalent to EPA's current estimate of what is safe.
Scientific abstract:
Exposure to di (n-butyl) phthalate (DBP) in utero impairs the development of the male rat reproductive tract. The adverse effects are due in part to a coordinated decrease in expression of genes involved in cholesterol transport and steroidogenesis with a resultant reduction in testosterone production in the fetal testis. To determine the dose-response relationship for the effect of DBP on steroidogenesis in fetal rat testes, pregnant Sprague-Dawley rats received corn oil (vehicle control) or DBP (0.1, 1.0, 10, 50, 100, or 500 mg/kg/day) by gavage daily from gestation day (GD) 12 to 19. Testes were isolated on GD 19, and changes in gene and protein expression were quantified by RT-PCR and Western analysis. Fetal testicular testosterone concentration was determined by radioimmunoassay. DBP exposure resulted in significant dose-dependent reductions in mRNA and protein concentration of scavenger receptor, steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage, 3beta-hydroxysteroid dehydrogenase, and cytochrome P450c17. Testicular testosterone was reduced at doses of 50 mg/kg/day and above. Whole-testis expression of peripheral benzodiazepine receptor (PBR) mRNA, which functions with StAR to transport cholesterol across the mitochondrial membrane, was upregulated following exposure to DBP at 500 mg/kg/day. By immunocytochemistry, however, PBR protein was reduced in interstitial cells and also expressed but not reduced in gonocytes. Our results demonstrate a coordinate, dose-dependent reduction in the expression of key genes and proteins involved in cholesterol transport and steroidogenesis and a corresponding reduction in testosterone in fetal testes following maternal exposure to DBP, at dose levels below which adverse effects are detected in the developing male reproductive tract. Alterations in gene and protein expression and testosterone synthesis may serve as sensitive indicators of testicular response to DBP.
The increased use of organophosphorus insecticides in agriculture and their widespread existence in the environment poses a potential health hazard. To determine the relationship between exposure to pesticides and intrauterine growth retardation (IUGR), live newborns from singleton pregnancies, with (n = 79) and without (n = 292) IUGR were studied. During the gestational period the mothers were living in agricultural communities in the state of Chihuahua, Mexico. Exposure to agrochemical products was evaluated. A significant association between the history of positive exposure to pesticides (i.e. the women themselves or their newborns who showed acetylcholinesterase activity levels lower than 20%) and the presence of IUGR was found. The proportions of exposure in the cases were 18% and 8% in the control group; the adjusted OR (fat free mass, anti-cytomegalovirus antibodies and placental weight) was 2.33 (p = 0.04).
The aim of the present study was to investigate if environmental doses of PCB 153 and PCB 126 could produce effects in a controlled animal model. Possible adverse effects on the hypothalamic-pitutitary-gonadal axis were examined by measuring gonadotrophins and gonadal steroid hormone concentrations in goat kids exposed during gestation and lactation. The concentrations of PCB 153 and PCB 126 in adipose tissue in the goat kids 9 months post-partum were 5800 ng/g (fat-weight, range; 2900-12700 ng/g) and 0.49 ng/g (fat-weight, range; 0.28-0.80 ng/g), respectively. The pre- and post-pubertal plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (Prl) and progesterone (P4) were analysed. LH, FSH, Prl, and P4 were also measured during an induced oestrus cycle. The prepubertal LH concentration was significantly lower, the puberty was delayed and the P4 level during the luteal phase of an estrous cycle was higher in the group exposed to PCB 153. No significant effect of PCB 153 exposure was found on Prl and FSH. PCB 126 did not produce any effects at the exposure level tested in this study. In conclusion, perinatal exposure to PCB 153 affected the reproductive function and the puberty maturation in goats.
Study Synopsis: A large retrospective study of UK veterans who served in 1990-91 Gulf War finds indications of fertility impairment. Vets who served in the Gulf have an increased risk of fertility and a longer time to conception compared to other veterans.
Scientific abstract:
OBJECTIVES: To examine the hypothesis that, theoretically at least, exposure to toxicants of the type present in the Gulf war could affect spermatogenesis, which might be observed as increased levels of infertility. DESIGN: Retrospective reproductive cohort analysis. SETTING: Male UK Gulf war veterans and matched comparison group of non-deployed servicemen, surveyed by postal questionnaire. PARTICIPANTS: 42,818 completed questionnaires were returned, representing response rates of 53% for Gulf veterans and 42% for non-Gulf veterans; 10,465 Gulf veterans and 7376 non-Gulf veterans reported fathering or trying to father pregnancies after the Gulf war. MAIN OUTCOME MEASURES: Failure to achieve conceptions (type I infertility) or live births (type II infertility) after the Gulf war, having tried for at least a year and consulted a doctor; time to conception among pregnancies fathered by men not reporting fertility problems. RESULTS: Risk of reported infertility was higher among Gulf war veterans than among non-Gulf veterans (odds ratio for type I infertility 1.41, 95% confidence interval 1.05 to 1.89; type II 1.50, 1.18 to 1.89). This small effect was constant over time since the war and was observed whether or not the men had fathered pregnancies before the war. Results were similar when analyses were restricted to clinically confirmed diagnoses. Pregnancies fathered by Gulf veterans not reporting fertility problems also took longer to conceive (odds ratio for > 1 year 1.18, 1.04 to 1.34). CONCLUSIONS: We found some evidence of an association between Gulf war service and reported infertility. Pregnancies fathered by Gulf veterans with no fertility problems also reportedly took longer to conceive.
Key Words: Adult, Aged, Cohort Studies, Female, Great Britain/epidemiology, Humans, Infertility, Male/*epidemiology, Male, Middle Aged, Military Personnel/*statistics & numerical data, Odds Ratio, Persian Gulf Syndrome/*epidemiology, Pregnancy/*statistics & numerical data, Prevalence, Prognosis, Research Support, Non-U.S. Gov't, Retrospective Studies
BACKGROUND: We examined the association of uterine leiomyoma with menstrual cycle characteristics in a population of non-care-seeking women. METHODS: This cross-sectional study uses data from the Seveso Women's Health Study (SWHS), a population-based cohort in Italy. Participants included 341 premenopausal women, 30-60 years old, who had an intact uterus and were not pregnant, lactating, or using oral contraception or intra-uterine devices. We examined the presence of any ultrasound-detected uterine leiomyoma in relation to self-reported menstrual cycle length, flow length and heaviness of flow. The association of leiomyoma number, volume, tissue layer location and axial position with menstrual cycle characteristics was also examined. RESULTS: Uterine leiomyomata were detected in 73 women (21.4%). After adjustment for covariates, the presence of a leiomyoma was not significantly related to menstrual cycle length, flow length or heaviness of flow [odds ratio (OR) for scanty flow =1.9, 95% confidence interval (CI) 0.8-4.3; OR for heavy flow =1.3, 95% CI 0.7-2.5; relative to moderate flow]. Number, volume, tissue layer location (subserosal or intramural) and axial position (anterior or posterior) of the leiomyoma were also not related to menstrual cycle characteristics. CONCLUSION: In this Italian population of women not seeking gynaecological care, menstrual characteristics are not related to leiomyoma.
Key Words: Adult, Cohort Studies, Cross-Sectional Studies, Female, Humans, Incidence, Italy/epidemiology, Leiomyoma/epidemiology/*physiopathology/ultrasonography, *Menstrual Cycle, Middle Aged, Premenopause, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Uterine Neoplasms/epidemiology/*physiopathology/ultrasonography
Most of the general population is exposed to carbaryl and other contemporary-use insecticides at low levels. Studies of laboratory animals, in addition to limited human data, show an association between carbaryl exposure and decreased semen quality. In the present study we explored whether environmental exposures to 1-naphthol (1N), a metabolite of carbaryl and naphthalene, and 3,5,6-trichloro-2-pyridinol (TCPY), a metabolite of chlorpyrifos and chlorpyrifos-methyl, are associated with decreased semen quality in humans. Subjects (n=272) were recruited through a Massachusetts infertility clinic. Individual exposures were measured as spot urinary concentrations of 1N and TCPY adjusted using specific gravity. Semen quality was assessed as sperm concentration, percent motile sperm, and percent sperm with normal morphology, along with sperm motion parameters (straight-line velocity, curvilinear velocity, and linearity). Median TCPY and 1N concentrations were 3.22 and 3.19microg/L, respectively. For increasing 1N tertiles, adjusted odds ratios (ORs) were significantly elevated for below-reference sperm concentration (OR for low, medium, and high tertiles = 1.0, 4.2, 4.2, respectively; p-value for trend =0.01) and percent motile sperm (1.0, 2.5, 2.4; p-value for trend = 0.01). The sperm motion parameter most strongly associated with 1N was straight-line velocity. There were suggestive, borderline-significant associations for TCPY with sperm concentration and motility, whereas sperm morphology was weakly and nonsignificantly associated with both TCPY and 1N. The observed associations between altered semen quality and 1N are consistent with previous studies of carbaryl exposure, although suggestive associations with TCPY are difficult to interpret because human and animal data are currently limited.
BACKGROUND: Members of the general population are exposed to non-persistent insecticides at low levels. The present study explored whether environmental exposures to carbaryl and chlorpyrifos are associated with DNA damage in human sperm. METHODS: Subjects (n=260) were recruited through a Massachusetts infertility clinic. Individual exposures were measured as spot urinary metabolite concentrations of chlorpyrifos [3,5,6-trichloro-2-pyridinol (TCPY)] and carbaryl [1-naphthol (1N)], adjusted using specific gravity. Sperm DNA integrity was assessed by neutral comet assay and reported as comet extent, percentage DNA in comet tail (Tail%) and tail distributed moment (TDM). RESULTS: A statistically significant increase in Tail% was found for an interquartile range (IQR) increase in both 1N [coefficient=4.1; 95% confidence interval (CI) 1.9-6.3] and TCPY (2.8; 0.9-4.6), while a decrease in TDM was associated with IQR changes in 1N (-2.2; -4.9 to 0.5) and TCPY (-2.5; -4.7 to -0.2). A negative correlation between Tail% and TDM was present only when stratified by comet extent, suggesting that Tail% and TDM may measure different types of DNA damage within comet extent strata. CONCLUSIONS: Environmental exposure to carbaryl and chlorpyrifos may be associated with increased DNA damage in human sperm, as indicated by a change in comet assay parameters.
Chemicals found in the environment as industrial byproducts or pollutants as well as those that are prescribed or part of our daily lives can have multiple effects on the human body. The manner in which we are exposed, and the levels we are exposed to are significant contributing factors. Adults have the bodily defense mechanisms in place to combat exposures to adverse toxicants and general pollution at a variety of levels. However, developing organisms may not have adequate defense mechanisms, and toxicants can have a significant effect on their health and development. In this review, we take particular note of the toxicities of chemicals on the developing female reproductive system as a result of in utero exposure. Environmental and prescribed chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), diethylstilbestrol, and genistein, as well as others, will be reviewed for their in utero toxicity in the neuroendocrine system, the ovary, oviduct, placenta, uterus, vagina, cervix, and mammary gland.
OBJECTIVE: To investigate the relation between the fetal environment and endometriosis. DESIGN: Prospective cohort study. SETTING: Nurses' Health Study II with 10 years of follow-up. PARTICIPANT(S): Eighty-four thousand, four hundred forty-six women aged 25-42 who had never been diagnosed with endometriosis, infertility, or cancer at baseline in 1989. MAIN OUTCOME MEASURE(S): Incidence of laparoscopically confirmed endometriosis according to birthweight, prematurity, multiple gestation, diethylstilbestrol (DES) exposure, and having been breastfed. RESULT(S): During 566,250 woman-years of follow-up, 1,226 cases of laparoscopically-confirmed endometriosis were reported among women with no past infertility. After adjusting for age, calendar time, parity, race, and body mass index at age 18, we observed a linear increase in the incidence rate with decreasing birthweight (rate ratio [RR] = 1.3 for birthweight <5.5 pounds versus 7.0-8.4 pounds, 95% confidence interval [CI] = 1.0-1.8, P value, test for trend = .01). In addition, women who were born as one of a multiple gestation (i.e., twins or greater number) were at increased risk even after controlling for birthweight (RR = 1.7, CI = 1.2-2.5). The rate of endometriosis was also 80% greater among women exposed to diethylstilbestrol in utero (RR = 1.8, CI = 1.2-2.8). Neither premature delivery nor having been breastfed were associated with the incidence of endometriosis. None of these effect estimates were modified by infertility status at the time of endometriosis diagnosis. CONCLUSION(S): The fetal environment is associated with subsequent laparoscopically confirmed endometriosis in this cohort of US women.
Study Synopsis: Pollutant levels in NYC air undermine fetal development. A study of mothers and babies in two NYC minority communities finds that environmental tobacco smoke (ETS) and polycyclic aromatic hydrocarbons (PAHs) are both associated with reduced birth weight and head circumference. The PAH effect is apparent, however, only in subjects exposed to ETS.
Scientific abstract:
Inner-city, minority populations are high-risk groups for adverse birth outcomes and also are more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), benzo[a]pyrene (BaP), and other polycyclic aromatic hydrocarbons (PAHs) found in urban air. In a sample of nonsmoking African-American and Dominican women, we evaluated the effects on birth outcomes of prenatal exposure to ETS, using questionnaire data and plasma cotinine as a biomarker of exposure, and environmental PAHs using BaP-DNA adducts as a molecular dosimeter. We previously reported that among African Americans, high prenatal exposure to PAHs estimated by prenatal personal air monitoring was associated with lower birth weight (p = 0.003) and smaller head circumference (p = 0.01) after adjusting for potential confounders. In the present analysis, self-reported ETS was associated with decreased head circumference (p = 0.04). BaP-DNA adducts were not correlated with ETS or dietary PAHs. There was no main effect of BaP-DNA adducts on birth outcomes. However, there was a significant interaction between the two pollutants such that the combined exposure to high ETS and high adducts had a significant multiplicative effect on birth weight (p = 0.04) and head circumference (p = 0.01) after adjusting for ethnicity, sex of newborns, maternal body mass index, dietary PAHs, and gestational age. This study provides evidence that combined exposure to environmental pollutants at levels currently encountered in New York City adversely affects fetal development.
Key Words: Adolescent, Adult, African Americans, Benzo(a)pyrene, Biological Markers/blood, Birth Weight/drug effects, Body Constitution, Carcinogens, Environmental/analysis, Cotinine/blood, DNA Adducts/blood, Embryonic and Fetal Development/*drug effects, Environmental Pollutants/*toxicity, Female, Hispanic Americans, Humans, Infant, Newborn, New York City, Polycyclic Hydrocarbons, Aromatic/analysis, Pregnancy, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Tobacco Smoke Pollution/analysis, Urban Health
In the past years, there has been increased interest in assessing the relationship between impaired male fertility and environmental factors. Human male fertility is a complex process and therefore a great variety of sites may be affected by exogenous noxae. Lifestyle factors as well as various environmental and occupational agents may impair male fertility. Many studies have been published reporting on reproductive dysfunctions in male animals and humans. Especially environmental pollutants with endocrine activity are discussed as a possible cause of this detrimental development. Evidence from animal experiments show that substances with oestrogenic and antiandrogenic properties may cause hypospadia, cryptorchidism, reduction of sperm density and an increase of testicular tumours. Many adverse effects on animal male fertility have been documented for phthalates and some chlorinated hydrocarbons such as polychlorinated biphenyls and polychlorinated dibenzo-p-dioxins. For other chemicals such as bisphenol A and nonylphenols animal data are conflicting. Environmental pollutants may mediate their effects by receptor binding, modulation of hormone-regulated mechanisms or direct toxic effects. Data on environmental chemicals and human male fertility are scarce, and risk assessment is mostly based on the results of animal studies. However, there are indications that exposure to endocrine active chemicals during early development may alter hormone responsiveness in adulthood. Furthermore, some of the chemicals are found in fluids that are associated with human reproduction, such as follicular fluid, seminal fluid and cervical mucus. Recent studies suggest a correlation between pesticide exposure and standard semen parameters as well as in vitro fertilization rates.
AIMS: To study the association between fetal death and paternal agricultural occupation in areas and time periods with different levels of use of agricultural pesticides. METHODS: A total of 1 473 146 stillbirths and births occurring in Spain between 1995 and 1999 were analysed. RESULTS: The offspring of agricultural workers had the highest risk of fetal death from congenital anomalies in the southern and eastern area (where pesticide use is greatest) and the lowest risk in the rest of Spain. In both areas the offspring of agricultural workers had a similar excess risk of fetal death from the remaining causes of death. The relative risk of fetal death from congenital anomalies in infants conceived between April and September (the months of greater use of pesticides) in the southern and eastern area was 0.90 in manual workers and 1.62 in agricultural workers, compared to non-manual workers; in individuals who were conceived during the rest of the year, the relative risk was 0.87 and 0.85, respectively. In both periods the offspring of agricultural workers had an excess risk of fetal death from the remaining causes of death. CONCLUSIONS: Paternal agricultural work in the areas where pesticides are massively used increases the risk of fetal death from congenital anomalies. The risk is also increased for fetuses conceived during the time periods of maximum use of pesticides The higher risk of fetal death from the remaining causes of death in the offspring of agricultural workers seems unrelated to pesticide exposure.
Previous studies have suggested an association between subfertility and testicular cancer by using fecundity and semen characteristics to measure fertility. The occurrence of twinning in offspring may be used to investigate male reproductive health, because dizygotic twinning is reduced by male subfertility. We therefore assessed number of children and offspring twinning rates among 4592 Swedish patients with testicular cancer and 12 254 control subjects. Before diagnosis, case patients had a decreased number of children (for testicular cancer, odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.62 to 0.81; at least three children compared with no children), with a lower frequency of dizygotic twinning (for unlike-sex twins, OR for the father having testicular cancer = 0.49, 95% CI = 0.22 to 1.08). The ratio of unlike-sex to same-sex twins was 0.22 among children of case patients and 0.66 among children of control subjects (adjusted P =.03, two-sided Wald test). We also found an increased occurrence of twinning after diagnosis, probably attributable to treatment for iatrogenic subfertility. Our study strongly supports evidence of an association between subfertility and the subsequent risk for testicular cancer.
BACKGROUND: During the last decades, there has been concern that exposure to endocrine disruptors, such as persistent organochlorine pollutants (POPs), may contribute to an impairment of male reproductive function. To investigate whether exposure to 2,2'4,4'5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) affects semen quantity and quality and reproductive hormones, 195 Swedish fishermen, aged 24-65 years, were investigated. METHODS: The men provided semen samples which were analysed in a mobile laboratory unit. Blood samples and information relating to lifestyle, medical and reproductive history were obtained. RESULTS: The subjects had a median CB-153 serum level of 193 ng/g lipid (range 39-1460) and a median p,p'-DDE serum level of 240 ng/g lipid (range 334-2251). When CB-153 was categorized into quintiles, the subjects in the quintile with the highest concentration (> 328 ng/g lipid), tended to have decreased sperm motility compared with the subjects in the lowest quintile (< 113 ng/g lipid). The age-adjusted mean difference was 9.9% (95% confidence interval -1.0 to 21% P = 0.08). We found no significant associations between p,p'-DDE and semen characteristics or reproductive hormones. CONCLUSION: The association between CB-153 and sperm motility, although not formally significant, is of interest considering the possible endocrine-disrupting effects of polychlorinated biphenyls (PCBs).
The proposed National Children's Study has helped raise awareness of the issues related to children's health and the importance of monitoring the growth and development of children from preconception through adulthood. Many genetic predispositions can adversely impact the normal development process, and various environmental exposures have been linked to adverse reproductive health in rodent models and a small number of accidental human exposures. To monitor reproductive health and identify adverse effects at the earliest possible juncture, investigators must develop a network of biomarkers covering all stages and aspects of reproductive development and function. Biomarkers are biological indicators that can be measured repeatedly and are informative on one or more aspects of biological development or function. They can range from the anatomical level down to the molecular level and may provide information on the nature of an exposure, the effect of an exposure, or the susceptibility of individuals or populations to the toxic effects of an exposure. In theory, biomarkers can be used to monitor a wide variety of conditions and responses ranging from abnormal development to early indicators of late-onset disease. The main stumbling block with this theory has been finding appropriate biomarkers for particular conditions and exposures. Such biomarkers must be easily accessible, robust, and sensitive. Ideally, they will be expressed across a large section of the population, and can be monitored quickly, easily, conveniently, and with minimal cost. In this review, we discuss some of the current and emerging biomarkers of human pubertal development.
Our objective was to evaluate alterations in sperm chromatin structure in men occupationally exposed to a mixture of organophosphorus pesticides (OP) because these alterations have been proposed to compromise male fertility and offspring development. Chromatin susceptibility to in situ acid-induced denaturation structure was assessed by the sperm chromatin structure assay (SCSA). Urinary levels of alkylphosphates (DAP) were used to assess exposure. Diethylthiophosphate (DETP) was the most frequent OP metabolite found in urine samples indicating that compounds derived from thiophosphoric acid were mainly used. Chromatin structure was altered in most samples. About 75% of semen samples were classified as having poor fertility potential (>30% of Percentage of DNA Fragmentation Index [DFI%]), whereas individuals without OP occupational exposure showed average DFI% values of 9.9%. Most parameters of conventional semen analysis were within normality except for the presence of immature cells (IGC) in which 82% of the samples were above reference values. There were significant direct associations between urinary DETP concentrations and mean DFI and SD-DFI but marginally (P = 0.079) with DFI%, after adjustment for potential confounders, including IGC. This suggests that OP exposure alters sperm chromatin condensation, which could be reflected in an increased number of cells with greater susceptibility to DNA denaturation. This study showed that human sperm chromatin is a sensitive target to OP exposure and may contribute to adverse reproductive outcomes. Further studies on the relevance of protein phosphorylation as a possible mechanism by which OP alter sperm chromatin are required.
Surveys show that the public suspects that synthetic (manmade) chemicals released into the environment, especially pesticides, have adverse effects on human health and cause disease, including cancer. In reality, few scientifically documented examples support this view, especially for effects on the general population. However, the observation that many synthetic chemicals have intrinsic hormonal activity—they are endocrine disruptors—has reopened this debate. Pressure groups have called for all synthetic environmental chemicals with the potential to cause harm to be phased out or banned, whereas the chemical industry argues that such action must be based on proof of harm. Vociferous cases have been made on both sides, each lacking definitive data. Yet it is clear that environmental and lifestyle factors are key determinants of human disease—accounting for perhaps 75% of most cancers. New understanding and emerging results are reshaping our thinking, as is the recognition that establishing cause and effect for environmental chemical exposures is a daunting task.
This study was performed to investigate the serum levels of bisphenol A (BPA), an endocrine disruptor, in women with ovarian dysfunction and obesity. Fasting serum samples were obtained from 19 non-obese and 7 obese women with normal menstrual cycles: 7 patients with hyperprolactinemia, 21 patients with hypothalamic amenorrhea, and 13 non-obese and 6 obese patients with polycystic ovary syndrome (PCOS). BPA was measured by an enzyme-linked immunosorbent assay. BPA was detected in all human sera. Serum BPA concentrations were significantly higher in both non-obese and obese women with polycystic ovary syndrome (1.05 +/- 0.10 ng/ml, 1.17 +/- 0.16 ng/ml; p<0.05, respectively) and obese normal women (1.04 +/- 0.09 ng/ml, p<0.05) compared with those in non-obese normal women (0.71 +/- 0.09 ng/ml). There was no difference among women with hyperprolactinemia, women with hypothalamic amenorrhea, and non-obese normal women. There were significant positive correlations between serum BPA and total testosterone (r = 0.391, p<0.001), free testosterone (r = 0.504, p<0.001), androstenedione (r = 0.684, p<0.001), and DHEAS (r = 0.514, p<0.001) concentrations in all subjects. These findings show that there is a strong relationship between serum BPA and androgen concentrations, speculatively due to the effect of androgen on the metabolism of BPA.
Organochlorines are widespread pollutants in humans. Concern about adverse reproductive effects of these compounds arises from accidental exposure of humans and experimental studies. Recently, this issue has been addressed by a number of studies of exposed populations and hospital-based case-referent studies. These studies indicate that high concentrations of persistent organochlorines may adversely affect semen quality and cause testicular cancer in males, induce menstrual cycle abnormalities and spontaneous abortions in females, and cause prolonged waiting time pregnancy, reduced birth weight, skewed sex ratio, and altered age of sexual development. However, most effects have been demonstrated at exposure levels above the present day exposure level in European and North American populations. Due to inherent methodological problems in several of the available studies, additional research is needed to fully elucidate the possible adverse effects of organochlorines on human reproductive health.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, is associated with delays in pubertal development in animal studies. On 10 July 1976, as a result of a chemical explosion, residents of Seveso, Italy, experienced the highest levels of TCDD exposure experienced by a human population. Twenty years later, we initiated the Seveso Women's Health Study (SWHS), a retrospective cohort study of female residents of the most contaminated areas, to determine whether the women were at higher risk for reproductive disease. We examined the association of TCDD serum levels, based on measurements in serum collected soon after the explosion, with reported age at menarche among the 282 SWHS women who were premenarcheal at the time of the explosion. We found no change in risk of onset of menarche with a 10-fold increase in TCDD (e.g., 10-100 ppt; hazard ratio = 0.95; 95% confidence interval, 0.83-1.09; p-value for trend = 0.46). When TCDD levels were categorized, there was also no evidence of a dose-response trend (p = 0.65). In summary, we found that individual serum TCDD measurements are not significantly related to age at menarche among women in the SWHS cohort. The women in this study experienced substantial TCDD exposure during the postnatal but prepubertal developmental period. Given that animal evidence suggests in utero exposure has the most significant effect on onset of puberty, continued follow-up of the offspring of the SWHS cohort is important.
Key Words: Accidents, Occupational, Adolescent, Adult, Age of Onset, Child, Child, Preschool, Cohort Studies, Dose-Response Relationship, Drug, *Environmental Exposure, Environmental Pollutants/*blood, Female, Humans, Infant, Italy, *Menarche, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Retrospective Studies, Risk Assessment, Tetrachlorodibenzodioxin/*blood
Research notes: Comment in Environ Health Perspect. 2005 Jan;113(1):A17; author reply A18.
Study Synopsis: Pregnant women exposed to higher levels of two insecticides had smaller babies than other mothers, but after an EPA phase-out not only were exposures substantially lower but the association between newborn size and exposure disappeared. Newborn size is an important predictor of health later in life.
Scientific abstract:
We reported previously that insecticide exposures were widespread among minority women in New York City during pregnancy and that levels of the organophosphate chlorpyrifos in umbilical cord plasma were inversely associated with birth weight and length. Here we expand analyses to include additional insecticides (the organophosphate diazinon and the carbamate propoxur), a larger sample size (n = 314 mother-newborn pairs), and insecticide measurements in maternal personal air during pregnancy as well as in umbilical cord plasma at delivery. Controlling for potential confounders, we found no association between maternal personal air insecticide levels and birth weight, length, or head circumference. For each log unit increase in cord plasma chlorpyrifos levels, birth weight decreased by 42.6 g [95% confidence interval (CI), -81.8 to -3.8, p = 0.03] and birth length decreased by 0.24 cm (95% CI, -0.47 to -0.01, p = 0.04). Combined measures of (ln)cord plasma chlorpyrifos and diazinon (adjusted for relative potency) were also inversely associated with birth weight and length (p < 0.05). Birth weight averaged 186.3 g less (95% CI, -375.2 to -45.5) among newborns with the highest compared with lowest 26% of exposure levels (p = 0.01). Further, the associations between birth weight and length and cord plasma chlorpyrifos and diazinon were highly significant (p < or = 0.007) among newborns born before the 2000-2001 U.S. Environmental Protection Agency's regulatory actions to phase out residential use of these insecticides. Among newborns born after January 2001, exposure levels were substantially lower, and no association with fetal growth was apparent (p > 0.8). The propoxur metabolite 2-isopropoxyphenol in cord plasma was inversely associated with birth length, a finding of borderline significance (p = 0.05) after controlling for chlorpyrifos and diazinon. Results indicate that prenatal chlorpyrifos exposures have impaired fetal growth among this minority cohort and that diazinon exposures may have contributed to the effects. Findings support recent regulatory action to phase out residential uses of the insecticides.
Key Words: Adolescent, Adult, *Birth Weight, Body Height, Cohort Studies, Embryonic and Fetal Development/drug effects, Female, Humans, Infant, Newborn, Insecticides/*poisoning, Male, *Maternal Exposure, New York City/epidemiology, Pregnancy, Pregnancy Outcome, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Urban Population
To investigate the potential effects of common early life exposures on age at menarche, the authors examined data collected in a follow-up study of pregnancies that occurred during the 1960s in California. Among 994 female offspring interviewed as adolescents, 98% had started their menstrual periods at a mean age of 12.96 years. After adjustment, the mean age at menarche was a few months earlier among girls whose mothers smoked a pack or more of cigarettes daily during pregnancy compared with unexposed girls (difference = -0.22 years, 95% confidence interval (CI): -0.49, 0.05) and more so among girls who were not White (difference = -0.52 years, 95% CI: -1.1, 0.08). Girls with both high prenatal and childhood passive smoke exposure had an adjusted mean age at menarche about 4 months earlier than those unexposed. The daughter's mean age at menarche varied little by maternal prenatal alcohol consumption. Daughters of tea consumers had a later mean age (difference = 0.41 years at >/= 3 cups (0.7 liter)/day, 95% CI: 0.03, 0.80) and were more likely to start menarche later (>13 years) (odds ratio = 1.7, 95% CI: 0.91, 3.2), but daughters of coffee consumers did not. These suggestive findings, which merit further investigation, may be related to hormonal effects.
Key Words: Adolescent, Adult, *Alcohol Drinking/adverse effects/epidemiology, Analysis of Variance, Birth Weight, Body Mass Index, Child, *Coffee/adverse effects, Confounding Factors (Epidemiology), Female, Follow-Up Studies, *Food Habits, Humans, Least-Squares Analysis, Logistic Models, *Maternal-Fetal Exchange, *Menarche/drug effects/physiology, Pregnancy, *Prenatal Exposure Delayed Effects, Questionnaires, Research Support, U.S. Gov't, P.H.S., San Francisco/epidemiology, *Smoking/adverse effects/epidemiology, Socioeconomic Factors, *Tea/adverse effects
Polychlorinated biphenyls (PCBs) are ubiquitous man-made toxicants capable of endocrine disruption. Studies in several species have shown that exposure to PCBs and their hydroxylated metabolites reduces fecundity and decreases circulating concentrations of thyroid hormones, causing serious reproductive and developmental defects. Thyroid hormones modulate both follicular development and steroidogenesis, and affect estrogen metabolism and the regulation of estrogen receptor. This study was designed (1). to determine whether exposure to a commercially prepared PCB mixture (Aroclor 1016) exerts detrimental effects on follicle maturation in the Long-Evans hooded rat; and (2). to determine whether the modulatory effects of Aroclor can be attenuated by levo-thyroxine sodium (T(4)) supplementation. Animals were treated on gestation days 7-13 with a single daily intraperitoneal injection (2.5 mg/kg per day) of Aroclor. Half of the Aroclor-treated dams were also given T(4) supplements (2.89 microg/kg per day) via drinking water. Female pups were sacrificed on postnatal days 24/25, and the ovaries were excised, fixed for histology and analyzed. The analysis included a count, measurement and classification of healthy and atretic preantral and antral follicles in the greatest cross-sectional area. The results indicated that treatment with Aroclor significantly reduced the number of preantral follicles <50000 microm(2) and the total number of antral follicles in the 50-100000 and >100000 microm(2) size classes. T(4) circumvented the Aroclor effect on the number of preantral follicles <50000 microm(2); however, a significant reduction in the antral follicle number persisted in the 50-100000 and >100000 microm(2) size classes. In addition, we observed a significant increase in atresia in the Aroclor-treated ovaries in the antral <50000 microm(2) size class, which was not present in ovaries exposed to both Aroclor and T(4). These data support the hypothesis that Aroclor reduces the number of preantral and antral follicles of certain size classes in rats exposed during the critical period of development, and that supplementation with T(4) can attenuate the effects of Aroclor on small, but not medium or large antral follicles. Atresia of small, antral follicles may constitute one of the underlying mechanisms by which folliculogenesis is modulated by Aroclor 1016.
OBJECTIVE: To determine the relationships among seminal lead levels, acrosome status, and artificial insemination cycle fecundity (AI f) in semen donors. DESIGN: Longitudinal analysis of seminal lead levels, sperm function testing, and fecundity. SETTING: University medical center andrology and research laboratories. PATIENT(S): Semen donors (n = 15) participating in a therapeutic donor insemination program.INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Seminal plasma lead levels, acrosome sensitivity to progesterone (P) and voltage-gated potassium channel inhibitors (e.g., charybdotoxin [CBTx]), and AI f. RESULT(S): Seminal plasma lead levels and AI f were strongly negatively correlated. Semen donors were divided into three groups by acrosome response to P: normal (CBTx sensitive [Rs] or CBTx resistant [Rr]: responders) and reduced (nonresponders [NR]) (Rs > Rr >> NR). Seminal lead differed among the three groups (NR > Rr > Rs). Comparison of 330 artificial insemination cycles from four Rs, four Rr, and two NR demonstrated that cycle AI f also differed significantly between groups (Rs >Rr >>NR). CONCLUSION(S): Measurements of seminal plasma lead, P-stimulated acrosome loss, and sensitivity to CBTx may provide prognostic information on the fertility status of potential donors as well as male infertility patients. Such evaluations may assist in donor acceptance, or in the case of patients, in selection of the appropriate treatment regimen.
We found significant elevated incidence of hypospadias in two towns in Southeastern Sicily selected on the basis of the presence of intense industrial (Augusta) and agricultural (Vittoria) activities. Cases and controls were chosen in records collected from a surveillance system on abnormal live births in the same area and in a large city (Catania) located in an area at low risk of exposure to environmental pollutants. From 1991 to 1998, 16 cases of isolated hypospadias were recorded among male live births in Augusta (12.1 per 1000 male live births) and 24 cases in Vittoria (7.4 per 1000 male live births) with an incidence significantly higher than that expected (3.2 per 1000 in Southeastern Sicily). Relative risks in Augusta and Vittoria were 3.8 (95% confidence interval: 2.16-6.14) and 2.3 (95% confidence interval: 1.48-3.43; P=0.00003 and 0.04, respectively). In Augusta, the incidence of hypospadias was higher than in Vittoria. Significant log odds ratios were found for occupational exposure in fathers both in Augusta and Vittoria (P=0.0478 and 0.026, respectively). However, daily contact with pollutants in Augusta may not be sufficient by itself to determine hypospadias and other factors might be involved. Similar factors may act also in Vittoria. Thus, contact with large amounts of pesticides is, by itself, a risk factor for hypospadias, though genetic and other environmental factors might be involved.
Developing organisms have increased susceptibility to cancer if they are exposed to environmental toxicants during rapid growth and differentiation. Human studies have demonstrated clear increases in cancer after prenatal exposure to ionizing radiation, and there is suggestive evidence that brain tumors and leukemia are associated with parental exposures to chemicals. Animal experiments have demonstrated increased tumor formation induced by prenatal or neonatal exposure to a variety of chemicals, including direct-acting carcinogens and drugs. Recently, natural estrogens have been classified as known human carcinogens. Prenatal exposure to natural and synthetic estrogens is associated with increases in breast and vaginal tumors in humans as well as uterine tumors in animals. Synthetic halogenated chemicals increase liver tumors after early life-stage exposure. Recently, a prototypical endocrine-disrupting compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin, has been shown to be a developmental toxicant of the mammary gland in rodents. Dioxin alters multiple endocrine systems, and its effects on the developing breast involve delayed proliferation and differentiation of the mammary gland, as well as an elongation of the window of sensitivity to potential carcinogens. Implications of these new findings suggest that causes of endocrine-related cancers or susceptibility to cancer may be a result of developmental exposures rather than exposures existing at or near the time of tumor detection.
Prenatal pesticide exposures may adversely affect children's health. However, exposure and health research is hampered by the lack of reliable fetal exposure data. No studies have been published that report measurements of commonly used nonpersistent pesticides in human amniotic fluid, although recent studies of pesticides in urine from pregnant women and in meconium indicate that fetuses are exposed to these chemicals. Amniotic fluid collected during amniocentesis is the only medium available to characterize direct fetal exposures early in pregnancy (approximately 18 weeks of gestation). As a first step in validating this exposure biomarker, we collected 100 amniotic fluid samples slated for disposal and evaluated analytical methods to measure organophosphate and carbamate pesticides and metabolites, synthetic pyrethroid metabolites, herbicides, and chlorinated phenolic compounds. The following six phenols were detected (detection frequency): 1- and 2-naphthol (70%), 2,5-dichlorophenol (55%), carbofuranphenol (5%), ortho-phenylphenol (30%), and pentachlorophenol (15%), with geometric mean concentrations of 0.72, 0.39, 0.12, 0.13, and 0.23 microg/L, respectively, for positive values. The organophosphate metabolites diethylphosphate and dimethylphosphate were detected in two (10%) samples, and dimethylthiophosphate was detected in one (5%) sample, with geometric mean concentrations of 0.31, 0.32, and 0.43 microg/L, respectively, for positive values. These levels are low compared with levels reported in urine, blood, and meconium in other studies, but indicate direct exposures to the young fetus, possibly during critical periods of development. Results of this pilot study suggest that amniotic fluid offers a unique opportunity to investigate fetal exposures and health risks.
Key Words: Adolescent, Adult, Amniotic Fluid/*chemistry, Biological Markers/*analysis, *Environmental Exposure, Female, Humans, Pesticides/analysis/*pharmacokinetics, Phenols/*pharmacokinetics, Pregnancy, *Prenatal Exposure Delayed Effects, Reproducibility of Results, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Risk Assessment, Sensitivity and Specificity
Study Synopsis: Calculations suggest high adverse impacts of DDT use on infant mortality. Writing in Emerging Infectious Diseases, a publication of the US Centers for Disease Control, two scientists from the National Institute of Environmental Health Sciences conclude that DDT may cause an increase in infant mortality comparable to the number of infant lives that are saved when DDT is used to control malaria in Africa. They base their calculations on research that has shown associations between DDE in mothers' blood and increased risks of preterm birth and decreased length of time spent breastfeeding, both of which cause increases in infant mortality. While far from definitive, their research opens a new chapter in the international debate about whether, when and where to use DDT
Scientific abstract:
Although dichlorodiphenyl trichloroethane (DDT) is being banned worldwide, countries in sub-Saharan Africa have sought exemptions for malaria control. Few studies show illness in children from the use of DDT, and the possibility of risks to them from DDT use has been minimized. However, plausible if inconclusive studies associate DDT with more preterm births and shorter duration of lactation, which raise the possibility that DDT does indeed have such toxicity. Assuming that these associations are causal, we estimated the increase in infant deaths that might result from DDT spraying. The estimated increases are of the same order of magnitude as the decreases from effective malaria control. Unintended consequences of DDT use need to be part of the discussion of modern vector control policy.
Key Words: Africa South of the Sahara, DDT/*adverse effects/blood/therapeutic use, Female, Humans, *Infant Mortality, Infant, Newborn, Malaria/prevention & control, Milk, Human/*chemistry, Obstetric Labor, Premature/*chemically induced, Pregnancy
Bisphenol A has been shown to affect the reproduction of male rats and mice. However, the mechanism of action of bisphenol A on the epididymal sperm is not elucidated. The present study was undertaken to evaluate the effect of bisphenol A on the antioxidant system of rat epididymal sperm. Bisphenol A was administered orally to male rats at the dose levels of 0.2, 2 and 20 microg/Kg body weight per day for 45 days. After 24 h of the last treatment, rats were weighed and killed using anesthetic ether. The body weight of treated rats did not show significant change as compared with the corresponding control groups. In bisphenol A-treated rats there was a significant decrease in the weight of the testis and epididymis; the weight of ventral prostate increased significantly whereas there was no significant change in the weight of seminal vesicles as compared with the corresponding group of control animals. Sperm collected from the epididymis were used for sperm count and biochemical estimations. Administration of bisphenol A caused a reduction in the epididymal sperm motility and sperm count in a dose-dependent manner. The activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase were decreased while the levels of H(2)O(2) and lipid peroxidation increased significantly in the treated rats as compared with the corresponding group of control animals. The results suggested that graded doses of bisphenol A elicit depletion of antioxidant defence system and induce oxidative stress in epididymal sperm of rats. In conclusion, the adverse effect of bisphenol A on male reproduction may be due to induction of oxidative stress in sperm.
BACKGROUND: Emerging evidence suggests a potential role for ubiquitous environmental contaminants in the physiopathology of endometriosis. Di-(2-ethylhexyl)-phthalate (DEHP), the most commonly used plasticizer in flexible polyvinylchloride (PVC) formulations, is a widespread environmental contaminant with potentially adverse effects on fertility in animal models. In the present study, we tested the hypothesis that DEHP and/or and its main metabolite, mono-ethylhexyl phthalate (MEHP), play a role in the pathogenesis of endometriosis. METHODS: Specimens of blood and peritoneal fluid were collected in a group of women with endometriosis (n = 55), and in age-matched control women (n = 24). Concentrations of DEHP and MEHP were measured in plasma and peritoneal fluid by using high performance liquid chromatography (HPLC). Differences between groups were tested using the Fisher's exact test, Wilcoxon-test, and Kruskal-Wallis analysis of variance. RESULTS: Endometriotic women showed significantly higher plasma DEHP concentrations than controls (median 0.57 micro g/ml, interquartile range: 0.06-1.23; values range: 0-3.24 versus median 0.18 micro g/ml, interquartile range: 0-0.44; values range: 0-1.03; P = 0.0047) and 92.6% of them had detectable DEHP and /or MEHP in the peritoneal fluid. No significant differences in either the DEHP/MEHP plasma concentrations (P >/= 0.31) or DEHP/MEHP peritoneal fluid concentrations (P >/= 0.66) were observed in the endometriotic patients as a function of the disease stage at the time of diagnosis. CONCLUSIONS: The present findings showed for the first time an association between DEHP plasma concentrations and endometriosis, suggesting a possible role for phthalate esters in the pathogenesis.
Reproductive-tract anomalies after administration of the potent oestrogen, diethylstilboestrol, in pregnant women raised concerns about the reproductive effects of exposure to weakly oestrogenic environmental contaminants such as bis[4-chlorophenyl]-1,1,1-trichloroethane (p,p'-DDT) or its metabolites, such as bis[4-chlorophenyl]-1,1-dichloroethene (p,p'-DDE). We measured p,p'-DDT and p,p'-DDE in preserved maternal serum samples drawn 1-3 days after delivery between 1960 and 1963. We recorded time to pregnancy in 289 eldest daughters 28-31 years later. Daughters' probability of pregnancy fell by 32% per 10 microg/L p,p'-DDT in maternal serum (95% CI 11-48). By contrast, the probability of pregnancy increased 16% per 10 microg/L p,p'-DDE (6-27). The decreased fecundability associated with prenatal p,p'-DDT remains unexplained. We speculate that the antiandrogenic activity of p,p'-DDE may mitigate harmful androgen effects on the ovary during gestation or early life. The study by Cohn et al. is the first piece of scientific evidence that DDT can exert long-term reproductive effects in the female offspring of exposed women. The findings support the controversial theory that environmental exposure to pesticides and other contaminants that mimic sex hormones might be contributing to human infertility.
The aim of this study was to evaluate the influence of maternal exposure to pesticides in the 1st and 2nd trimesters of pregnancy on infant birthweight in a population of Polish farmers. The subjects were women who delivered in 25 maternity hospitals in the region of Lodz (Central Poland), including 117 women who delivered infants with low birthweight (LBW) and 377 infants with birthweight > or = 2500 g delivered on randomly selected 70 days between 31 January 1998 and 30 June 2001. A questionnaire on maternal demographic and anthropometric characteristics as well as the occurrence of several occupational hazards, including pesticide use and involvement in heavy physical work on the farm in each of pregnancy trimesters, was administered by a physician 1-2 days after delivery. The pesticides used most frequently included: phenoxyacetic acid derivatives, organophosphates, ureas, triazines, synthetic pyrethroids and N-phenylamides (anilides). Infants born to women exposed to pesticides in 1st or 2nd trimester had birthweight lower by 189 g than that of infants of the non-exposed women. When adjusted for pregnancy duration, the women exposed to pesticides were found to deliver infants with birthweight lower by about 100 g (p = 0.067) than that of infants of the non-exposed women. After adjusting for the variables that may have impact on pregnancy duration, we noted that mothers exposed to pesticides, on average delivered half a week earlier than those non-exposed. Our results indicate that maternal exposure to pesticides may contribute to a slight reduction in the duration of pregnancy. A slower pace of fetal development, corresponding to the small-for-gestational-age effect, was observed, but the increment in the risk was of borderline significance.
Inuit inhabitants of Nunavik (northern Quebec, Canada) consume great quantities of marine food and are therefore exposed to high doses of food chain contaminants. In this study, we report the time trends of persistent organic pollutants, mercury, and lead in umbilical cord blood of infants from three communities of the east coast of Hudson Bay in Nunavik. We analyzed 251 cord blood samples collected from 1994 through 2001 for polychlorinated biphenyls (PCBs), dichlorodiphenyl trichloroethane (DDT), dichlorodiphenyl dichloroethylene (DDE), hexachlorobenzene (HCB), chlordanes, lead, and mercury. Using an exponential model, we found strongly significant decreasing trends for PCBs (7.9% per year, p < 0.001), DDE (9.1% per year, p < 0.001), DDT (8.2% per year, p < 0.001), and HCB (6.6% per year, p < 0.01). No significant trends were detected for chlordanes. A significant reduction of lead and mercury concentrations was found, but there was no clear linear or exponential trend. The decreases observed could be explained by a decrease in food contamination, by changes in dietary habits, or, most likely, by a combination of both.
BACKGROUND: There is scientific and public concern about commonly used chemicals, including phthalates, that are associated with reproductive toxicity in laboratory animals and are hormonally active. People are exposed to phthalates through diet, consumer products and medical devices. The present study explored whether environmental levels of phthalates are associated with altered semen quality in humans. METHODS: We recruited 168 men who were part of subfertile couples and who presented to the Massachusetts General Hospital andrology laboratory for semen analysis between January 2000 and April 2001. Semen parameters were dichotomized based on 1999 World Health Organization reference values for sperm concentration (< 20 million/ml) and motility (< 50% motile), as well as Tygerberg Strict criteria for morphology (< 4% normal). The comparison group was men for whom these semen parameters were all above the reference values. In urine, eight phthalate metabolites were measured with high-performance liquid chromatography and tandem mass spectrometry. Specific gravity-adjusted phthalate metabolite levels were categorized into tertiles. RESULTS: There was a dose-response relation between tertiles of mono-butyl phthalate and sperm motility (odds ratio per tertile = 1.0, 1.8, 3.0; P-value for trend = 0.02) and sperm concentration (1.0, 1.4, 3.3; P-value for trend = 0.07). In addition, there was a dose-response relation between tertiles of mono-benzyl phthalate and sperm concentration (1.0, 1.4, 5.5; P-value for trend = 0.02). CONCLUSIONS: There were dose-response relations for monobutyl phthalate and monobenzyl phthalate with one or more semen parameters, and suggestive evidence for monomethyl phthalate with sperm morphology. The lack of a relation for other phthalates may indicate a difference in spermatotoxicity among phthalates.
2,3,7,8-Tetrachlorodibenzo-(italic)para(/italic)-dioxin (TCDD), a ubiquitous environmental contaminant, is associated with increased fetal loss and reduced birth weight in animal studies. In 1976, an explosion at a trichlorophenol plant near Seveso, Italy, resulted in the highest TCDD exposure known in human residential populations. In 1996, we initiated the Seveso Women's Health Study, a retrospective cohort study of women who resided in the most contaminated areas, zones A and B. We examined the relation of pregnancy outcome in 510 women (888 total pregnancies) to maternal TCDD levels measured in serum collected shortly after the explosion. Ninety-seven pregnancies (10.9%) ended as spontaneous abortions (SABs). There was no association of log(subscript)10(/subscript) TCDD with SAB [adjusted odds ratio (OR) = 0.8; 95% confidence interval (CI), 0.6-1.2], with birth weight (adjusted beta = -4 g; 95% CI, -68 to 60), or with births that were small for gestational age (SGA) (adjusted OR = 1.2; 95% CI, 0.8-1.8). However, associations with birth weight (adjusted beta = -92 g; 95% CI, -204 to 19) and with SGA (adjusted OR = 1.4; 95% CI, 0.6-2.9) were stronger for pregnancies within the first 8 years after exposure. TCDD was associated with a 1.0-1.3 day nonsignificant adjusted decrease in gestational age and a 20-50% nonsignificant increase in the odds of preterm delivery. It remains possible that the effects of TCDD on birth outcomes are yet to be observed, because the most heavily exposed women in Seveso were the youngest and the least likely to have yet had a pregnancy.
Key Words: Abortion, Spontaneous/chemically induced, Adult, Chemical Industry, Cohort Studies, Environmental Exposure/*adverse effects, Explosions, Female, Humans, Italy, Maternal Exposure/*adverse effects, Pregnancy, *Pregnancy Outcome, Prenatal Exposure Delayed Effects, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Tetrachlorodibenzodioxin/*blood/poisoning
BACKGROUND: Trihalomethanes (THMs) are byproducts of drinking water chlorination whose effects on semen quality have not been previously studied in humans. METHODS: We examined the relationship of THMs to semen quality in 157 healthy men from couples without known risk factors for infertility. Total THM (TTHM) levels were assigned based on water utility measurements taken during the 90 days preceding semen collection. We analyzed continuous semen parameters in relation to total and individual THMs, adjusting for potential confounders by using repeated measures analyses. RESULTS: TTHM level was not associated with decrements in semen quality. Percent normal morphology decreased and percent head defects increased at higher levels of an ingestion metric (TTHM multiplied by cold home tap water consumption). At the highest level of the ingestion metric (>160 mug/L x glasses/day, which is equivalent to >2 glasses/day of water containing 80 mug/L) we observed a difference of -7.1 (95% confidence interval = -12.7 to -1.6) for percent morphologically normal sperm compared with the lowest level (Key Words: Adolescent, Adult, California, Chlorine/chemistry, Female, Humans, Male, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., *Semen/drug effects, Sperm Motility/drug effects, Trihalomethanes/*analysis, Water Pollutants, Chemical/*analysis, Water Supply/*analysis
BACKGROUND: The disorders comprising human 'testicular dysgenesis syndrome' (TDS) may be increasing in incidence. TDS originates in fetal life but the mechanisms are not known, and discerning them requires an animal model. METHODS AND RESULTS: The study investigated whether male rats exposed in utero to dibutyl phthalate [DBP; 500 mg/kg on gestational days (GD) 13-21] would provide a suitable model for human TDS. DBP induced a high rate (>60%) of cryptorchidism (mainly unilateral), hypospadias, infertility and testis abnormalities, similar to those in human TDS. Cell-specific immunohistochemistry and confocal microscopy were used to track development of Sertoli [anti-Mullerian hormone (AMH), Wilm's tumour (WT-1) protein, p27(kip)], Leydig [3beta-hydroxysteroid dehydrogenase (3beta-HSD)], germ (DAZL protein) and peritubular myoid (smooth muscle actin) cells from fetal life to adulthood. In scrotal and cryptorchid testes of DBP-exposed males, areas of focal dysgenesis were found that contained Sertoli and Leydig cells, and gonocytes and partially formed testicular cords; these dysgenetic areas were associated with Leydig cell hyperplasia at all ages. Suppression ( approximately 90%) of testicular testosterone levels on GD 19 in DBP-exposed males, coincident with delayed peritubular myoid cell differentiation, may have contributed to the dysgenesis. Double immunohistochemistry using WT-1 (expressed in all Sertoli cells) and p27(kip) (expressed only in mature Sertoli cells) revealed immature Sertoli cells in dysgenetic areas. DBP-exposed animals also exhibited Sertoli cell-only (SCO) tubules, sporadically in scrotal and predominantly in cryptorchid, testes, or foci of SCO within normal tubules in scrotal testes. In all SCO areas the Sertoli cells were immature. Intratubular Leydig cells were evident in DBP-exposed animals and, where these occurred, Sertoli cells were immature and spermatogenesis was absent. Abnormal Sertoli cell-gonocyte interaction was evident at GD 19 in DBP-exposed rats coincident with appearance of multinucleated gonocytes, although these disappeared by postnatal day 10 during widespread loss of germ cells. CONCLUSIONS: Abnormal development of Sertoli cells, leading to abnormalities in other cell types, is our hypothesized explanation for the abnormal changes in DBP-exposed animals. As the testicular and other changes in DBP-exposed rats have all been reported in human TDS, DBP exposure in utero may provide a useful model for defining the cellular pathways in TDS.
There is increasing concern among Canadian women that unwitting and unwanted exposures to environmental contaminants are adversely affecting their health, particularly their ability to become pregnant and have a healthy baby. Evidence of adverse reproductive outcomes among populations exposed to environmental contaminants in the workplace via accidental poisoning, together with detection of environmental contaminant residues in serum and ovarian follicular fluid, has led to the hypothesis that chemical contaminants may be contributing to adverse reproductive outcomes such as infertility, endometriosis, polycystic ovary syndrome, spontaneous abortion, preterm labour, intrauterine growth restriction, and pregnancy-induced hypertension in the general population. The lack of clear evidence concerning the association between exposure to environmental contaminants and adverse reproductive outcomes hampers the clinician's ability to counsel women who are trying to conceive or who have concerns about their pregnancy. This review summarizes the evidence linking environmental contaminant exposure to selected adverse health outcomes by examining the changes in health-outcome trends, the consistency of the epidemiological evidence of an association between the health outcome of concern and exposure to environmental contaminants, and the biological plausibility for environmental contaminant mediated effects on human reproductive health. At best, only a moderate association can be found linking exposure to environmental contaminants with evidence of deleterious reproductive effects in women. Lack of disease trend data, weak exposure assessments, and limited mechanistic data supporting the biological plausibility of potential effects are the primary limitations to the hypothesis that exposure to environmental contaminants adversely affects human reproductive physiology.
Globally there is increasing concern that the environment is having a negative impact on human health. Hormone-like activity and endocrine toxicity of environmental toxicants have been documented in the contemporary literature raising concern that exposure to these chemicals could alter human reproductive function and affect fertility. In addition, epidemiological reports of an association between exposure to chemical toxicants in the workplace and adverse reproductive outcomes together with detection of environmental toxicant residues in serum and ovarian follicular fluid, has led to widespread concern that chemical contaminants may be a contributing factor in the pathobiology of idiopathic infertility in the general population. While the epidemiological evidence is equivocal, animal studies provide biological plausibility for a potential association between environmental toxicant exposures and altered reproductive function. Furthermore, cell and organ culture experiments illustrate potential mechanisms of toxicant action on the reproductive system. This review summarizes the evidence linking environmental toxicant exposure and infertility and examines the biological plausibility for this association.
Study Synopsis: Risks of infertility higher in women using herbicides and fungicides. A study comparing infertile and fertile women in Wisconsin finds that women who were infertile were 27 times more likely to have mixed or applied herbicides in the two years prior to attempting conception than women who were fertile. The weight of animal and human evidence now clearly indicates that risks of infertility rise in association with current uses of agricultural chemicals
Scientific abstract:
BACKGROUND: Recent studies have suggested that agricultural occupations or exposure to pesticides may impair female fertility. METHODS: The Fertility Risk Factor Study retrospectively examined agricultural and residential exposures and the risk of female infertility. Cases and controls (N = 322 each) came from women who sought treatment at a large group medical clinic in Wisconsin. Women and their male partners provided information on health, occupational and lifestyle exposures in response to a telephone interview during 1997-2001. RESULTS: Mixing and applying herbicides 2 years before attempting conception was more common among infertile women (odds ratio [OR] = 27; 95% confidence interval [CI] = 1.9-380), as was the use of fungicides (OR = 3.3; CI = 0.8-13). Residing on a farm, ranch or in a rural area during this time period was protective of female fertility. Households supplied with central Wisconsin groundwater were at less risk for infertility than households using municipal sources (OR = 0.6; CI = 0.4-0.9). Behavioral risk factors included alcohol consumption (OR = 1.8; 1.2-2.5), smoking (1.6; 0.9-2.9), passive smoke exposure (1.8; 1.2-2.5), steady weight gain in adult life (3.5; 2.0-6.1), and having a male partner over the age of 40 (4.5; 1.2-16.3). Drinking 3 or more glasses of milk per day was protective of female fertility (0.3; 0.1-0.7). CONCLUSION: These results suggest that certain agricultural, residential and lifestyle choices may modify the risk of female infertility.
Key Words: Adult, Age Factors, *Agriculture, Alcohol Drinking/adverse effects, Case-Control Studies, Diet, Female, Human, Infertility, Female/epidemiology/*etiology, Life Style, Male, Pesticides/*poisoning, Retrospective Studies, Risk Factors, Rural Population, Support, Non-U.S. Gov't, Support, U.S. Gov't, P.H.S., Tobacco Smoke Pollution/adverse effects, Water Supply, Weight Gain, Wisconsin/epidemiology
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and related polyhalogenated aromatic hydrocarbons (PHAHs) alter the reproductive development of laboratory animals. Therefore, we exposed animals to a mixture of dioxins, furans, and polychlorinated biphenyls (PCBs) that included TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzofuran (1-PeCDF), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), octachlorodibenzofuran (OCDF), 3,3',4,4'-tetrachlorobiphenyl (PCB77), 3,3',4,4',5-pentachlorobiphenyl (PCB126), and 3,3',4,4',5,5'-hexachlorobiphenyl (PCB169). The mixture composition approximated the relative abundance of these compounds in foodstuff (L. S. Birnbaum and M. J. DeVito, 1995, Toxicology Vol. 105, pp. 391-401). Following the work of Gray et al. with TCDD (1997, Toxicology and Applied Pharmacology Vol. 146, pp. 11-20), we exposed time-pregnant dams on gestation day (GD) 15 at doses up to 1.0 microgram TCDD toxic equivalency (TEQ)/kg and the development of offspring was monitored. This mixture significantly increased the time to puberty in both male and female offspring. At postnatal day (PND) 32 seminal vesicle weights were decreased; however, only ventral prostate weight was affected at PND 49 and no effects were seen at PND 63. In female offspring, the mixture caused dose-dependent increases in the incidence of vaginal thread. Ethoxyresorufin-O-deethylase (EROD) activity was higher than with TCDD the comparable TEQ exposure. Based on the slightly lowered responsiveness to the mixture, we used 2.0 microgram TEQ/kg to examine reproductive effects. This dose elicited the responses observed with 1.0 microgram TCDD/kg. Results indicate that the mixture causes a similar spectrum of effects seen with TCDD and the slightly lowered degree of response based on administered dose appears to be due to decreased transfer of mixture components to the offspring. Thus, the use of the WHO consensus TEFs (M. Van den Berg et al., 1998, Environ. Health Perspec. 106, 775-792) reasonably predicts the developmental toxicity of this mixture of dioxin-like PHAHs.
Key Words: Abnormalities, Drug-Induced/pathology, Animals, Birth Weight/drug effects, Body Weight/drug effects, Cytochrome P-450 CYP1A1/biosynthesis/genetics, Dioxins/pharmacokinetics/*toxicity, Dose-Response Relationship, Drug, Female, Furans/pharmacokinetics/*toxicity, Genitalia, Male/drug effects/growth & development, Litter Size/drug effects, Male, Microsomes, Liver/drug effects/enzymology, Organ Size/drug effects, Placenta/drug effects/enzymology, Polychlorinated Biphenyls/pharmacokinetics/*toxicity, Pregnancy, Rats, Rats, Long-Evans, Reproduction/*drug effects, Research Support, U.S. Gov't, Non-P.H.S., Sex Characteristics, Sexual Maturation/drug effects, Sperm Count, Tissue Distribution
Study Synopsis: Man's risk of testicular cancer related to mother's organochlorine levels. Although testicular cancer is a disease primarily of young adulthood, growing evidence points to developmental failure in the fetal testis as its principal origin. A number of factors have been suggested as possible causes of this developmental failure, including endocrine disrupting chemicals. In this paper, Hardell et al. report a strong association between testicular cancer risk for a man and the levels of organochlorines in his mother's serum. They found only a limited link between OCs in the man's own blood and the likelihood of developing testicular cancer.
Scientific abstract:
An increasing incidence of testicular cancer has been reported from several countries in the Western world during the last decades. According to current hypothesis, testicular cancer is initiated during the fetal period, and exposure to endocrine disruptors, i.e., xenoestrogens, has been of concern. In this investigation we studied the concentrations of the sum of 38 polychlorinated biphenyls (PCBs), p,p'-dichlorodiphenyl-dichloroethylene, hexachlorobenzene (HCB), and chlordanes, in 61 cases with testicular cancer and 58 age-matched controls. Furthermore, case and control mothers were also asked to participate, and 44 case mothers and 45 control mothers agreed. They were of similar age. In cases only the concentration on lipid basis of cis-nonachlordane was significantly increased, whereas case mothers showed significantly increased concentrations of the sum of PCBs, HCB, trans- and cis-nonachlordane, and the sum of chlordanes. Among case mothers the sum of PCBs yielded an odds ratio (OR) of 3.8; 95% confidence interval (CI), 1.4-10 was calculated using the median concentration for the control mothers as cutoff value. For HCB, OR = 4.4 (95% CI, 1.7-12); for trans-nonachlordane, OR = 4.1 (95% CI, 1.5-11); for cis-nonachlordane, OR = 3.1 (95% CI, 1.2-7.8); and for sum of chlordanes, OR = 1.9 (95% CI, 0.7-5.0). No consistent different risk pattern was found for seminoma or nonseminoma testicular cancer.
Scientific and public concern exists about potential reproductive health effects of persistent chlorinated organic chemicals, such as polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE, the most stable daughter compound of DDT). To explore the hypothesis that environmental exposures to PCBs and DDE are associated with altered semen parameters, we conducted a cross-sectional study of 212 male partners of subfertile couples who presented to the Massachusetts General Hospital Andrology Laboratory. Semen parameters were analyzed as both a continuous measure and dichotomized based on World Health Organization reference values for sperm concentration (< 20 million/mL), motility (< 50% motile), and Kruger strict criteria for morphology (< 4% normal). The comparison group for the dichotomized analysis was men with all three semen parameters above the reference values. In serum, 57 PCB congeners and p,p -DDE were measured by congener-specific analysis using gas chromatography with electron capture detection. There were dose-response relationships among PCB-138 and sperm motility (odds ratio per tertile, adjusted for age, abstinence, and smoking, and p-value for trend were, respectively, 1.00, 1.68, 2.35, and p-value = 0.03) and morphology (1.00, 1.36, 2.53, p-value = 0.04). There was limited evidence of an inverse relationship between sum of PCBs, as well as those PCBs classified as cytochrome P450 enzyme inducers, with sperm motility and sperm morphology, as well as limited evidence of an inverse association between p,p -DDE and sperm motility. The lack of a consistent relationship among semen parameters and other individual PCB congeners and groupings of congeners may indicate a difference in spermatotoxicity between congeners.,
Study Synopsis: Bisphenol A speeds puberty in mice. Howdeshell et al. found that when female mice are exposed in the womb by delivering low doses of bisphenol A through food to the mother that the female mice pass a milestone in sexual development significantly earlier than do unexposed mice.
Scientific abstract:
Bisphenol A (BPA) is a monomer with estrogenic activity that is used in the production of food packaging, dental sealants, polycarbonate plastic, and many other products. The monomer has previously been reported to hydrolyze and leach from these products under high heat and alkaline conditions, and the amount of leaching increases as a function of use. We examined whether new and used polycarbonate animal cages passively release bioactive levels of BPA into water at room temperature and neutral pH. Purified water was incubated at room temperature in new polycarbonate and polysulfone cages and used (discolored) polycarbonate cages, as well as control (glass and used polypropylene) containers. The resulting water samples were characterized with gas chromatography/mass spectrometry (GC/MS) and tested for estrogenic activity using an MCF-7 human breast cancer cell proliferation assay. Significant estrogenic activity, identifiable as BPA by GC/MS (up to 310 micro g/L), was released from used polycarbonate animal cages. Detectable levels of BPA were released from new polycarbonate cages (up to 0.3 micro g/L) as well as new polysulfone cages (1.5 micro g/L), whereas no BPA was detected in water incubated in glass and used polypropylene cages. Finally, BPA exposure as a result of being housed in used polycarbonate cages produced a 16% increase in uterine weight in prepubertal female mice relative to females housed in used polypropylene cages, although the difference was not statistically significant. Our findings suggest that laboratory animals maintained in polycarbonate and polysulfone cages are exposed to BPA via leaching, with exposure reaching the highest levels in old cages.
Key Words: Animals, *Animals, Laboratory, Biological Assay, Breast Neoplasms/pathology, *Environmental Exposure, Estrogens, Non-Steroidal/*analysis/chemistry, Female, *Housing, Animal, Humans, Mass Fragmentography, Mice, Phenols/*analysis/chemistry, Reproducibility of Results, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Solubility, Temperature, Tumor Cells, Cultured, Uterus/anatomy & histology, Water/chemistry
Study Synopsis: Aneuploidy in mice linked to exposure to bisphenol a in the womb. This research links a common contaminant, bisphenol A, to an error in cell division called aneuploidy that causes spontaneous miscarriages and birth defects in people, including Down Syndrome, and is also associated with a series of cancers. Hunt et al. report that in mice, bisphenol A causes aneuploidy even at extremely low doses.
Scientific abstract:
BACKGROUND: There is increasing concern that exposure to man-made substances that mimic endogenous hormones may adversely affect mammalian reproduction. Although a variety of reproductive complications have been ascribed to compounds with androgenic or estrogenic properties, little attention has been directed at the potential consequences of such exposures to the genetic quality of the gamete.RESULTS: A sudden, spontaneous increase in meiotic disturbances, including aneuploidy, in studies of oocytes from control female mice in our laboratory coincided with the accidental exposure of our animals to an environmental source of bisphenol A (BPA). BPA is an estrogenic compound widely used in the production of polycarbonate plastics and epoxy resins. We identified damaged caging material as the source of the exposure, as we were able to recapitulate the meiotic abnormalities by intentionally damaging cages and water bottles. In subsequent studies of female mice, we administered daily oral doses of BPA to directly test the hypothesis that low levels of BPA disrupt female meiosis. Our results demonstrated that the meiotic effects were dose dependent and could be induced by environmentally relevant doses of BPA. CONCLUSIONS: Both the initial inadvertent exposure and subsequent experimental studies suggest that BPA is a potent meiotic aneugen. Specifically, in the female mouse, short-term, low-dose exposure during the final stages of oocyte growth is sufficient to elicit detectable meiotic effects. These results provide the first unequivocal link between mammalian meiotic aneuploidy and an accidental environmental exposure and suggest that the oocyte and its meiotic spindle will provide a sensitive assay system for the study of reproductive toxins.
Study Synopsis: Bisphenol A (often abbreviated BPA) is a chemical used in clear, solid plastic products such as baby and water bottles as well as in medical devices, dental fillings and the inner lining of food and beverage cans. Human exposure to BPA is widespread. This landmark study was prompted by observations of abnormalities in the genetic material of mice eggs after plastic cages and water bottles were cleaned with the wrong product. Researchers show that the abnormalities, were due to leaching of BPA from the plastic and reproduced the same effects by directly exposing mice to low doses of BPA. The chromosomal abnormalities included abnormal quantities of chromosomes in eggs, which is an important cause of miscarriage.
Scientific abstract:
BACKGROUND: There is increasing concern that exposure to man-made substances that mimic endogenous hormones may adversely affect mammalian reproduction. Although a variety of reproductive complications have been ascribed to compounds with androgenic or estrogenic properties, little attention has been directed at the potential consequences of such exposures to the genetic quality of the gamete. RESULTS: A sudden, spontaneous increase in meiotic disturbances, including aneuploidy, in studies of oocytes from control female mice in our laboratory coincided with the accidental exposure of our animals to an environmental source of bisphenol A (BPA). BPA is an estrogenic compound widely used in the production of polycarbonate plastics and epoxy resins. We identified damaged caging material as the source of the exposure, as we were able to recapitulate the meiotic abnormalities by intentionally damaging cages and water bottles. In subsequent studies of female mice, we administered daily oral doses of BPA to directly test the hypothesis that low levels of BPA disrupt female meiosis. Our results demonstrated that the meiotic effects were dose dependent and could be induced by environmentally relevant doses of BPA. CONCLUSIONS: Both the initial inadvertent exposure and subsequent experimental studies suggest that BPA is a potent meiotic aneugen. Specifically, in the female mouse, short-term, low-dose exposure during the final stages of oocyte growth is sufficient to elicit detectable meiotic effects. These results provide the first unequivocal link between mammalian meiotic aneuploidy and an accidental environmental exposure and suggest that the oocyte and its meiotic spindle will provide a sensitive assay system for the study of reproductive toxins.
In the epidemiologic study of reproductive capacity, the assessment of fecundity as a functional measure is complementary to approaches that focus on biomedical mechanisms and/or that use biomarkers such as semen quality. More research is needed on time trends, spatial patterns, and particular groups, especially those exposed to potentially toxic agents. Although specific research projects will always be important, much could be gained by general population surveillance, which could be introduced into existing multipurpose surveys and repeated periodically. The core measurement would be time to pregnancy, which can be carried out using a short, acceptable questionnaire that has good validity at the group level. This should be accompanied by questions on time periods of unprotected intercourse that do not end with conception, to avoid bias resulting from exclusion of relatively infertile couples. Information is also required on contraceptive failures, recent contraceptive use, and other covariates and possibly on behavioral variables, such as the degree of planning and persistence in trying to conceive, and couples' knowledge of fertile days of the menstrual cycle. Existing statistical methods can deal with possible biases due to "accidental" pregnancies and the effects of fertility treatment. Further methodological work is needed to avoid or measure more subtle biases, for example, to determine the best way to deal with pregnancies occurring to couples whose approach to family formation is relaxed, for whom the concept of "pregnancy planning" does not apply.
Key Words: Female, *Fertility, Humans, Infertility/therapy, Male, Population Surveillance/*methods, Questionnaires, Time Factors
Research notes: Comment in Am J Epidemiol. 2003 Jan 15;157(2):94-7.
Study Synopsis: Cadmium provokes estrogenic responses at extremely low levels of exposure. Research published in Nature Medicine reveals that cadmium provokes estrogenic responses in rats at levels much less than 1% of those traditionally used in toxicological studies. The effects include alterations in the uterus and mammary gland, increases in estrogen-controlled gene expression, and, following exposure in the womb, increases in adult weight and the speed of reaching sexual maturity. The authors call for more research on links between breast cancer and cadmium exposure.
Scientific abstract:
It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.
Genomic imprinting is a system of non-Mendelian inheritance that is unique to mammals. Two types of imprinted genes show parent-of-origin-specific expression patterns: the paternally expressed genes (Pegs), and the maternally expressed genes (Megs). Parental genomic imprinting memory is maintained in the somatic cell lineage and regulates the expression of Pegs and Megs, while it is erased and re-established in the germ cell lineage according to the sex of the individual. The paternal and maternal imprinting mechanisms, which regulate different sets of Pegs and Megs, are essential for establishing the parental expression profiles of imprinted genes that are observed in sperms and eggs. Based on recent evidence, we outline the relationship between parental imprinting and the expression profiles of Pegs and Megs and discuss a novel view of the regulation of genomic imprinting. We also discuss the biological significance of genomic imprinting and propose hypotheses on the essential nature of genomic imprinting and the close relationship between genomic imprinting and the acquisition of placental tissues during mammalian evolution.
Study Synopsis: Phthalate linked to preterm birth. A study from Italy finds that not only are DEHP and MEHP detectable in most Italian newborns, but that those with higher levels of MEHP are more likely to be born prematurely. This result suggests that at least some of the scientific effort to understand why the incidence of premature birth in the US has increased 23% since the early 1980's should focus on environmental contaminants in the womb, and specifically on phthalates.
Scientific abstract:
Di-(2-ethylhexyl)phthalate (DEHP), the most commonly used plasticizer in flexible polyvinylchloride formulations, is a ubiquitous environmental contaminant. To date, no information exists on the potential health hazards from exposure to DEHP and/or its main metabolite, mono-(2-ethylhexyl)phthalate (MEHP), in high-risk conditions, such as pregnancy and during the neonatal period. The aim of this study was to evaluate prenatal exposure to DEHP and/or MEHP and its possible biologic effects. We measured serum DEHP and MEHP concentrations in the cord blood of 84 consecutive newborns by high-performance liquid chromatography. Relationships between DEHP/MEHP and infant characteristics were tested using Fisher's exact test, unpaired t-tests, and univariate linear regression analyses, and significant differences on univariate analysis were evaluated using multiple logistic regression analysis. We found detectable cord blood DEHP and/or MEHP concentrations in 88.1% of the samples. Either DEHP or MEHP was present in 65 of 84 (77.4%) of the examined samples. Mean concentrations of DEHP and MEHP were 1.19 +/- 1.15 microg/mL [95% confidence interval (CI), 0.93-1.44, range = 0-4.71] and 0.52 +/- 0.61 microg/mL (95% CI, 0.39-0.66, range = 0-2.94), respectively. MEHP-positive newborns showed a significantly lower gestational age compared with MEHP-negative infants (p = 0.033). Logistic regression analysis results indicated a positive correlation between absence of MEHP in cord blood and gestational age at delivery (odds ratio = 1.50, 95% CI, 1.013-2.21; p = 0.043). These findings confirm that human exposure to DEHP can begin in utero and suggest that phthalate exposure is significantly associated with a shorter pregnancy duration.
There is a significant public health concern about the potential effects of occupational exposure to toxic substances on reproductive outcomes. Several toxicants with reported reproductive and developmental effects are still in regular commercial or therapeutic use and thus present potential exposure to workers. Examples of these include heavy metals, organic solvents, pesticides and herbicides, and sterilants, anesthetic gases, and anticancer drugs used in health care. Many other substances are suspected of producing reproductive or developmental toxicity but lack sufficient data. Progress has been limited in identifying hazards and quantifying their potencies and in separating the contribution of these hazards from other etiologic factors. Identifying the causative agents, mechanisms by which they act, and any potential target populations, present the opportunity to intervene and protect the reproductive health of workers. The pace of laboratory studies to identify hazards and to underpin the biologic plausibility of effects in humans has not matched the pace at which new chemicals are introduced into commerce. Though many research challenges exist today, recent technologic and methodologic advances have been made that allow researchers to overcome some of these obstacles. The objective of this article is to recommend future directions in occupational reproductive health research. By bridging interdisciplinary gaps, the scientific community can work together to improve health and reduce adverse outcomes.
Phthalates are high-production-volume synthetic chemicals with ubiquitous human exposures because of their use in plastics and other common consumer products. Recent epidemiologic evidence suggests that women have a unique exposure profile to phthalates, which raises concern about the potential health hazards posed by such exposures. Research in our laboratory examines how phthalates interact with the female reproductive system in animal models to provide insights into the potential health effects of these chemicals in women. Here we review our work and the work of others studying these mechanisms and propose a model for the ovarian action of di-(2-ethylhexyl) phthalate (DEHP). In vivo, DEHP (2 g/kg) causes decreased serum estradiol levels, prolonged estrous cycles, and no ovulations in adult, cycling rats. In vitro, monoethylhexyl phthalate (MEHP; the active metabolite of DEHP) decreases granulosa cell aromatase RNA message and protein levels in a dose-dependent manner. MEHP is unique among the phthalates in its suppression of aromatase and in its ability to activate peroxisome proliferator-activated receptors (PPARs). We hypothesize that MEHP activates the PPARs to suppress aromatase in the granulosa cell. MEHP-, PPAR alpha-, and PPAR gamma-specific ligands all similarly decreased estradiol production and RNA message levels of aromatase in vitro. Our model shows that MEHP acts on the granulosa cell by decreasing cAMP stimulated by follicle stimulating hormone and by activating the PPARs, which leads to decreased aromatase transcription. Thus, the environmental contaminant DEHP, through its metabolite MEHP, acts through a receptor-mediated signaling pathway to suppress estradiol production in the ovary, leading to anovulation.
Polybrominated Diphenyl Ethers in Maternal and Fetal Blood Samples. concentrations of total PBDEs in maternal sera ranged from 15-580 ng/g lw, fetal samples ranged from 14-460 ng/g lw. There is a high correlation b/w PBDE in mothers milk and fetal exposure. In this study there was no correlation b/w serum PBDEs and thyroid hormone concentrations.
Our previous studies analyzing umbilical cords show that human fetuses in Japan are exposed to multiple chemicals. Because of these findings, we believe it is necessary to establish a new strategy for examining the possible delayed long-term effects caused by prenatal exposure to multiple chemical combinations and evaluating the health risk to human fetuses. In this commentary we describe our attempts to apply toxicogenomic analysis of umbilical cords, using DNA microarray for future risk assessment. Because the umbilical cord is part of the fetal tissue, it is possible to estimate the effects of chemicals on the fetus by analyzing alteration of the gene expression. This type of toxicogenomic analysis could be a powerful and effective tool for developing a new risk assessment strategy to help investigators understand and possibly prevent long-term effects caused by fetal exposure to multiple chemicals. Worldwide cooperation is needed to establish a new stragegy for risk assessment using toxicogenomic analysis that focuses on the human fetus.
A number of investigators have pointed to the possibility of a secular decline in human fecundity due to changes in sperm concentration. It is unlikely that any historical trends will be definitively quantified, but a good case can be made for more precise monitoring of this phenomenon in the future. Such monitoring would be justified on the grounds of the importance of early detection of environmental effects on the capacity of humans to reproduce. Establishing a surveillance system that will be sensitive enough to detect changes in fecundity over time is, however, a challenging enterprise because of methodological concerns. It may be impossible to obtain a quality of design that will pick up subtle changes in fecundity.
Key Words: Environment, Female, *Fertility, Humans, Infertility/therapy, Male, Population Surveillance/*methods, Questionnaires, Research Support, Non-U.S. Gov't, Seasons, Sperm Count/*methods
Research notes: Comment on Am J Epidemiol. 2003 Jan 15;157(2):89-93.
Inner-city, minority populations are high-risk groups for adverse birth outcomes and also are more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), polycyclic aromatic hydrocarbons (PAHs), and pesticides. In a sample of 263 nonsmoking African-American and Dominican women, we evaluated the effects on birth outcomes of prenatal exposure to airborne PAHs monitored during pregnancy by personal air sampling, along with ETS estimated by plasma cotinine, and an organophosphate pesticide (OP) estimated by plasma chlorpyrifos (CPF). Plasma CPF was used as a covariate because it was the most often detected in plasma and was highly correlated with other pesticides frequently detected in plasma. Among African Americans, high prenatal exposure to PAHs was associated with lower birth weight (p = 0.003) and smaller head circumference (p = 0.01) after adjusting for potential confounders. CPF was associated with decreased birth weight and birth length overall (p = 0.01 and p = 0.003, respectively) and with lower birth weight among African Americans (p = 0.04) and reduced birth length in Dominicans (p < 0.001), and was therefore included as a covariate in the model with PAH. After controlling for CPF, relationships between PAHs and birth outcomes were essentially unchanged. In this analysis, PAHs and CPF appear to be significant independent determinants of birth outcomes. Further analyses of pesticides will be carried out. Possible explanations of the failure to find a significant effect of PAHs in the Hispanic subsample are discussed. This study provides evidence that environmental pollutants at levels currently encountered in New York City adversely affect fetal development.
Key Words: Adolescent, Adult, African Continental Ancestry Group, Birth Weight, Child Development, Chlorpyrifos/*adverse effects/blood, Dominican Republic/ethnology, *Environmental Exposure, Ethnic Groups, Female, Humans, Infant, Newborn, Insecticides/*adverse effects/blood, Male, *Maternal-Fetal Exchange, New York City, Polycyclic Hydrocarbons, Aromatic/*adverse effects/blood, Pregnancy, *Pregnancy Outcome, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Social Class, Tobacco Smoke Pollution/*adverse effects
Study Synopsis: Hexachlorobenzene disrupts male reproductive tract development. This new paper opens up an important new front in the search for causes for this increasingly common disease, demonstrating that the ubiquitous organochlorine contaminant hexachlorobenzene (HCB) disrupts normal development of the male reproductive tract by interfering with androgen action. Many other contaminants share the same mechanisms of action of HCB and thus are also implicated by these results.
Scientific abstract:
Hexachlorobenzene (HCB) is a persistent environmental contaminant that has the potential to interfere with steroid hormone regulation. The prostate requires precise control by androgens to regulate its growth and function. To determine if HCB impacts androgen action in the prostate, we used a number of methods. Our in vitro cell-culture-based assay used a firefly luciferase reporter gene driven by an androgen-responsive promoter. In the presence of dihydrotestosterone, low concentrations (0.5-5 nM) of HCB increased the androgen-responsive production of firefly luciferase and high concentrations of HCB (> 10 microM) suppressed this transcriptional activity. Results from a binding assay showed no evidence of affinity between HCB and the androgen receptor. We also tested HCB for in vivo effects using transgenic mice in which the transgene was a prostate-specific, androgen-responsive promoter upstream of a chloramphenicol acetyl transferase (CAT) reporter gene. In 4-week-old mice, the proportion of dilated prostate acini, a marker of sexual maturity, increased in the low HCB dose group and decreased in the high HCB dose mice. In the 8-week-old mice, there was a significant decrease in both CAT activity and prostate weight upon exposure to 20 mg/kg/day HCB. Therefore, in vitro and in vivo data suggest that HCB weakly agonizes androgen action, and consequently, low levels of HCB enhanced androgen action but high levels of HCB interfered. Environmental contaminants have been implicated in the rising incidence of prostate cancer, and insight into the mechanisms of endocrine disruption will help to clarify their role.
A time-related deterioration in male reproductive function caused by exposure to endocrine disrupters, including persistent organochlorines (POCs), has been hypothesized. In animal studies, POCs were found to have adverse effects on male reproductive function. However, little is known about the impact of POC exposure on reproductive parameters in men. In a study of 305 young Swedish men 18-21 years old from the general population, we correlated lipid-adjusted serum levels of 2,2',4,4',5,5' -hexachlorobiphenyl (CB-153)--an index substance for POC exposure--to markers of male reproductive function: testis size assessed by ultrasound, sperm concentration, total sperm count, sperm motility assessed manually and with a computer-aided sperm analyzer (CASA), and serum levels of follicle-stimulating hormone, inhibin B, testosterone, sexual hormone-binding globulin (SHBG), luteinizing hormone, and estradiol. We found weak but statistically significant, negative correlations between CB-153 levels and both the testosterone:SHBG ratio (r = -0.25, p < 0.001)--a measure of the biologically active free testosterone fraction--and CASA sperm motility (r = -0.13, p = 0.02). No statistically significant association with other seminal, hormonal, or clinical markers of male reproductive function was found. In previous studies of more highly POC-exposed groups of adult men, the correlation between POC exposure, including CB-153, and free testosterone levels was not statistically significant. The present study gives some tentative support for weak negative effects of CB-153 exposure on sperm motility and free testosterone levels in young men, but further semen studies on more highly exposed groups may give more firm conclusions on the hazard for male reproductive function from dietary POC exposure.
Endometriosis is a common gynecologic problem of unknown etiology. Estrogen dependence and immune modulation are established features of this disease, and environmental contaminants have been suggested to play a role in the pathobiology of this disease as well. Previous work in nonhuman primates has shown that exposure to the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with an increased prevalence and severity of endometriosis. Further animal experiments have implicated dioxin and dioxin-like compounds in this disease. Rodent studies support the plausibility of a role of environmental contaminants in the pathophysiology of endometriosis, although a convincing mechanistic hypothesis has yet to be advanced. Small hospital-based case-control studies have failed to provide compelling evidence for or against an association of environmental contaminants and endometriosis. Herein we review evidence that dioxin and dioxin-like compounds are potent modulators of immune and endocrine function critical to the pathobiology of endometriosis. Furthermore, perspectives on the potential mechanism(s) of dioxin and dioxin-like compound-induced toxicity in endometriosis, important knowledge needs, potential animal models for endometriosis studies, and considerations integral to future human case-control studies are discussed.
The primary purpose of this study was to evaluate whether the coadministration of testosterone (TE; 200 micro g) with 10 micro g of diethylstilbestrol (DES) between days 2 and 12 postnatally could prevent the adverse gross reproductive tract changes and associated loss of androgen receptor (AR) expression induced by DES treatment alone. Various endpoints (rete testis area, efferent duct lumen area, epithelial cell height of efferent ducts, and vas deferens) were quantified to check for the abnormal changes that have been shown to occur after neonatal treatment with a high dose (10 micro g) of DES. Additionally, DES induction of an aberrant pattern of estrogen receptor alpha (ER-alpha) immunoexpression in the vas deferens and seminal vesicles was evaluated. The coadministration of DES with TE prevented the induction of all but one of the abnormalities induced by DES treatment on its own, coincident with the restoration of normal/supranormal TE levels and normal immunoexpression of the AR and ER-alpha in the tissues studied. The exception was DES-induced lumenal distension of the efferent ducts, which was only partially prevented by the coadministration of DES with TE. These evaluations were made on day 18, but the described abnormalities were already somewhat evident by day 8 in DES-treated animals. It was therefore tested whether a delay of TE replacement until days 8-12 was still able to reverse the abnormalities already induced by DES treatment alone. A delayed treatment with TE reversed the adverse changes in epithelial cell height and in ER-alpha and AR immunoexpression in the same tissues by day 18; however, rete testis overgrowth was only partially prevented, and efferent duct distension was not prevented at all. These results provide further evidence that DES-induced disorders of reproductive tract development in the male result from a disturbance of the androgen-estrogen balance rather than from estrogen action alone.
BACKGROUND: Environmental lead exposure has been linked to alterations in growth and endocrine function. It is not known whether such exposure affects pubertal development. METHODS: We analyzed the relations between blood lead concentration and pubertal development among girls (defined as females 8 to 18 years of age) who were enrolled in a cross-sectional study (the third National Health and Nutrition Examination Survey) in which race was self-reported or proxy-reported: 600 were non-Hispanic white, 805 were non-Hispanic African-American, and 781 were Mexican-American girls. Puberty was measured on the basis of the age at menarche and Tanner stage for pubic-hair and breast development. RESULTS: Geometric mean lead concentrations were less than 3 microg per deciliter (0.144 micromol per liter) in all three groups. As compared with concentrations of 1 microg per deciliter (0.048 micromol per liter), lead concentrations of 3 microg per deciliter were associated with decreased height (P<0.001), after adjustment for age, race, and other factors, but not with body-mass index or weight. Blood lead concentrations of 3 microg per deciliter were associated with significant delays in breast and pubic-hair development in African-American and Mexican-American girls. The delays were most marked among African-American girls; in this group, the delays in reaching Tanner stages 2, 3, 4, and 5 associated with a lead concentration of 3 microg per deciliter as compared with 1 microg per deciliter were 3.8, 5.3, 5.8, and 2.1 months, respectively, for breast development and 4.0, 5.5, 6.0, and 2.2 months, respectively, for pubic-hair development; the associated delay in age at menarche was 3.6 months. In white girls, there were nonsignificant delays in all pubertal measures in association with a lead concentration of 3 microg per deciliter. CONCLUSIONS: These data suggest that environmental exposure to lead may delay growth and pubertal development in girls, although confirmation is warranted in prospective studies.
Key Words: Adolescent, African Continental Ancestry Group, Child, Cross-Sectional Studies, Environmental Exposure/adverse effects, European Continental Ancestry Group, Female, Humans, Lead/adverse effects/*blood, Lead Poisoning/complications, Logistic Models, Menarche/drug effects/ethnology, Mexican Americans, Nutrition Surveys, Puberty/*drug effects/ethnology, United States
Research notes: Comment in N Engl J Med. 2003 Apr 17;348(16):1515-6.
Study Synopsis: A large body of literature demonstrate that exposure to lead affects child development. Few studies have however evaluated whether lead may affect the timing of puberty onset in girls. In this study, researchers measured lead levels in the blood of 2,186 girls and assessed puberty onset based on age at menarche (first period), as well as pubic hair and breast development. Higher blood lead levels were associated with delayed puberty in African-American and Mexican-American, but not in White, girls. Delays were most marked in African-American girls. In this group, those with higher (> 3 ug/dl) blood lead concentration reached puberty about 4 months later on average than girls with lower blood lead levels, based on pubic hair and breast development. Higher exposure to lead was also associated with a 3.6 months delay in age at menarche in African-American girls. Results suggest that exposure to lead may delay puberty onset in some, but not all, racial groups.
Scientific abstract:
BACKGROUND: Environmental lead exposure has been linked to alterations in growth and endocrine function. It is not known whether such exposure affects pubertal development. METHODS: We analyzed the relations between blood lead concentration and pubertal development among girls (defined as females 8 to 18 years of age) who were enrolled in a cross-sectional study (the third National Health and Nutrition Examination Survey) in which race was self-reported or proxy-reported: 600 were non-Hispanic white, 805 were non-Hispanic African-American, and 781 were Mexican-American girls. Puberty was measured on the basis of the age at menarche and Tanner stage for pubic-hair and breast development. RESULTS: Geometric mean lead concentrations were less than 3 microg per deciliter (0.144 micromol per liter) in all three groups. As compared with concentrations of 1 microg per deciliter (0.048 micromol per liter), lead concentrations of 3 microg per deciliter were associated with decreased height (P<0.001), after adjustment for age, race, and other factors, but not with body-mass index or weight. Blood lead concentrations of 3 microg per deciliter were associated with significant delays in breast and pubic-hair development in African-American and Mexican-American girls. The delays were most marked among African-American girls; in this group, the delays in reaching Tanner stages 2, 3, 4, and 5 associated with a lead concentration of 3 microg per deciliter as compared with 1 microg per deciliter were 3.8, 5.3, 5.8, and 2.1 months, respectively, for breast development and 4.0, 5.5, 6.0, and 2.2 months, respectively, for pubic-hair development; the associated delay in age at menarche was 3.6 months. In white girls, there were nonsignificant delays in all pubertal measures in association with a lead concentration of 3 microg per deciliter. CONCLUSIONS: These data suggest that environmental exposure to lead may delay growth and pubertal development in girls, although confirmation is warranted in prospective studies.
Key Words: Adolescent, African Continental Ancestry Group, Child, Cross-Sectional Studies, Environmental Exposure/adverse effects, European Continental Ancestry Group, Female, Humans, Lead/adverse effects/*blood, Lead Poisoning/complications, Logistic Models, Menarche/drug effects/ethnology, Mexican Americans, Nutrition Surveys, Puberty/*drug effects/ethnology, United States
The original 'oestrogen hypothesis' postulated that the apparent increase in human male reproductive developmental disorders (testis cancer, cryptorchidism, hypospadias, low sperm counts) might have occurred because of increased oestrogen exposure of the human foetus/neonate; five potential routes of exposure were considered. This review revisits this hypothesis in the light of the data to have emerged since 1993. It addresses whether there is a secular increasing trend in the listed disorders and highlights the limitations of available data and how these are being addressed. It considers whether new data has emerged to support the suggestion that increased oestrogen exposure could cause these abnormalities and reviews new data on potential routes via which such increased exposure could have occurred. Secular trends: The disorders listed above are now considered to represent a syndrome of disorders (testicular dysgenesis syndrome, TDS) with a common origin in foetal life. Testicular cancer has increased in incidence in Caucasian men worldwide and lifetime risk is 0.3-0.8%. Secular trends in cryptorchidism are unclear but it is by far the commonest (2-4% at birth) congenital abnormality in either sex. Secular trends for hypospadias are not robust, although most studies suggest a progressive increase; registry data probably under-estimates incidence, but based on this data hypospadias is the second most common (0.3-0.7% at birth) congenital malformation. Retrospective analyses of sperm count data show a global downward trend but this is inconclusive - prospective studies using standardized methodology show significant differences between countries and very low sperm counts in the youngest cohort of men. For all disorders, other then testis cancer, standardized prospective studies are the best way forward and are in progress across Europe. Oestrogen effects: Evidence that foetal exposure to oestrogens can induce the above disorders has strengthened. New pathways via which such changes could be induced have been identified, including suppression of testosterone production by the foetal testis, suppression of androgen receptor expression and suppression of insulin-like factor-3 (InsL3) production by foetal Leydig cells. Other evidence suggests that the balance between androgen and oestrogen action may be important in induction of reproductive tract abnormalities. Oestrogen exposure: Although many new environmental oestrogens have been identified, their uniformly weak oestrogenicity excludes the possibility that they could induce the above disorders. However, emerging data implicates various environmental chemicals in being able to alter endogenous levels of androgens (certain phthalates) and oestrogens (polychlorinated biphenyls, polyhalogenated hydrocarbons), and the former have been shown to induce a similar collection of disorders to TDS. Other mechanisms via which increased fetal exposure to pregnancy oestrogens might occur (increasing trend in obesity, dietary changes) are also discussed.
Disorders of testicular function may have their origins in fetal or early life as a result of abnormal development or proliferation of Sertoli cells. Failure of Sertoli cells to mature, with consequent inability to express functions capable of supporting spermatogenesis, is a prime example. In a similar way, failure of Sertoli cells to proliferate normally at the appropriate period in life will result in reduced production of spermatozoa in adulthood. This review focuses on the control of proliferation of Sertoli cells and functional maturation, and is motivated by concerns about 'testicular dysgenesis syndrome' in humans, a collection of common disorders (testicular germ-cell cancer, cryptorchidism, hypospadias and low sperm counts) which are hypothesized to have a common origin in fetal life and to reflect abnormal function of Sertoli (and Leydig) cells. The timing of proliferation of Sertoli cells in different species is reviewed, and the factors that govern the conversion of an immature, proliferating Sertoli cell to a mature, non-proliferating cell are discussed. Protein markers of maturity and immaturity of Sertoli cells in various species are reviewed and their usefulness in studies of human testicular pathology are discussed. These markers include anti-Mullerian hormone, aromatase, cytokeratin-18, GATA-1, laminin alpha5, M2A antigen, p27(kip1), sulphated glycoprotein 2, androgen receptor and Wilms' tumour gene. A scheme is presented for characterization of Sertoli-cell only tubules in the adult testis according to whether or not there is inherent failure of maturation of Sertoli cells or in which the Sertoli cells have matured but there is absence, or acquired loss, of germ cells. Functional 'de-differentiation' of Sertoli cells is considered. It is concluded that there is considerable evidence to indicate that disorders of maturation of Sertoli cells may be a common underlying cause of human male reproductive disorders that manifest at various life stages. This recognition emphasizes the important role that animal models must play to enable identification of the mechanisms via which failure of proliferation and maturation of Sertoli cells can arise, as this failure probably occurs in fetal life.
In the Western world fertility rates are low and infertility is a major health problem. Unofficial statistics from Denmark reveal that about 6% of all Danish children are now born after assisted reproduction techniques, including in vitro fertilization, intracytoplasmic sperm injection, donor insemination or homologous insemination. However, there are no retrospective data on trends in fecundity (ability to conceive). We, and others, have focused on some aspects of adverse trends in male reproductive health such as the rising incidence of testicular cancer, low and probably declining semen quality, high and possibly increasing frequencies of undescended testes and hypospadias. Due to medical specialization and the different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, for instance paediatric endocrinologists, urologists, andrologists or oncologists. There is evidence that poor semen quality, testicular cancer, undescended testes and hypospadias are symptoms of one underlying entity, testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental and epidemiological studies suggest that TDS is the result of disruption of embryonal programming and gonadal development during fetal life. An endocrine disrupter hypothesis to explain the adverse trends has been proposed. It is recommended that future epidemiological studies on trends in male reproductive health should not focus on one symptom alone, but be more comprehensive and take all aspects of TDS into account. (from previous paper) Genetics or environmental factors, or both, could be causing testicular dysgenesis syndrome. Danish researchers argue that a host of male reproductive disorders have a common origin they recognize as testicular dysgenesis syndrome. Environmental and genetic factors are thought to be possible causes. Endocrine disruptors are a prime suspect
BACKGROUND: There has been an apparent decline in sperm density during the last 5 decades in Denmark, a country in which women have among the highest rates of smoking in Europe. We examined semen quality and sex hormones in men in relation to their mothers' tobacco smoking during pregnancy. METHODS: Male participants were selected from the population-based Danish Twin Registry and the Danish Civil Registration System as part of a study on hereditary and environmental determinants of semen quality. From November 1999 to May 2000 we collected one fresh semen and blood sample from each of 316 men. Data on prenatal tobacco exposure were obtained for 265 of these men from a questionnaire filled in by their mothers. RESULTS: Adjusting for age, current smoking status and other factors, sperm density was 48% lower(95% confidence interval = -69% to -11) among sons of mothers who smoked more than 10 cigarettes per day during pregnancy. Total sperm counts and levels of inhibin-B were also reduced among this group, whereas follicular stimulating hormone levels were somewhat higher (16% increase; 95% confidence interval = -13% to 54%). These effects were not seen in the lower smoking category (1-10 cigarettes per day). CONCLUSIONS: High levels of smoking (> 10 cigarettes per day) during pregnancy may be a partial explanation for the apparent secular decline and the geographic differences in sperm counts.
PROBLEM: A case-control study was designed to evaluate any associations between high exposure to polychlorinated biphenyls (PCB), hexachlorobenzene (HCB) and the 1,1,1,-trichloro-2,2-bis (p-chlorophenyl) ethane (DDT) metabolite 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (DDE) and recurrent miscarriage and immunoendocrine abnormalities. METHODS OF STUDY: A total of 18 kinds of co-planer PCBs, HCB, DDE, natural killer cell (NK) activity, antiphospholipid antibodies, antinuclear antibody, prolactin, progesterone, thyroid-stimulating hormone (TSH) and free T4 were examined in 45 patients with a history of three or more (3-11) consecutive first-trimester miscarriages and 30 healthy women with no history of live birth and infertility. RESULTS: There were no differences in mean +/- S.D. values in serum samples for PCBs, HCB and DDE between patients and controls. Hypothyroidism, hyperprolactinemia, luteal phase defects, NK cell activity and the presence of autoantibodies were also not associated with levels of any of the compounds in the patients. CONCLUSION: PCBs, HCB and DDE are not associated with miscarriage and immunoendocrine abnormalities in patients with a history of recurrent miscarriage.
Swan SH, Brazil C, Drobnis EZ, Liu F, Kruse RL, Hatch M, Redmon JB, Wang C, Overstreet JW; Study For Future Families Research Group. Geographic differences in semen quality of fertile U.S. males. Environ Health Perspect. 2003 Apr;111(4):414-20.
Study Synopsis: A comprehensive study demonstrates geographic differences in semen quality. Men in Missouri have the lowest sperm count compared to New York, Minneapolis and Los Angeles. The cause of these differences are not yet known. The scientists conducting the study hypothesize it may be related to the intensity of pesticide use in industrial agriculture in Missouri compared to the other, more urban areas.
Scientific abstract:
Although geographic variation in semen quality has been reported, this is the first study in the United States to compare semen quality among study centers using standardized methods and strict quality control. We evaluated semen specimens from partners of 512 pregnant women recruited through prenatal clinics in four U.S. cities during 1999-2001; 91% of men provided two specimens. Sperm concentration, semen volume, and motility were determined at the centers, and morphology was assessed at a central laboratory. Study protocols were identical across centers, and quality control was rigorously maintained. Sperm concentration was significantly lower in Columbia, Missouri, than in New York, New York; Minneapolis, Minnesota; and Los Angeles, California. Mean counts were 58.7, 102.9, 98.6, and 80.8 X 10(6)/mL (medians 53.5, 88.5, 81.8, and 64.8 X 10(6)/mL) in Missouri, New York, Minnesota, and California, respectively. The total number of motile sperm was also lower in Missouri than in other centers: 113, 196, 201, and 162 X 10(6) in Missouri, New York, Minnesota, and California, respectively. Semen volume and the percent morphologically normal sperm did not differ appreciably among centers. These between-center differences remained significant in multivariate models that controlled for abstinence time, semen analysis time, age, race, smoking, history of sexually transmitted disease, and recent fever (all p-values < 0.01). Confounding factors and differences in study methods are unlikely to account for the lower semen quality seen in this mid-Missouri population. These data suggest that sperm concentration and motility may be reduced in semirural and agricultural areas relative to more urban and less agriculturally exposed areas.
Key Words: Adult, Agriculture, *Environmental Exposure, Epidemiologic Studies, Geography, Humans, Infertility, Male/*epidemiology, Male, Research Support, U.S. Gov't, P.H.S., Rural Population, *Semen, Sperm Count/*statistics & numerical data, *Sperm Motility, United States/epidemiology, Urban Population
We previously reported reduced sperm concentration and motility in fertile men in a U.S. agrarian area (Columbia, MO) relative to men from U.S. urban centers (Minneapolis, MN; Los Angeles, CA; New York, NY). In the present study we address the hypothesis that pesticides currently used in agriculture in the Midwest contributed to these differences in semen quality. We selected men in whom all semen parameters (concentration, percentage sperm with normal morphology, and percentage motile sperm) were low (cases) and men in whom all semen parameters were within normal limits (controls) within Missouri and Minnesota (sample sizes of 50 and 36, respectively) and measured metabolites of eight current-use pesticides in urine samples provided at the time of semen collection. All pesticide analyses were conducted blind with respect to center and case-control status. Pesticide metabolite levels were elevated in Missouri cases, compared with controls, for the herbicides alachlor and atrazine and for the insecticide diazinon [2-isopropoxy-4-methyl-pyrimidinol (IMPY)]; for Wilcoxon rank test, p = 0.0007, 0.012, and 0.0004 for alachlor, atrazine, and IMPY, respectively. Men from Missouri with high levels of alachlor or IMPY were significantly more likely to be cases than were men with low levels [odds ratios (ORs) = 30.0 and 16.7 for alachlor and IMPY, respectively], as were men with atrazine levels higher than the limit of detection (OR = 11.3). The herbicides 2,4-D (2,4-dichlorophenoxyacetic acid) and metolachlor were also associated with poor semen quality in some analyses, whereas acetochlor levels were lower in cases than in controls (p = 0.04). No significant associations were seen for any pesticides within Minnesota, where levels of agricultural pesticides were low, or for the insect repellent DEET (N,N-diethyl-m-toluamide) or the malathion metabolite malathion dicarboxylic acid. These associations between current-use pesticides and reduced semen quality suggest that agricultural chemicals may have contributed to the reduction in semen quality in fertile men from mid-Missouri we reported previously.
Fifty seven female workers at mean age 32 years (range, 23-45 years), employed in a storage battery plant and a capacitor factory were investigated. The lead exposure period was 7.4 years (range, 1-17 years). The retrospective method was used to analyse reproductive functions of women: menses, libido, abortion and delivery. The results were compared with the control group (62 female workers, mean age 32 years; range, 24-45 years). The incidence of polymenorrhea, prolonged and abnormal menstruations, hypermenorrhea was significantly higher in the lead exposed group than in controls. The incidence of spontaneous abortions was reported by 6 exposed female workers whereas it was not observed in the control group (p = 0.01). The authors conclude that occupational lead exposure of female workers could lead to the impairment of the functions of reproductive system, however poor working conditions and workload may prove to be additional factors responsible for functional disorders in the subjects under study.
Key Words: Abortion, Spontaneous/epidemiology/etiology, Adult, *Electric Power Supplies, Female, Humans, Incidence, Lead/*adverse effects, Menstruation Disturbances/epidemiology/etiology, *Metallurgy, Occupational Exposure/*adverse effects, *Reproduction, Research Support, Non-U.S. Gov't, Retrospective Studies, Time Factors
Study Synopsis: Overall, this study did not demonstrate any relation between maternal HCB level and preterm birth. However, a non-significant increased risk of preterm birth in relation to elevated p,p-DDE serum levels was observed (adjusted odds ratio (OR) = 1.67, 95% confidence interval (CI) = 0.84-3.31). There was also a suggestion of an increased risk of preterm birth among women in the group with the highest level of beta-HCH (OR = 1.85, 95% CI = 0.94-3.66, p-value test for trend = 0.08) compared with the lowest levels.
Scientific abstract:
PURPOSE: To evaluate the associations of serum levels of p,pacute;-DDE and two other persistent organochlorine pesticides, beta-HCH and HCB, in relation to preterm birth. METHODS: During 1995 we performed a case-cohort study and 233 mothers were recruited at three large maternity hospitals in Mexico City. Serum levels were obtained shortly after delivery. RESULTS: A non-significant increased risk of preterm birth in relation to serum p,p'-DDE levels was observed. There was also a suggestion of an increased risk of preterm birth among women in the highest tertile of beta-HCH (adjusted odds ratio 1.85, 95% CI = 0.94-3.66, p value for test of trend p = 0.08) compared with the lowest tertile. No association was found between HCB serum levels and preterm births. CONCLUSIONS: These findings suggest that p,pacute;-DDE and other organochlorine pesticides may pose a risk to preterm birth in countries that continue to use such insecticides for malaria control.
Information concerning the fundamental mechanisms of action of both natural and environmental hormones, combined with information concerning endogenous hormone concentrations, reveals how endocrine-disrupting chemicals with estrogenic activity (EEDCs) can be active at concentrations far below those currently being tested in toxicological studies. Using only very high doses in toxicological studies of EEDCs thus can dramatically underestimate bioactivity. Specifically: a) The hormonal action mechanisms and the physiology of delivery of EEDCs predict with accuracy the low-dose ranges of biological activity, which have been missed by traditional toxicological testing. b) Toxicology assumes that it is valid to extrapolate linearly from high doses over a very wide dose range to predict responses at doses within the physiological range of receptor occupancy for an EEDC; however, because receptor-mediated responses saturate, this assumption is invalid. c) Furthermore, receptor-mediated responses can first increase and then decrease as dose increases, contradicting the assumption that dose-response relationships are monotonic. d) Exogenous estrogens modulate a system that is physiologically active and thus is already above threshold, contradicting the traditional toxicological assumption of thresholds for endocrine responses to EEDCs. These four fundamental issues are problematic for risk assessment methods used by regulatory agencies, because they challenge the traditional use of extrapolation from high-dose testing to predict responses at the much lower environmentally relevant doses. These doses are within the range of current exposures to numerous chemicals in wildlife and humans. These problems are exacerbated by the fact that the type of positive and negative controls appropriate to the study of endocrine responses are not part of traditional toxicological testing and are frequently omitted, or when present, have been misinterpreted.
Key Words: Dose-Response Relationship, Drug, Endocrine System/*drug effects, *Environmental Exposure, Environmental Pollutants/*toxicity, Estrogens/*toxicity, Humans, Receptors, Estrogen/*drug effects/physiology, Reproducibility of Results, Research Design, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Risk Assessment
We analyzed data from a prospective study of menstrual cycle function and early pregnancy loss to explore further the effects of trihalomethanes (THM) on reproductive end points. Premenopausal women ((italic)n(/italic) = 403) collected urine samples daily during an average of 5.6 cycles for measurement of steroid metabolites that were used to define menstrual parameters such as cycle and phase length. Women were asked about consumption of various types of water as well as other habits and demographics. A THM level was estimated for each cycle based on residence and quarterly measurements made by water utilities during a 90-day period beginning 60 days before the cycle start date. We found a monotonic decrease in mean cycle length with increasing total THM (TTHM) level; at > 60 microg/L, the adjusted decrement was 1.1 days [95% confidence interval (CI), -1.8 to -0.40], compared with less than or equal to 40 microg/L. This finding was also reflected as a reduced follicular phase length (difference -0.94 day; 95% CI, -1.6 to -0.24). A decrement in cycle and follicular phase length of 0.18 days (95% CI, -0.29 to -0.07) per 10 microg/L unit increase in TTHM concentration was found. There was little association with luteal phase length, menses length, or cycle variability. Examining the individual THMs by quartile, we found the greatest association with chlorodibromomethane or the sum of the brominated compounds. Incorporating tap water consumption showed a similar pattern of reduced cycle length with increasing TTHM exposure. These findings suggest that THM exposure may affect ovarian function and should be confirmed in other studies.
Using data from the Third National Health and Nutrition Examination Survey, we assessed measures of puberty in U.S. girls in relation to blood lead levels to determine whether sexual maturation may be affected by current environmental lead exposure. The study sample included 1,706 girls 8-16 years old with pubic hair and breast development information; 1,235 girls 10-16 years old supplied information on menarche. Blood lead concentrations (range = 0.7-21.7 micro g/dL) were categorized into three levels: 0.7-2.0, 2.1-4.9, and 5.0-21.7 micro g/dL. Sexual maturation markers included self-reported attainment of menarche and physician determined Tanner stage 2 pubic hair and breast development. Girls who had not reached menarche or stage 2 pubic hair had higher blood lead levels than did girls who had. For example, among girls in the three levels of blood lead described above, the unweighted percentages of 10-year-olds who had attained Tanner stage 2 pubic hair were 60.0, 51.2, and 44.4%, respectively, and for girls 12 years old who reported reaching menarche, the values were 68.0, 44.3, and 38.5%, respectively. The negative relation of blood lead levels with attainment of menarche or stage 2 pubic hair remained significant in logistic regression even after adjustment for race/ethnicity, age, family size, residence in metropolitan area, poverty income ratio, and body mass index. In conclusion, higher blood lead levels were significantly associated with delayed attainment of menarche and pubic hair among U.S. girls, but not with breast development.
Polycystic ovary syndrome (PCOS) is a common but complex endocrine disorder and is a major cause of anovulation and consequent subfertility. It is also associated with a metabolic disturbance, characterized by hyperinsulinaemia and insulin resistance that carries an increased risk of type 2 diabetes in later life. Despite its prevalence little is known about its aetiology, but there is increasing evidence for an important genetic involvement. On the basis of experimental observations in the prenatally androgenized sheep and rhesus monkey, and supported by data from human studies, we propose that the clinical and biochemical features of PCOS can arise as a consequence of genetically determined hypersecretion of androgens by the ovary during, or very likely long before, puberty. The resulting hyperandrogenism results in 'programming' of the hypothalamic-pituitary unit to favour excess LH secretion, and encourages preferential abdominal adiposity that predisposes to insulin resistance. The severity of hyperinsulinaemia and insulin resistance (which has a profound influence on the phenotype of PCOS) is further influenced by both genetic factors (such as polymorphism in the insulin gene regulatory region) and environmental factors, notably obesity. This hypothesis therefore suggests a unifying, 'linear' model to explain the aetiology of the heterogeneous phenotype.
The aim of this investigation was to evaluate the effect of bisphenol A (BPA), a contaminant of resin-based dental composites and sealants, on the fertility of male mice. Forty adult male Swiss mice were divided into four groups of 10. BPA (5, 25 and 100 micro g kg(-1) [corrected] was administered intragastrically daily to the mice in the test groups and distilled water to the control group for 28 d. Male fertility was assessed by mating each mouse with two untreated females. Females mated with male mice having ingested 25 and 100 micro g kg(-1) [corrected] BPA showed a significant reduction in pregnancy rates. Furthermore, the total number of resorptions out of the total number of implantations was significantly increased in females impregnated with males having ingested all three doses of BPA. Males having ingested 25 and 100 micro g kg(-1) [corrected] BPA showed a significant reduction in testicular sperm counts and in the efficiency of sperm production. Epididymal sperm counts were also significantly reduced in males that had ingested BPA. There were significant reductions in the absolute weights of the testes and seminal vesicles. These results suggest that male fertility and reproduction is impaired by bisphenol A.
Endocrine disruptors can affect the endocrine system without directly interacting with receptors, for example, by interfering with the synthesis or metabolism of steroid hormones. The aromatase that converts testosterone to 17beta-estradiol is a possible target. In this paper we describe an assay that simultaneously detects aromatase inhibition and estrogenicity. The principle is similar to that of other MCF-7 estrogenicity assays, but with a fixed amount of testosterone added. The endogenous aromatase activity in MCF-7 cells converts some of the testosterone to 17beta-estradiol, which is assayed by quantifying differences in the expression level of the estrogen-induced pS2 mRNA. Potential aromatase inhibitors can be identified by a dose-dependent reduction in the pS2 mRNA expression level after exposure to testosterone and the test compound. Using this assay, we have investigated several compounds, including synthetic chemicals and phytoestrogens, for aromatase inhibition. The phytoestrogens, except genistein, were aromatase inhibitors at low concentrations (< 1 micro M) but estrogenic at higher concentrations (greater than or equal to 1 micro M), resulting in U-shaped dose-response curves. None of the tested synthetic chemicals were aromatase inhibitors. The low-dose aromatase inhibition distinguished phytoestrogens from other estrogenic compounds and may partly explain reports about antiestrogenic properties of phytoestrogens. Aromatase inhibition may play an important role in the protective effects of phytoestrogens against breast cancer.
We examined the effects on female CD-1 mice of fetal exposure to low doses of the drug diethylstilbestrol (DES) (0.1 microg/kg/day) and the insecticide methoxychlor (MXC) (10 microg/kg/day) as well as 1000-fold higher doses: 100 microg/kg/day DES and 10,000 microg/kg/day MXC. Pregnant females were administered these chemicals on gestation days 12-18. At 7-8 months of age, female offspring were ovariectomized and implanted for 7 days with a Silastic capsule containing estradiol. Relative to controls, females exposed to the 0.1 microg DES dose showed significantly heavier uteri, while females exposed to the 100 microg DES dose showed significantly lighter uteri. Females exposed prenatally to the 10 microg/kg dose of MXC had significantly heavier uteri relative to females exposed to the 10,000 microg/kg dose of MXC, but neither group differed significantly from controls. Liver weight for females exposed to both doses of DES was significantly greater than controls. Using a microarray approach to analyze DNA methylation, an increase in ribosomal DNA (rDNA) methylation was observed. Sequence data and Southern analysis indicate an increase in 18S rDNA and 45S pre-rDNA methylation in uterine samples exposed prenatally to low and high doses of DES. We thus found opposite effects of fetal exposure to a low and a high dose of DES on the uterine response to estradiol (inverted-U dose-response relationship). In contrast, there was a monotonic dose-response relationship found for prenatal DES exposure on both liver weight and ribosomal DNA hypermethylation.
Key Words: Analysis of Variance, Animals, Body Weight/drug effects, Carcinogens/administration & dosage/*toxicity, DNA Methylation/*drug effects, Diethylstilbestrol/administration & dosage/*toxicity, Dose-Response Relationship, Drug, Estradiol/*pharmacology, Female, Fetus/*drug effects, Insecticides/administration & dosage/*toxicity, Methoxychlor/administration & dosage/*toxicity, Mice, Organ Size/drug effects, Ovariectomy, Pregnancy, Research Support, U.S. Gov't, P.H.S., Uterus/*drug effects
A potential connection exists between exposure to organochlorine chemicals and the increasing prevalence of endometriosis. Evidence shows that dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) can increase the incidence and severity of the disease in monkeys and can promote the growth or survival of endometrial tissue implanted into rodents in a surgically induced model of endometriosis. The mechanism of the connection between organochlorine chemicals and endometriosis is not clear. Effects on growth factors, cytokines, and hormones (components of the immune and endocrine systems) are potential means of mediating the possible promotion of endometriosis by dioxins. Studies on epidemiology and on structure-activity relationships of organochlorine chemicals and endometriosis have been additional approaches to this problem. In this regard, toxic equivalence (TEQ) appears to be an important determinant of the effects of organochlorine chemicals on endometriosis. In this article, we review the literature related to endometriosis and dioxins and attempt to integrate the various sources of information that bolster the hypothesis connecting dioxins and endometriosis.
Study Synopsis: Polybrominated biphenyls (PBBs) are synthetic chemicals formerly used as flame retardants. In 1973, the Michigan food supply was contaminated with PBBs when the cattle feed supplement NutriMaster was accidently replaced with the flame retardant FireMaster. More than 4,000 individuals were exposed to PBBs, 308 of which were exposed during pregnancy and were enrolled in the current study. Researchers estimated maternal exposure to PBBs and to closely related chemicals named polychlorinated biphenyls (PCBs) based on blood measurements. PCBs were formerly used in electrical transformers, inks, plastics and other consumer products. Though no associations were found between prenatal exposure to PBBs and daughters' height or weight, mothers with PCB blood levels above the median had daughters whose weights were on average 11 pounds lower relative to daughters whose mother had PCB blood levels below the median. These results suggest that prenatal exposure to PCBs, but not PBBs, may be related with lower body weight.
Scientific abstract:
BACKGROUND: Accidental contamination with polybrominated biphenyls (PBBs) of the Michigan food supply in 1973 led to the exposure of more than 4000 individuals and to formation of the PBB cohort registry (1976-1979). At enrollment, measurements were taken of serum PBB and polychlorinated biphenyl (PCB), possible endocrine disrupting chemicals. METHODS: We examined the association of estimated PBB and PCB exposure during pregnancy with current height and weight in 308 daughters, 5-24 years of age (mean age 15.2 years), born to women in the cohort. We estimated prenatal PBB exposure using maternal enrollment serum PBB and a model of PBB elimination. Prenatal PCB exposure was estimated using maternal enrollment serum PCB because background-level exposure through diet was ongoing. Self-reported height and weight were obtained from a 1997-1998 health survey. RESULTS: We found no association between prenatal PBB exposure and either daughter's current height or daughter's weight adjusted for height; however, prenatal PCB exposure above 5 parts per billion was associated with reduced weight adjusted for height. Exposure through breastfeeding did not modify the association. CONCLUSIONS: Mothers with PCB levels above the median had daughters whose current weights were 11 pounds lower than that of the daughters whose mothers had levels below the median. This study provides evidence that prenatal exposure to PCBs may affect growth.
Endocrine disrupting chemicals (EDCs) are natural or synthetic chemicals that mimic, enhance, or inhibit endogenous hormones. In this article, we review possible targets of EDCs within the ovary and explore whether EDCs may be acting as estrogen mimics, interfering with apoptosis, altering cell signaling pathways, or affecting estrogen metabolism. Though the study of EDCs has remained controversial, it is important to study them because our society continues to release large amounts of industrial chemicals into our environment and uncovering the mechanisms of action may lead to treatments of any potential adverse effects. In addition, studying how EDCs affect the ovary may lead to serendipitous discoveries about ovarian function and dysfunction. Finally, understanding the science behind endocrine disruption may influence the political and regulatory handling of EDCs.
Key Words: Animals, Apoptosis/drug effects, Estrogen Receptor Modulators/*pharmacology/toxicity, Estrogens/physiology, Female, Models, Biological, Ovary/cytology/*drug effects/growth & development/physiology, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Signal Transduction/drug effects
Concern for exposures to drinking water contaminants and their effects on adverse birth outcomes has prompted several studies evaluating chlorination disinfection by-products and chlorinated solvents. Some of these contaminants are found to be teratogenic in animal studies. This review evaluates 14 studies on chlorination disinfection by-products such as trihalomethanes (THMs) and five studies on chlorinated solvents such as trichloroethylene (TCE). The adverse birth outcomes discussed in this review include small for gestational age (SGA), low birth weight, preterm birth, birth defects, spontaneous abortions, and fetal deaths. Because of heterogeneities across the studies in the characterization of birth outcomes, the assessment and categorization of exposures, and the levels and mixtures of contaminants, a qualitative review was conducted. Generally, the chief bias in these studies was exposure misclassification that most likely underestimated the risk, as well as distorted exposure-response relationships. The general lack of confounding bias by risk factors resulted from these factors not being associated with drinking water exposures. The studies of THMs and adverse birth outcomes provide moderate evidence for associations with SGA, neural tube defects (NTDs), and spontaneous abortions. Because fewer studies have been conducted for the chlorinated solvents than for THMs, the evidence for associations is less clear. Nevertheless, the findings of excess NTDs, oral clefts, cardiac defects, and choanal atresia in studies that evaluated TCE-contaminated drinking water deserve follow-up.
Objective: To compare blood mercury concentrations of infertile couples with those of fertile couples in Hong Kong, and to examine the relationship between blood mercury concentrations and seafood consumption. Design: Case-control study. Setting: In vitro fertilisation (IVF) Unit and Antenatal Unit of a university teaching hospital. Sample: One hundred fifty-seven infertile couples attending IVF treatment and 26 fertile couples attending antenatal care without known occupational exposure to mercury. Methods: Mercury concentrations in whole blood were measured by cold vapour atomic absorption spectrophotometry. A dietitian recorded the quantity of seafood consumption among infertile couples via a food-frequency questionnaire. Blood mercury concentrations and quantity of seafood consumption were compared between infertile and fertile couples. Main outcome measures: Whole blood mercury concentrations, quantity of seafood consumption. Results: Infertile couples had higher blood mercury concentrations than fertile couples. `Infertile males with abnormal semen' and `infertile females with unexplained infertility' also had higher blood mercury concentrations than their fertile counterparts. Blood mercury concentrations were positively correlated with quantity of seafood consumption. Infertile subjects with elevated blood mercury concentrations consumed a larger amount of seafood. Conclusion: Higher blood mercury concentration is associated with male and female infertility. Higher seafood consumption is associated with elevated blood mercury concentrations in our infertile population.
Study Synopsis: The results suggested that higher body burdens of DDE were associated with earlier onset of natural menopause, but no association was found with PCBs. In a study examining the effects of exposure to PCB-contaminated cooking oil (YuCheng's disease) there was no difference in menopausal status comparing exposed and unexposed women. Other estrogenic exposures, such as age at menarche and oral contraceptive use, have not been consistently associated with onset of natural menopause in previous studies.
Scientific abstract:
BACKGROUND: The effect of potential endocrine-modulating organochlorines on menopause has not been extensively examined. METHODS: We evaluated the associations of plasma polychlorinated biphenyls (PCBs) and 1,1-dichloro-2,2-bis( -chlorophenyl)ethylene (DDE) with age at natural menopause. We analyzed data from 1407 women in a population-based, case-control study of breast cancer that was carried out in 1993-1996 in North Carolina. RESULTS: The adjusted hazard ratio estimating the rate of onset of natural menopause was 1.4 (95% confidence interval = 0.9-2.1) for the top decile of DDE compared with values below the median. This association is similar in magnitude to the association between smoking and menopause (hazard ratio = 1.4 [1.1-1.9]). No association was seen with PCBs. CONCLUSIONS: The suggested effect of DDE on timing of natural menopause encourages further research to corroborate these findings and evaluate potential mechanisms. Prospective studies, in which exposure measurements are taken before menopause, would be particularly useful.
Key Words: Adult, Age Distribution, Aged, Case-Control Studies, Dichlorodiphenyl Dichloroethylene/adverse effects/*blood, Environmental Exposure/adverse effects, Female, Humans, *Menopause/blood, Middle Aged, North Carolina, Polychlorinated Biphenyls/adverse effects/*blood, Research Support, U.S. Gov't, P.H.S., Risk Factors
A retrospective cohort study was conducted to compare pregnancy outcomes in farming households that used pesticides conventionally with those that practiced integrated pest management (IPM) in Nueva Ecija, Philippines, in the period 1998-1999. Conventional pesticide users (CPUs) were defined as pesticide appliers who used pesticides routinely and regularly, whereas users of IPM were those who used pesticides as necessary, and on economically injured crop areas only. The data sets were subjected to the chi-square test of association, Fisher's exact probability test, and logistic regression analysis. At a significance level at 0.05, spontaneous abortion occurred significantly more often among the 345 CPU households than among the 331 IPM households (adjusted risk ratio 6.17). Likewise, birth defects were significantly more common in the CPU group (adjusted risk ratio 4.56). Thus, people of reproductive age who plan to have children should avoid any use of pesticides.
BACKGROUND: Various studies have been performed in which potential effects of xenoestrogens on fertility or sperm parameters were investigated by comparing groups of subjects exposed to different levels of these chemicals. METHODS: In our study we used an alternative approach, as we selected one group of men with very poor semen quality and another group with normal semen quality and determined the blood organochlorine contents in order to determine whether a difference in these levels could be established. Organochlorine compounds, including polychlorinated biphenyls (PCB) and PCB metabolites, were detected using gas chromatography. The concentrations were compared between both groups, and related to semen parameters. RESULTS: A comparison of both groups did not reveal significant differences in organochlorine levels. Linear relationships were found when PCB and metabolite concentrations were related to the age of the volunteers. Focusing on the subgroup of men with normal semen quality showed that sperm count and sperm progressive motility were inversely related to the concentrations of PCB metabolites within this group. CONCLUSIONS: The finding of a significantly decreased sperm count in relation to an elevated PCB metabolite level within the subgroup of men with normal semen quality is important. This is the first time that a correlation between exposure to environmental pollutants with endocrine-disrupting capacity and human sperm quality has been observed.
Here, we explore the influence of fetal programming and early life exposures on lifelong reproductive health through modification of the hypothalamic-pituitary-gonadal axis. A range of programming issues are considered with examples from the literature demonstrating that environmental or nutritive exposures have a crucial role in reproductive performance, fetal growth, postnatal development and reproduction-related disease risk. We pay particular attention to recent research on associations between indicators of fetal and postnatal growth and the etiology of polycystic ovary syndrome in women. We conclude that the concept of programming can be applied to reproductive development and related health outcomes, and that the complex potential for interactions between parameters controlling fetal development and postnatal exposures invokes a need to adopt a perspective across the life course of an individual.
Study Synopsis: Men exposed to polychlorinated byphenyls in youth father fewer male off-spring. Results from Taiwan provide strong support for earlier studies suggesting that exposure prior to adulthood to dioxin-like compounds will decrease the likelihood of fathering male offspring. This effect of contamination may be contributing to declines in the proportion of boys born in a number of industrialized countries.
Scientific abstract:
We studied the sex of children born to individuals involved in the Yucheng oil disaster, Taiwan, who were exposed to polychlorinated byphenyls (PCBs) after an oil contamination accident in 1979. Men exposed to PCBs before age 20 years had a lower chance of having a baby boy than did age-matched and neighbourhood-matched controls (odds ratio 0.65, 95% CI 0.45-0.93). The male-to-female sex ratio of children born to men exposed to PCBs after age 20 years, however, approached that seen in controls (0.90, 0.59-1.35). We noted no significant difference in the birth ratio of infants born to exposed and unexposed mothers (0.93, 0.77-1.12). Our findings suggest that paternal exposure to PCBs before age 20 years affects the sex of a subsequently born child.
Key Words: Adult, Case-Control Studies, Environmental Exposure, Female, Humans, Infant, Newborn, Logistic Models, Male, *Paternal Exposure, Polychlorinated Biphenyls/*pharmacology, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., *Sex Ratio
Dioxin, a ubiquitous contaminant of industrial combustion processes including medical waste incineration, has been implicated in the etiology of endometriosis in animals. We sought to determine whether dioxin exposure is associated with endometriosis in humans. We conducted a population-based historical cohort study 20 years after the 1976 factory explosion in Seveso, Italy, which resulted in the highest known population exposure to 2,3,7,8-tetrachlorodibenzo-(italic)p(/italic)-dioxin (TCDD). Participants were 601 female residents of the Seveso area who were (3/4) 30 years old in 1976 and had adequate stored sera. Endometriosis disease status was defined by pelvic surgery, current transvaginal ultrasound, pelvic examination, and interview (for history of infertility and pelvic pain). "Cases" were women who had surgically confirmed disease or an ultrasound consistent with endometriosis. "Nondiseased" women had surgery with no evidence of endometriosis or no signs or symptoms. Other women had uncertain status. To assess TCDD exposure, individual levels of TCDD were measured in stored sera collected soon after the accident. We identified 19 women with endometriosis and 277 nondiseased women. The relative risk ratios (RRRs) for women with serum TCDD levels of 20.1-100 ppt and >100 ppt were 1.2 [90% confidence interval (CI) = 0.3-4.5] and 2.1 (90% CI = 0.5-8.0), respectively, relative to women with TCDD levels (3/4) 20 ppt. Tests for trend using the above exposure categories and continuous log TCDD were nonsignificant. In conclusion, we report a doubled, nonsignificant risk for endometriosis among women with serum TCDD levels of 100 ppt or higher, but no clear dose response. Unavoidable disease misclassification in a population-based study may have led to an underestimate of the true risk of endometriosis.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread industrial environmental contaminant. Animal studies suggest that TCDD exposure alters the estrus cycle. Twenty years after a 1976 industrial explosion in Seveso, Italy, the authors interviewed female residents to determine whether there was an association between TCDD exposure and current menstrual cycle characteristics. The authors analyzed serum samples collected soon after the explosion to quantify individual TCDD levels. Among women who were premenarcheal at the time of the explosion, a 10-fold increase in serum TCDD level was associated with a lengthening of the menstrual cycle by 0.93 days (95% confidence interval (CI): -0.01, 1.86) and a reduction in the odds of scanty menstrual flow (adjusted odds ratio = 0.33, 95% CI: 0.10, 1.06). However, among women who were postmenarcheal at the time of the explosion, TCDD was not associated with menstrual cycle length (adjusted beta = -0.03 days, 95% CI: -0.61, 0.54) or scantiness of flow (adjusted odds ratio = 1.36, 95% CI: 0.70, 2.64). In both menarche groups, TCDD levels were associated with decreased odds of having irregular cycles (adjusted odds ratio = 0.46, 95% CI: 0.23, 0.95) but were not related to days of flow (adjusted beta = 0.16 days, 95% CI: -0.08, 0.41). These results are consistent with effects of TCDD on ovarian function noted in some animal species and with greater sensitivity to TCDD during development.
Key Words: Adult, Chemical Industry, *Environmental Exposure, Environmental Pollutants/*adverse effects/blood, Explosions, Female, Follow-Up Studies, Humans, Italy, Menstrual Cycle/*drug effects, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Tetrachlorodibenzodioxin/*adverse effects/blood
Atrazine is currently one of the most widely used agricultural pesticides in the US and is the most frequently detected pesticide in ground and surface water. Earlier work by others has raised the possibility that atrazine can act as an endocrine disrupter in rat males. The current study examined testosterone levels following in vivo and in vitro exposure to atrazine. For in vivo exposures, juvenile rat males were administered atrazine 50mg/kg body weight per day by gavage acutely (from postnatal day (pnd) 46 to 48) and chronically (from pnd 22 to 48). In both acutely- and chronically-treated animals, serum and intratesticular levels of testosterone were significantly reduced by approximately 50%. For in vitro exposures, Leydig cells isolated from rats on pnd 49 were co-cultured with 232 microM atrazine in the presence of a maximally stimulating concentration of luteinizing hormone. Compared with cells cultured with vehicle and luteinizing hormone alone, testosterone production by Leydig cells treated with atrazine was reduced by 35%. A similar decrease was observed when Leydig cells were stimulated with dibuterol cAMP (db-cAMP) in lieu of luteinizing hormone, but not when cells were stimulated with hydroxycholesterol, indicating that the effects of atrazine on testosterone production can be bypassed. Taken together, these results demonstrate that atrazine acts as an endocrine disrupter in rat males by directly inhibiting Leydig cell testosterone production.
Key Words: Androgen Antagonists/*toxicity, Animals, Atrazine/*toxicity, Cells, Cultured, Cyclic AMP/pharmacology, Herbicides/*toxicity, Leydig Cells/*drug effects/metabolism, Luteinizing Hormone/pharmacology, Male, Rats, Rats, Sprague-Dawley, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Sexual Maturation/drug effects/physiology, Testosterone/antagonists & inhibitors/*metabolism
In the current study, there was a modest but significant increase in risk (1.6- to 2-fold) for miscarriages and/or fetal loss occurring throughout the year in the spouses of applicators who use fungicides. There is a surprisingly significant deficit in the number of male children born to the spouses of fungicide applicators. First-trimester miscarriages occur most frequently in the spring, during the time when herbicides are applied. Use of sulfonylurea (odds ratio OR = 2.1), imidizolinone (OR = 2.6) containing herbicides, and the herbicide combination Cheyenne (OR = 2.9) by male applicators was statistically associated with increased miscarriage risk in the spring. Limited survey data from women who are the spouses of applicators did not show major alterations of long-term endocrinologic status (menarche, menopause, endometriosis). With regard to personal pesticide exposures, only women who engaged in pesticide application where there is direct exposure to these products are at demonstrable risk (OR = 1.8) for miscarriage. It was hypothesized that the overall reproductive toxicity observed in this population is, for the greater part, a male-mediated event. Clarification of exposure events leading to reproductive toxicity through direct measurements of exposure in both men and women is needed to resolve this issue.
Study Synopsis: Atrazine, the most abundantly used herbicide in the world, disrupts the development of frogs at extraordinarily low levels of exposure. Over 15% of males of the classic "laboratory rat" of the frog world, Xenopus laevus, developed hermaphroditic reproductive tracts when exposed, during development, to 0.1 parts per billion atrazine. The researcher team, led by Dr. Tyrone Hayes at the University of California, Berkeley,also noted demasculinization of secondary sexual characteristics and alterations in serum hormone levels.
Scientific abstract:
Atrazine is the most commonly used herbicide in the U.S. and probably the world. It can be present at several parts per million in agricultural runoff and can reach 40 parts per billion (ppb) in precipitation. We examined the effects of atrazine on sexual development in African clawed frogs (Xenopus laevis). Larvae were exposed to atrazine (0.01-200 ppb) by immersion throughout larval development, and we examined gonadal histology and laryngeal size at metamorphosis. Atrazine (> or =0.1 ppb) induced hermaphroditism and demasculinized the larynges of exposed males (> or =1.0 ppb). In addition, we examined plasma testosterone levels in sexually mature males. Male X. laevis suffered a 10-fold decrease in testosterone levels when exposed to 25 ppb atrazine. We hypothesize that atrazine induces aromatase and promotes the conversion of testosterone to estrogen. This disruption in steroidogenesis likely explains the demasculinization of the male larynx and the production of hermaphrodites. The effective levels reported in the current study are realistic exposures that suggest that other amphibian species exposed to atrazine in the wild could be at risk of impaired sexual development. This widespread compound and other environmental endocrine disruptors may be a factor in global amphibian declines.
Key Words: Animals, Atrazine/*adverse effects, Dose-Response Relationship, Drug, Estrogens/metabolism, Female, Herbicides/*adverse effects, Hermaphroditism, Hydrogen-Ion Concentration, Male, Metamorphosis, Biological/drug effects, Muscles/drug effects, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Sex Characteristics, Sex Differentiation/drug effects, Sex Factors, Testosterone/biosynthesis, Time Factors, Xenopus laevis
Study Synopsis: Significant exposure to bisphenol A occurs in the womb. Ikezuki et al. report biologically significant levels of bisphenol A (BPA) can be found in human amniotic fluid during the first trimester of pregnancy. Their data add to the weight of evidence now demonstrating that human fetal exposure to BPA is widespread and at levels that, based on animal experiments, creates plausible risks of adverse health effects.
Scientific abstract:
BACKGROUND: There is broad human exposure to bisphenol A (BPA), an estrogenic endocrine-disrupting chemical widely used for the production of plastic products. BPA is reported to affect preimplantation embryos or fetuses and alter their postnatal development at doses typically found in the environment. We measured contamination of BPA in various kinds of human biological fluids by a novel enzyme-linked immunosorbent assay. METHODS: Blood samples were obtained from healthy premenopausal women, women with early and full-term pregnancy, and umbilical cord at full-term delivery. Ovarian follicular fluids obtained during IVF procedures and amniotic fluids obtained at mid-term and full-term pregnancy were also subject to BPA measurements. RESULTS: BPA was present in serum and follicular fluid at approximately 1-2 ng/ml, as well as in fetal serum and full-term amniotic fluid, confirming passage through the placenta. Surprisingly, an approximately 5-fold higher concentration, 8.3 +/- 8.7 ng/ml, was revealed in amniotic fluid at 15-18 weeks gestation, compared with other fluids. CONCLUSION: These results suggest accumulation of BPA in early fetuses and significant exposure during the prenatal period, which must be considered in evaluating the potential for human exposure to endocrine-disrupting chemicals.
Study Synopsis: Best semen quality located in areas with the lowest risk of testicular cancer. Trends in sperm quality in the Nordic-Baltic region of Europe are consistent with predictions from the testicular dysgenesis syndrome theory. This theory proposes that four male reproductive maladiesłtesticular cancer, hypospadias, cryptorchidism and poor sperm qualityłare all part of the same syndrome, with many cases due to environmental causes.
Scientific abstract:
BACKGROUND: Denmark and Norway have a three-fold higher incidence of testicular cancer than Estonia and Finland. Groups of young men from Denmark, Norway, Finland and Estonia were investigated to elucidate whether semen parameters and other related parameters follow a gradient between these countries, as does the gradient in incidence of testicular cancer. METHODS: In total, 968 young men from the general population in these four countries were investigated according to the same protocol. Possible confounders were evaluated, and included in the statistical analysis when appropriate. Inter-laboratory differences in assessment of sperm concentrations were controlled by an external quality control programme and morphology assessment was centralized to one person. RESULTS: The Finnish and Estonian men had an adjusted median sperm concentration of 54 and 57 x 10(6)/ml, respectively and the Norwegian and Danish men 41 x 10(6)/ml. The corresponding total sperm counts were 185, 174, 133 and 144 x 10(6). The frequency of normal sperm in men from Finland was 8.9%, Estonia 9.2%, Norway 6.9% and Denmark 6.4%. Within all four groups of men, a relationship between increasing levels of inhibin-B and increasing sperm counts was observed. However, inhibin-B levels were not predictive of sperm count differences between countries. CONCLUSIONS: It is believed that the men examined were representative of the normal population of young men in all four countries as they were recruited from groups attending a compulsory medical examination, and not selected for known fertility or semen quality. Moreover, the majority of participants had no prior knowledge of their fertility potential. It appears that an east-west gradient exists in the Nordic-Baltic area with regard to semen parameters, this being in parallel with the incidences of testicular cancer. Further investigations are required to determine whether these findings are due to genetic differences, to different environments, or perhaps to a combination of both factors.
Study Synopsis: Scientists challenge the conventional demographic interpretation of why fertility rates are falling in industrialized countries. Danish scientists propose that the decline may not be due solely to voluntary choices made by women about how many children they should have. They argue that involuntary factors may also be involved, specifically the increasing percentage of men whose sperm density is sufficiently low to impair fertility.
Scientific abstract:
During past decades, we have witnessed a remarkable decline in fertility rates (number of births per 1000 women of reproductive age) in the industrialized world. It seems beyond doubt that the enormous social changes of our societies play the major role in this decline, but can it be attributed to changing social structures alone or is a reduced fecundity in the population also a factor? To address this we have focused on trends in teenage pregnancies (which to a large extent are unplanned). During the period in question fertility rates among 15-19 year old Danish women have been falling and the decline in fertility rate is not counterbalanced by an increase in the rate of induced abortion. When seen together with recent results from Denmark, which have shown that more than 30% of 19 year old men from the general population now have sperm counts in the subfertile range, we argue that this fall may not be attributable to social factors, changes in conception practices or diminished sexual activity alone. It seems reasonable also to consider widespread poor semen quality among men as a potential contributing factor to low fertility rates among teenagers. Due to the concern caused by the low sperm count among younger Danish men, the Danish Ministries of Health and Environment have launched a surveillance programme which includes an annual examination of the semen quality in 600 young Danes from the general population. We propose that researchers in other countries with low and falling fertility rates among young women should consider the possibility that semen quality of their younger male cohorts may also have deteriorated.
Thousands of cycles of in vitro fertilization (IVF) are performed each year. In the US, multiple births occur after 39% of IVF cycles, whereas in Europe, the figure is 26%. Indeed, multiple births are a major factor in the costs attributable to IVF. Reducing the multiple birth rate may reduce the overall costs of IVF, and providing insurance coverage of IVF may contribute to lowering multiple birth rates. The use of IVF is likely to expand in response to increases in infertility and scientific advances.
Key Words: Female, Fertilization in Vitro/*economics/trends, Humans, Pregnancy, Pregnancy, Multiple, Reproductive Techniques, Assisted/*economics/*trends, Research Support, U.S. Gov't, P.H.S.
In a previous experiment, maternal exposure to a polychlorinated biphenyl (PCB) mixture reconstituted according to the congener pattern found in human breast milk resulted in decreased aromatase activity in the brain of newborn male rats, together with feminization of sweet preference behavior in adult male littermates. Both mixtures led to similar reductions of serum testosterone and testes weights. The purpose of the present study was (1) to examine the dose-response relationship for the reconstituted mixture and (2) to study if the rewarding properties of testosterone are affected at levels sufficient to alter sweet preference behavior. Female rats were fed diets with 0, 5, 20, or 40 mg PCBs/kg diet, resulting in an average daily intake of 0, 0.5, 2, or 4 mg/kg body wt. Exposure started 50 days prior to mating and was continued until birth of the offspring. A dose-dependent elevation of sweet preference was found in adult male offspring, indicating feminization of this sexually dimorphic behavior. Examination of conditioned place preference revealed a preference for the testosterone-paired side at the highest exposure condition. In weanling female offspring, dose-dependent reductions of serum testosterone and estradiol concentrations were detected. In addition, testosterone concentrations were reduced in a dose-dependent manner in adult male littermates long after termination of exposure. PCB concentrations in adipose tissue from offspring of the low dose group (0.5 mg/kg body wt) were approximately 10 times higher than values at the upper margin of current human exposure. Taken together, results indicate long-lasting and dose-dependent changes in sex-dependent behaviors and levels of sex steroid hormones in rats following developmental exposure to a PCB mixture that resembles the breast milk pattern.
BACKGROUND: Transgenerational effects of diethylstilbestrol (DES) have been reported in animals, but effects in human beings are unknown. Alerted by two case reports, we aimed to establish the risk of hypospadias in the sons of women who were exposed to DES in utero. METHODS: We did a cohort study of all sons of a Dutch cohort of 16284 women with a diagnosis of fertility problems. We used a mailed questionnaire assessing late effects of fertility treatment to identify boys with hypospadias. We compared the prevalence rate of hypospadias between boys with and without maternal DES exposure in utero. FINDINGS: 16284 mothers (response rate 67%) reported 8934 sons. The mothers of 205 boys reported DES exposure in utero. Four of these children were reported to have hypospadias. In the remaining 8729 children, only eight cases of hypospadias were reported (prevalence ratio 21.3 [95% CI 6.5-70.1]). All cases of hypospadias were medically confirmed. Maternal age or fertility treatment did not affect the risk of hypospadias. Children conceived after assisted reproductive techniques such as in-vitro fertilisation were not at increased risk of hypospadias compared with children conceived naturally (1.8, 0.6-5.7). INTERPRETATION: Our findings suggest an increased risk of hypospadias in the sons of women exposed to DES in utero. Although the absolute risk of this anomaly is small, this transgenerational effect of DES warrants additional studies.
Study Synopsis: Inconclusive support for the hypothesis that DDE acting as an anti-androgen causes reproductive tract birth defects in boys. The study, published in the American Journal of Epidemiology, assayed umbilical blood stored since the 1960s for DDE and looked for statistical associations between birth outcome and DDE level. Their analysis found indications of elevations in risk but the results remained ambigous.
Scientific abstract:
1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) is a metabolite of the insecticide 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) and is a ubiquitous environmental contaminant. Nearly everyone in the United States has a detectable serum level of DDE. DDE was recently found to inhibit binding of androgen to its receptor and to block androgen action in rodents. Normal development of male genitalia in mammals depends on androgen action. The authors used stored serum samples to examine the relation between maternal DDE levels during pregnancy and adjusted odds of cryptorchidism (n = 219), hypospadias (n = 199), and polythelia (extra nipples) (n = 167) among male offspring, using a nested case-control design with one control group (n = 552). Subjects were selected from the Collaborative Perinatal Project, a US birth cohort study begun in 1959-1966, when DDE levels were much higher than they are at present. Compared with boys whose mother's recovery-adjusted serum DDE level was less than 21.4 microg/liter, boys with maternal levels greater than or equal to 85.6 microg/liter had adjusted odds ratios of 1.3 (95% confidence interval (CI): 0.7, 2.4) for crypt-orchidism, 1.2 (95% CI: 0.6, 2.4) for hypospadias, and 1.9 (95% CI: 0.9, 4.0) for polythelia. For cryptorchidism and polythelia, the results were consistent with a modest-to-moderate association, but in no instance was the estimate very precise. The results were inconclusive.
The production and release of synthetic chemicals into the environment has been a hallmark of the "Second Industrial Revolution" and the "Green Revolution." Soon after the inception of these chemicals, anecdotal evidence began to emerge linking environmental contamination of rivers and lakes with a variety of developmental and reproductive abnormalities in wildlife species. The accumulation of evidence suggesting that these synthetic chemicals were detrimental to wildlife, and potentially humans, as a result of their hormonal activity, led to the proposal of the endocrine disruptor hypothesis at the 1991 Wingspread Conference. Since that time, experimental and epidemiological data have shown that exposure of the developing fetus or neonate to environmentally-relevant concentrations of certain synthetic chemicals causes morphological, biochemical, physiological and behavioral anomalies in both vertebrate and invertebrate species. The ubiquitous use, and subsequent human exposure, of one particular chemical, the estrogen mimic bisphenol A (BPA), is the subject of this present review. We have highlighted this chemical since it provides an arresting model of how chemical exposure impacts developmental processes involved in the morphogenesis of tissues and organs, including those of the male and female reproductive systems, the mammary glands and the brain.
Prenatal exposure to the herbicide linuron, a weak androgen receptor antagonist, has been shown to perturb androgen-dependent male rat reproductive development as evidenced by slight decreases in anogenital distance (AGD), increased retention of areolae/nipples, and induction of epididymal malformations in combination with testicular atrophy in the adult rat over dose levels ranging from 12.5 to 100 mg/kg/day. Studies were undertaken to determine whether linuron-mediated changes in AGD and nipple retention are permanent, whether linuron is a direct testicular toxicant, and if there was an association between areola/nipple retention and malformations. Pregnant rats were administered corn oil vehicle or linuron by gavage at 0 or 50 mg/kg/day (n = 8 controls, 20 treated) from gestation days 12 to 21. Male offspring were necropsied on postnatal days (PND) 35 and 56. Linuron-exposed male rats exhibited a significant (8%) decrease in AGD on PND 1 and a similar decrease was also observed on PND 56. Linuron-exposed male rats displayed an increase in areola retention on PND 13, as evidenced by 0.6 +/- 0.5 and 3.3 +/- 0.4 areolae per rat in the control and exposed groups, respectively. Male rats displayed a significant increase in nipple retention on PND 35 and 56 (collectively) of 0 +/- 0.5 and 1.7 +/- 0.3 nipples per rat in control and exposed groups, respectively. On PND 35, 4/51 rats (3/9 litters) from linuron-treated dams displayed enlarged testes in combination with malformed epididymides. Epididymal malformations were observed in 19/51 rats (6/9 litters) in the linuron-exposed dose group. On PND 56, grossly enlarged and edematous testes were seen in 16/56 linuron-exposed rats (6/9 litters). Epididymal lesions were observed in 23/58 rats (6/9 litters). Microscopically, all linuron-exposed animals that exhibited a testicular lesion on PND 56 also displayed an epididymal lesion. These lesions were not seen in control animals. Approximately 25 and 60% of the male offspring that had malformations of the epididymis and vas deferens did not exhibit either areolae on PND 13 or nipples at necropsy, respectively. These data indicate that in utero linuron exposure to 50 mg/kg/day results in permanent changes in AGD and nipple retention in male rats. Moreover, these findings indicate that linuron-induced testicular atrophy, which is observed in adult rats, is secondary to increased intratubular pressure resulting from obstruction of testicular fluid outflow subsequent to malformation of the epididymides. These data also suggest that although linuron-mediated retention of areolae on PND 13 and nipples at necropsy may be suggestive of altered testosterone-mediated reproductive development seen in adult rats, these endpoints are not predictive.
Endocrine-disrupting chemicals (EDCs) are hormone-like agents present in the environment that alter the endocrine system of wildlife and humans. Most EDCs have potencies far below those of the natural hormone 17beta-E2 when acting through the classic estrogen receptors (ERs). Here, we show that the environmental estrogen Bisphenol-A and the native hormone 17beta-E2 activate the transcription factor, cAMP-responsive element binding protein (CREB) with the same potency. Phosphorylated CREB (P-CREB) was increased after only a 5-minute application of either BPA or 17beta-E2 in a calcium-dependent manner. The effect was reproduced by the membrane-impermeable molecule E2 conjugated to horseradish peroxidase (E-HRP). The increase in P-CREB was not modified by the anti-estrogen ICI 182,780. Therefore, low-dose of BPA activates the transcription factor CREB via an alternative mechanism, involving a non-classical membrane estrogen receptor. Because these effects are elicited at concentrations as low as 10(-9) M, this observation is of environmental and public health relevance.
Study Synopsis: Indian study links phthalates and PCBs to lower sperm quality. Researchers in Andhra Pradesh, India, report that a series of sperm parameters were lower in a group of infertile men, and that these men also had higher levels of contaminants. Unfortunately, the sample sizes are extremely small and the chemical analysis technique used is vulnerable to contamination. No firm conclusions can be drawn from this study. But it surely points toward important areas of research.
Scientific abstract:
OBJECTIVE: To evaluate the role of the environmental estrogens polychlorinated biphenyls (PCBs) and phthalate esters (PEs) as potential environmental hazards in the deterioration of semen parameters in infertile men without an obvious etiology. DESIGN: Randomized controlled study. SETTING: Tertiary care referral infertility clinic and academic research center. PATIENT(S): Twenty-one infertile men with sperm counts <20 million/mL and/or rapid progressive motility <25% and/or <30% normal forms without evidence of an obvious etiology and 32 control men with normal semen analyses and evidence of conception.Semen and blood samples were obtained as part of the treatment protocol. MAIN OUTCOME MEASURE(S): Evaluation of semen parameters such as ejaculate volume, sperm count, motility, morphology, vitality, osmoregulatory capacity, sperm chromatin stability, and sperm nuclear DNA integrity. RESULT(S): PCBs were detected in the seminal plasma of infertile men but not in controls, and the concentration of PEs was significantly higher in infertile men compared with controls. Ejaculate volume, sperm count, progressive motility, normal morphology, and fertilizing capacity were significantly lower in infertile men compared with controls. The highest average PCB and PE concentrations were found in urban fish eaters, followed by rural fish eaters, urban vegetarians, and rural vegetarians. The total motile sperm counts in infertile men were inversely proportional to their xenoestrogen concentrations and were significantly lower than those in the respective controls. CONCLUSION(S): PCBs and PEs may be instrumental in the deterioration of semen quality in infertile men without an obvious etiology.
Study Synopsis: Russian male pesticide workers exposed to dioxin and dioxin-like compounds father fewer boys than would be expected on the basis of world-wide and regional sex ratios. Normally slightly more boys are born than girls, with a resulting sex ratio (# boys divided by # of total births) averaging 0.51. In Ufa, a town just west of the Urals where pesticides have been produced since the 1940s, the sex ratio of children born to exposed fathers was 0.38, and that of a highly exposed subgroup was 0.23.
Scientific abstract:
We investigated the sex ratio of children of pesticide workers who produced the biocide trichlorophenol and the herbicide 2,4,5-trichlorophenoxy acetic acid from 1961 to 1988 in the city of Ufa, Bashkortostan, Russia. We measured exposure of the two related cohorts to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxins by analyzing 84 blood samples, which produced median TCDD toxic equivalents blood lipid values of 240 ng/kg, which are more than 30 times higher than background or normal exposure from the region. The sex ratio (fraction male) of the combined cohort of 227 children from 150 male and 48 female workers was 0.40, significantly lower (z-test for proportions = 3.21; p < 0.001) than those for the city of Ufa (0.512) and elsewhere worldwide. When we analyzed the sex ratio of the children according to maternal or paternal exposure, we observed a decrease in the number of boys (ratio 0.38) for fathers and a normal number (ratio 0.51) for the mothers. Human exposure of these pesticide producers to high levels of dioxins is associated with the birth of more girls, but only for paternal exposures.
Bisphenol A (BPA), an endocrine disruptor, is employed in the manufacture of a wide range of consumer products. The suggestion that BPA, at amounts to which we are exposed, alters the reproductive organs of developing rodents has caused concern. At present, no information exists concerning the exposure of human pregnant women and their fetuses to BPA. We therefore investigated blood samples from mothers (n = 37) between weeks 32 and 41 of gestation. Afer the births, we also analyzed placental tissue and umbilical cord blood from the same subjects. We developed a novel chemical derivatization-gas chromatography/mass spectrometry method to analyze parent BPA at concentrations < 1 micro g/mL in plasma and tissues. Concentrations of BPA ranged from 0.3 to 18.9 ng/mL (median = 3.1 ng/mL) in maternal plasma, from 0.2 to 9.2 ng/mL (median = 2.3 ng/mL) in fetal plasma, and from 1.0 to 104.9 ng/g (median = 12.7 ng/g) in placental tissue. BPA blood concentrations were higher in male than in female fetuses. Here we demonstrate parent BPA in pregnant women and their fetuses. Exposure levels of parent BPA were found within a range typical of those used in recent animal studies and were shown to be toxic to reproductive organs of male and female offspring. We suggest that the range of BPA concentrations we measured may be related to sex differences in metabolization of parent BPA or variable maternal use of consumer products leaching BPA.
Key Words: Adult, *Environmental Exposure, Estrogens, Non-Steroidal/metabolism/*pharmacokinetics, Female, Humans, Male, Mass Fragmentography, *Maternal-Fetal Exchange, Phenols/metabolism/*pharmacokinetics, Placenta/*chemistry, Pregnancy, Sex Factors
Research notes: Comment in Environ Health Perspect. 2003 Jun;111(7):A382-3; author reply A383.
The effects of adult lifestyle--primarily smoking and diet in women, and sedentary habits generally--are important factors affecting the fertility of men and women, and can also impact the fertility of their children. This review summarizes the effects of season, modern lifestyles and environmental chemicals on human fertility, and discusses the implications of these effects for future generations.
Study Synopsis: Women with endometriosis are far more likely to suffer from other endocrine and immune system disorders. Infertility is high compared to women in the general US public, and the incidence of lupus, chronic fatigue syndrome, hypothyroidism and several other diseases is greatly elevated. This research may assist in treatment of these diseases and also help shed light on their causes.
Scientific abstract:
BACKGROUND: Women with endometriosis may also have associated disorders related to autoimmune dysregulation or pain. This study examined whether the prevalence of autoimmune, chronic pain and fatigue and atopic disorders is higher in women with endometriosis than in the general female population. METHODS AND RESULTS: A cross-sectional survey was conducted in 1998 by the Endometriosis Association of 3680 USA members with surgically diagnosed endometriosis. Almost all responders had pain (99%), and many reported infertility (41%). Compared with published rates in the general USA female population, women with endometriosis had higher rates of hypothyroidism (9.6 versus 1.5%, P < 0.0001), fibromyalgia (5.9 versus 3.4%, P < 0.0001), chronic fatigue syndrome (4.6 versus 0.03%, P < 0.0001), rheumatoid arthritis (1.8 versus 1.2%, P = 0.001), systemic lupus erythematosus (0.8 versus 0.04%, P < 0.0001), Sjogren's syndrome (0.6 versus 0.03%, P < 0.0001) and multiple sclerosis (0.5 versus 0.07%, P < 0.0001), but not hyperthyroidism or diabetes. Allergies and asthma were more common among women with endometriosis alone (61%, P < 0.001 and 12%, P < 0.001 respectively) and highest in those with fibromyalgia or chronic fatigue syndrome (88%, P < 0.001 and 25%, P < 0.001 respectively) than in the USA female population (18%, P < 0.001 and 5%, P < 0.001 respectively). CONCLUSIONS: Hypothyroidism, fibromyalgia, chronic fatigue syndrome, autoimmune diseases, allergies and asthma are all significantly more common in women with endometriosis than in women in the general USA population.
Vahter M, Berglund M, Akesson A, Lidén C. Metals and women's health. Environ Res. 2002 Mar;88(3):145-55.
Scientific abstract:
There is a lack of information concerning whether environmental-related health effects are more or less prevalent or manifested differently in women compared to men. Previously, most research in the area of toxicology and environmental and occupational health involved male subjects. The present work aims at reviewing exposure and health effects of cadmium, nickel, lead, mercury, and arsenic manifested differently in women than in men. The gender difference in exposure to nickel results in a much higher prevalence of nickel allergy and hand eczema in women than in men. The internal cadmium dose is generally higher in women than in men, due to a higher gastro-intestinal absorption at low iron stores. This was probably one major reason why Itai-itai disease was mainly a woman's disease. Yet, data are sparse regarding the risk for women relative to men to develop cadmium-induced kidney damage in populations exposed to low levels of cadmium. Lead is accumulated mainly in bone and increased endogenous lead exposure has been demonstrated in women during periods of increased bone turnover, e.g., menopause. Both lead and mercury exposure in pregnant women has to be kept low in order to prevent neurodevelopment effects in the developing fetus and child. Limited data indicate that women are more affected than men following exposure to methylmercury at adult age, while males seem to be more sensitive to exposure during early development. Regarding arsenic, some data indicate gender differences in the biotransformation by methylation, possibly also in susceptibility to certain arsenic-related cancers. Obviously, gender-related differences in exposure and health effects caused by metals are highly neglected research areas, which need considerable focus in the future.
Human populations throughout the world are exposed daily to low levels of environmental contaminants. The consequences of potential interactions of these compounds to human endocrine, reproductive, and immune function remain unknown. The current study examines the effects of subchronic oral exposure to a complex mixture of ubiquitous persistent environmental contaminants that have been quantified in human reproductive tissues. The dosing solution used in this study contained organochlorines (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], polychlorinated biphenyls [PCBs],p,p'-dichlorodiphenoxydichloroethylene [p,p'-DDE],p,p-dichlorodiphenoxytrichloroethane [p,p'-DDT], dieldrin, endosulfan, methoxychlor, hexachlorobenzene, and other chlorinated benzenes, hexachlorocyclohexane, mirex and heptachlor) as well as metals (lead and cadmium). Each chemical was included in the mixture at the minimum risk level (MRL) or tolerable daily intake (TDI) as determined by the U.S. EPA or ATSDR or, for TCDD, at the no observable effect level (NOEL) used to calculate the TDI. Sexually mature male rats were exposed to this complex mixture at 1, 10, 100, and 1000 times the estimated safe levels daily for 70 days. On day 71, all animals were sacrificed and a variety of physiological systems assessed for toxic effects. Evidence of hepatotoxicity was seen in the significant enlargement of the liver in the 1000x group, reduced serum LDH activity (100x), and increased serum cholesterol and protein levels (both 1000x). Hepatic EROD activities were elevated in animals exposed to10x and above. The mixture caused decreased proliferation of splenic T cells at the highest dose and had a biphasic effect on natural killer cell lytic activity with an initial increase in activity at 1x followed by a decrease to below control levels in response to 1000x. No treatment-related effects were seen on bone marrow micronuclei, daily sperm production, serum LH, FSH, or prolactin levels or weights of most organs of the reproductive tract. The weights of the whole epididymis and of the caput epididymis were significantly decreased at 10x and higher doses, although no effect was seen on cauda epididymal weight. The sperm content of the cauda epididymis was increased at the 1x level but not significantly different from control at higher dose levels. A slight, but significant, increase in the relative numbers of spermatids was seen in the animals from the 1000x group with a trend towards reduced proportion of diploid cells at the same dose. Only minor, nondose related changes were seen in parameters related to condensation of chromatin, as determined by flow cytometry, in epididymal sperm. We conclude that the mixture induced effects on the liver and kidney and on general metabolism at high doses but caused only minor effects on immune function, reproductive hormone levels, or general indices of reproductive function measures. These data suggest that additive or synergistic effects of exposure to contaminants resulting in residue levels representative of contemporary human tissue levels are unlikely to result in adverse effects on immune function or reproductive physiology in male rats.
Environmental chemicals are thought to adversely affect human reproductive function, however there are no studies that have explored the association between failed fertilization and exposure of both partners to environmental contaminants. Therefore, we collected blood and follicular fluid from the female partner and seminal plasma from the male partner of 21 couples attending an in vitro fertilization (IVF) program, in order to determine the extent of the existence of environmental chemicals in these fluids. Any relationship to the outcome of IVF was also considered. Sera and fluids were analysed for a variety of contaminants, including polychlorinated biphenyls, pesticides, cotinine, and the steroids progesterone and estradiol. Of the couples examined, 18 had fertilizations, three of whom became pregnant. There were no fertilizations in three other couples. The contaminants most frequently found in follicular fluid, more than 50% of the samples tested, were p,p'-DDE, mirex, hexachloroethane, 1,2,4-trichlorobenzene, PCB 49, PCB 153, and PCB 180. Cadmium was detected in eight of 21 (38.1%) samples of follicular fluid whereas cotinine was detected in 18 (85.7%). Residue levels of p,p'-DDE, endosulfan I, PCB 99, PCB 138, PCB 153, PCB 180 were quantified in more than 50% of the sera samples examined. Seminal plasma was relatively free of pollutants with mirex being the most frequently detected contaminant found in seven of 21 (33.3%) samples. Mirex could not be detected in the seminal plasma of the husbands whose partner's oocytes failed to fertilize whereas significant levels of mirex were found in the seminal plasma of all couples who had a pregnancy. Cadmium was also found in the follicular fluid of these pregnant subjects. No relationship was found between follicular fluid cotinine in pregnant and non-pregnant subjects. Where identical contaminants were found in both sera and follicular fluids, the levels were about twofold higher in serum and were positively correlated in both fluids. Fertilization was negatively correlated with serum and follicular fluid p,p'-DDE whereas pregnancy was positively correlated with follicular fluid PCB 49. These data reveal that more than 50% of the population of women attending a fertility program have had exposure to environmental chemicals sufficient to produce detectable concentrations in their serum and ovarian follicular fluid. Of the chemical contaminants detected in the serum and follicular fluid of these women, p,p'-DDE was the most frequently detected, had the highest residue levels, and was associated with failed fertilization.
