Jon Sharpe, EDGE Center, http://deohs.washington.edu/ceeh/
Almost all complex chronic diseases are influenced by gene-environment interactions. We provide an introduction to genetic and epigenetic mechanisms of health, disease and disability.
To understand how the environment interacts with our genome, the complete set of our genes, we must first understand that different versions of genes, known as variants, are found among individuals. These variants are differences in specific locations in the sequence of DNA, sequences that constitute individual genes. These variants, combined from all parts of the genome, are known as genotypes and are unique to each person. Genotypes contribute to the differences in traits between people. The physical expression of the genotype is called the phenotype, the observable expression of the genotype. For example, people with blue eyes have the gene variant, or genotype, that produces the observable phenotype of blue eyes.
In many genes, different variants (genotypes), alter the expressed outcomes (phenotype) even when exposed to the same environmental exposure. When health outcomes differ by genotype and require one or more environmental stimuli, the health outcome is said to result from a gene-environment interaction.
This gene-environment interaction makes one person able to drink a lot of coffee without becoming wired, while another person cannot handle more than a cup. In this case, one genetic variant in the enzyme that metabolizes caffeine can be more efficient in one person while another variant is less efficient in another person. Your ability to metabolize caffeine is dependent on which two variants you carry. Similarly, some people are less efficient at metabolizing environmental chemicals, putting them at a higher risk for disease. These variants can create a genetic susceptibility to disease, but the environmental exposure is still required for the disease to manifest.1 See the yellow column at the right for an analogy that may help clarify this.
Some gene variants can be beneficial, providing protection against the harmful effects of outside agents. That said, the risks for common chronic diseases, such as cancer, Parkinson’s disease and diabetes, are now known to result from the complex interactions between environmental exposures and gene variants.2
We are currently in the era of the genomic revolution. The Human Genome Project was a 13-year worldwide effort to decode the human genome. Launched in 1990 and completed in 2003, this project provided the research foundation to better understand the genetic variants in our population. Researchers are now investigating how the environment interacts with those gene variants to better understand how chronic diseases arise.3
The National Institutes of Health (NIH) launched the Precision Medicine Initiative in 2015 and Cancer Moonshot Initiative in 2016. The goal of these initiatives is to better understand and intervene on complex chronic disease by researching the interactions between genetic variation, some environmental factors and lifestyle choices of individuals. The Precision Medicine Initiative anticipates enrolling a cohort of one million US participants and will focus on four program components:
- Data and research support
- Participant technologies
- Healthcare provider organizations
The White House announced the initiative and called for $215 million of federal funding in 2016 to support this work.
In an open letter to Vice President Biden, some colleagues expressed concern that these efforts focus mostly on therapies, cures and individual actions and not enough on primary prevention of environmental exposures linked to various forms of cancer or the upstream, systems-based interventions to reduce the incidence of cancer.
Some environmental exposures that can impact people differently based on their genotypes:4
Research indicates that most human diseases manifest from the interaction of genetic variants that predispose people to disease and modifiable environmental exposures, such as these:5
- physical surroundings, both environmental and psychological
Diseases that involve gene-environment interactions are multifactorial, each developing from a contribution of genetics and environment. This is the case for all complex diseases. Some of these disease outcomes include:6
Genes and Exposures: An Analogy
Suppose that your body is like a house, and your genes are the appliances: the furnace, refrigerator, air conditioner, toaster, vacuum, faucets and so on. These appliances determine the physical state of your home. The warm or cool air inside, the fresh food and the clean clothes and carpets are your phenotypes—the physical expression of your genes. Having a cup of coffee (phenotype) requires you to first own a coffeemaker (gene). The quality of the coffee it produces depends on the brand and options (genotype or gene variants), but also on the quality of the coffee beans and water, plus a supply of electricity (the environmental inputs). Similarly, your genotype gives the instructions to produce your phenotype—your type of hair, your height, your body build and most of your physical characteristics, but these also depend in part on your environment.
During development our environment can modify the instructions our genes are sending. Perhaps not enough nutritious food was available when our body was growing, or we had a bout of infectious disease (malaria) or were exposed to toxic chemicals (air pollution); each of these can change how our body develops. We can develop a degree of mismatch between our genotype (genetic code) and our phenotype (physical characteristics). We would say that the person has not achieved their genetic potential.
Now suppose that you got a few faulty appliances. Your vacuum cleaner "gene" is weak and doesn’t clean the carpet well. Even though you are using your vacuum, your carpets remain dirty. Through time, the dirt accumulates. The amount of dirt that builds depends on how dirty the air is in your house. If the air in your house is clean, the vacuum is still sufficient. If your house’s air is filled with pollution, the dirt and chemicals will build up on your carpet. In your body, the vacuum could be a gene that controls cleaning your blood. If your blood is not cleaned effectively, it can lead to disease, but the disease manifests because of the quality of your environment. Research has been showing that there are gene variants that interact with environmental exposures differently. It takes the combination of having the faulty gene variant and the exposure(s) to result in some diseases and disabilities, such as Parkinson's disease and others discussed on this page.
This analogy is not perfect. Sometimes there are many genes that act together to influence the development of disease or disability. However, this analogy may help you understand some of the complex gene-environment interactions that influence our health.
- Autism. Research suggests that exposures to air pollution or pesticides in utero contribute to an increased risk for this disorder in those who are genetically susceptible.
- Breast cancer. Research has shown that breast cancer is caused by genetic, hormonal and environmental risk factors combined. Some exposures associated with an increased risk of breast cancer risk include combination hormonal therapies, oral contraceptives, ionizing radiation, obesity, alcohol use and some synthetic estrogens.7
- Parkinson’s disease. Exposures to pesticides, dietary nutrition, exercise and nicotine may have a stronger impact in those who are genetically susceptible (more detail below).
Example Gene-Environment Interactions
Below are some known gene-environment interactions that increase the risk for specific disease outcomes.
Organophosphate Pesticides and Parkinson’s Disease
Sporadic Parkinson’s disease (PD) manifests from a combination of multiple gene variants, environmental exposures and lifestyle choices. This complex interaction makes most types of Parkinson’s disease a multifactorial disorder. Organophosphate pesticides, commonly used in agriculture, are neurotoxins that have been implicated in the development of PD.8 Genetic variation in the gene that produces the enzymes that metabolize (detoxify) organophosphate pesticides leads some people to have genetic susceptibility to the toxic actions of organophosphate pesticides. This genetic susceptibility makes these people more susceptible to the development of PD when exposed. The PON1 gene codes for an enzyme paraoxonase, an aryl esterase, that metabolizes organophosphates.9 Some individuals carry a less efficient variant of PON1 and, when exposed to organophosphates, have double the risk of developing Parkinson’s disease versus a person who has a more efficient version of the same enzyme.10
Abuse and Antisocial Behavior
There are different variants in the monoamine oxidase A gene (MAOA), which produces a protein that metabolizes neurotransmitters in the brain (such as dopamine, norepinephrine and serotonin). Gene-environment research by Fergusson and others demonstrates that children with variants in the MAOA gene who are also exposed to child abuse have a higher risk of developing antisocial behavior than abused children who do not carry the risk variant. Children in that study who carried a low-activity MAOA variant and experience abuse were more likely later to be criminal offenders, demonstrate hostility and exhibit conduct problems.11 Though no child should be exposed to abuse in childhood, there appears to be a genetic subpopulation who carries a higher risk of adverse behavior outcomes resulting from this environmental exposure.
Asthma and Air Pollution
Two genes are known to detoxify exposures that cause oxidative stress, such as air pollution. The glutathione (GST) gene and the epoxide hydrolase (EPHX1) genes both have variants associated with an increased risk of developing asthma, especially if a person is exposed to air pollution. We now know the risk of asthma increases 50% if an individual carries a poorly functioning EPHX1 variant. The risk increases by 4-fold if a person carries both a poorly functioning EPHX1 and GST variant. Most striking, however, is the interaction between these variants and exposure to air pollution. Children who have both high-risk variants and live close to a major roadway have a 9-fold increased risk of developing asthma. You can read more about this interaction and the environmental drivers of asthma in CHE's A Story of Health chapter on Asthma: Brett's Story.
Esophageal Cancer and Alcohol
The aldehyde dehydrogenase 2 (ALDH2) gene produces an enzyme important to alcohol metabolism. There are two different variants in the gene, one that produces a functioning enzyme and one that produces a nonfunctioning enzyme. Individuals who carry the nonfunctioning variant of the ALDH2 gene have substantial problems metabolizing alcohol, as the broken enzyme causes aldehyde to build up in the body, known as flushing syndrome. It is believed that around 540 million people worldwide carry one or both non-functioning variants. When an individual carries one of the variants (heterozygotes), one nonfunctioning and one normal, they have a 100-fold reduction in alcohol metabolism. These heterozygotes have a higher risk of esophageal cancer when exposed to moderate or heavy ethyl alcohol use as compared to someone who has both functioning variants. Esophageal squamous cell carcinoma (ESCC) is an aggressive cancer with a five-year survival rate around 15 percent.12 Interestingly, carrying two copies of the nonfunctioning enzyme reduces risk for esophageal cancer since those individuals usually avoid alcohol due to the illness they experience after consuming.13
Epigenetics: An Analogy
Continuing our analogy of genes as appliances from above, let’s assume a gene your body needs is like your kitchen faucet. To get water out of the faucet, you have to physically turn it on and off. If you forget to turn the water off, it can flood the kitchen with too much water, doing considerable damage. If the faucet is jammed and you can’t get it to turn on, you will be thirsty and unable to cook or clean. Just as you physically controll a faucet, the epigenome controls if a gene is on or off. As such, if a gene that leads to cell growth is turned on at the wrong time, cancer will be fostered.
There are some parts of our genome we always want to keep dormant. In our analogy, let’s say you are going out of town for a long time. You want to make sure your house’s appliances remain off and no unwelcomed outsiders can enter your property. To ensure this, you turn the security system on and lock your doors as protection against outside intrusion and activity. Likewise, there are genes in our genome, conserved through our evolutionary history, that must stay off to conserve good health. Just as the security system locks down your dormant house, the epigenome silences these unneeded genes. Some environmental exposures, such as BPA, can break down this security system and turn on genes that disrupt healthy systems.
Whereas the genome is the full code for all of the proteins that make up a human being, the epigenome, in its simplest form, is a system of tags that surround the genome and controls what it does. It is these tags that can turn a gene on or off, controlling if a gene produces its product. Through epigenetic mechanisms, cells can become specialized.14 In fact, your development from one fertilized egg into a collection of 200 cell types across 3 trillion adult cells occurs through epigenetic regulation.15 Though every single cell in your body holds the entire genetic code for a human being, only specific genes are active in specific cells. This is how cells are specialized. For example, genes that allow cells to detect light are turned on in the eye but not the liver. Humans need different genes to function at different times, depending on if cells need to repair themselves, to fight off intruders, to divide into two cells, or to function as part of an organ. Epigenetic mechanisms allow this to happen.16
Environmental exposures can change gene expression through epigenetic mechanisms. For example, worker bees and a queen bee are genetically identical. When a developing bee is fed royal jelly, an epigenetic modification is made to the reproductive genes and they turn on. The genes are not changed, but whether they are active or not has. In humans, a hormone circulating in a mother’s bloodstream can affect the developing reproductive system of her baby (fetus). When the hormone enters a cell, it binds a receptor that then binds with a specific stretch of DNA. This stretch of DNA is called a “hormone response element” and precedes a specific target gene. By binding, the gene is turned on (transcribed), turning into a product. It is through this process that endocrine disrupting chemicals can alter gene function in pathways associated with infertility, obesity, cancer and osteoporosis.17 See the analogy at right.
The epigenome is heritable between generations. Each time a cell divides, not only is the DNA copied, but the epigenome around that DNA must be copied. This way, the daughter cell is as specialized as the cell it came from. It is especially important that the epigenome is copied correctly in cells of developing fetuses and children. Folate is an important part of the epigenetic tagging process. If there are not enough folate donors, such as from folic acid, to supply the dividing epigenome with the tags it needs, then disorders such as spina bifida can result. This is one reason the US supplements our foods with folic acid and doctors recommend folic acid supplements to pregnant women.18
One active area of epigenetic research is in cancer. Since alterations in the epigenome can change whether genes are on or off, those changes can affect uncontrolled cell growth and immune responses19 Likewise, there are specific genes in the genome that should never be turned on (such as retrotransposons). Epigenetic mechanisms are crucial in keeping those genes silenced. Laboratory studies show us that when developing young are exposed to bisphenol A (BPA), these silenced genes can turn on and disrupt normal genomic functioning. For rodents exposed to BPA in utero, there is a greater risk of developing cancer, obesity and diabetes. Interestingly, when the diet of the pregnant rodent who was also given BPA was supplemented with folic acid, those risks were lessened.20
Epigenetic Transfer across Generations: An Example
An example of the ability for epigenetic information to be transferred between generations was demonstrated by rodent research on the endocrine disruptive fungicide vinclozolin. When pregnant female rats (F0 generation) were exposed to vinclozolin, the third generation born after the exposed female (F3) experienced reproductive and kidney abnormalities. The researchers believed this was mediated by epigenetic marks.21
The epigenome is the final interface between an environmental exposure and a physiological response. During fetal development and infancy, the growing child’s body must learn how to function as a whole organism that is constantly adapting to specific environmental conditions. This ability makes the epigenome especially vulnerable to environmental exposures and environmental toxicants. Because development is a period of rapid cell division, effects of epigenetic alteration can last a lifetime. Establishing healthy epigenetic profiles across dividing cells is important for epigenetic health in adulthood. Maternal nutrition is especially important to ensuring there are enough folate donors and other precursors available for the epigenetic replication process to occur accurately.22
Organ systems undergo developmental programming in utero, and this programming governs an individual's capacity to adapt to physical and metabolic stressors later in life. For example, fat around the abdomen increases the risk for cardiovascular disease and diabetes later in life, even if the person isn't obese. Retarded fetal growth is associated with later abdominal fat. This suggests that the nutritional deficit experienced early in life programs the body to store more fat when calories are readily available and is believed to occur through epigenetic programming of genes responsible for metabolic activity.23 Whether from chemicals released by nearby cells, chemicals circulating in the maternal blood stream, or environmental exposures during early childhood, these exposures can become signals that alter metabolic set points and reproductive development in ways that create vulnerabilities for chronic diseases later in life.24
|Genetic toxicology, although not called that at the time, dates to 1927 when American geneticist Hermann J. Muller (1890-1967) demonstrated that x-rays increased the rate of gene mutations and chromosome changes in fruit flies.|
Genetic toxicology is the study of the effects of chemical and physical agents on genetic material. It includes the study of DNA damage in living cells that leads to cancer but also examines changes in DNA inherited across generations. The relevance of genetic toxicology is evident from heritable diseases such as phenylketonuria, cystic fibrosis, sickle cell anemia and Tay-Sachs disease. (See our Birth Defects webpage for more information.) Advances in molecular biology and genomic sciences are leading to a far greater understanding of the genetic cause of disease and even pointing the way to treatments.
Laboratory and human epidemiologic data demonstrate that common exposures have the ability to alter the animal and human epigenome in ways that can foster chronic disease, including cancer. Given that the chemical exposures described here can be found in everyday products such as motor vehicle exhaust, foods, household furniture, children’s products and electronics, developing children as well as adults can be exposed to epigenetic disruptors through air, water, food and skin contact on a daily basis. There is good evidence connecting the following exposures with the listed health outcomes.
Studies demonstrate that the components of air pollution can have these effects:
- Alter inflammatory gene expression
- Destabilize genomic function
- Disrupt epigenetic replication and advance chromosomal aging.
Endocrine Disrupting Chemicals
Many chemicals in this class can permanently change gene expression during the first trimester of pregnancy (organogenesis). They can also alter gene expression during development as a whole, alter hormonal signaling networks and alter the expression of detoxifying enzymes. This can increase the risk for childhood chronic diseases, obesity, reproductive disorders, immune dysfunction and cancer.26 See our EDCs webpage.
Persistent Organic Pollutants
Many chemicals in this class can have these effects:
- Alter estrogen-responsive gene expression
- Alter epigenomic regulation
- Alter imprinted gene expression
- Alter expression in cardiac, ovarian, sperm, skeletal and liver tissue.
Heavy metals, including methylmercury, arsenic, cadmium, copper, iron, aluminum and nickel, can disrupt epigenetic function. These exposures can change gene expression in the brain, activate transposable elements, alter the fetal epigenome, alter tumor suppression gene expression and alter neural growth expression. The resulting epigenetic alterations can increase the risk for poor birth outcomes, developmental abnormalities, cancer and neurodegeneration.28
Psychosocial stressors can induce epigenetic changes. Environments that are threatening, uncontrollable, or unpredictable can stimulate a stress response in the body, and chronic exposure to stress can erode a person's overall health. This deterioration is mediated by the ability of the stress response system to turn off once a stressor has passed.29
When experienced early in life, stressors can alter the epigenetic marks on a specific gene in the brain that affects the ability of the stress response system to turn off. Lab studies have shown that early-life stress, even in utero, can cause an epigenetic change in the brain that makes individuals more responsive to stressful stimuli, thus experiencing more internal stress over the life course. This heightened response increases the risk for behavior changes in adulthood, reduced parent-offspring interactions and cardiovascular disease. Humans who have heightened stress responses are at a greater risk for anxiety, hypertension, obesity, type 2 diabetes and autoimmune disorders. Human studies have shown that suicide completers also carry this epigenetic change in the brain. Though this research is in its infancy, it sheds light on the importance of early life experiences to lifelong health.30
Our expanding appreciation of the environment’s ability to affect genomic function through epigenetic changes should have an effect on risk assessment and really argues for a precautionary approach to chemicals during development. We have an ethical responsibility to ensure that our children live in an environment in which they can reach and maintain their full potential, free of exposures to chemicals and stressors that cause adverse epigenetic changes. In addition, we must move beyond just "doing no harm" to creating a positive and supportive environment for our children. Additionally, if the epigenetic signatures of chemical exposures can be detailed, communities who have experienced physiological changes from these exposures that manifest as disease or disability outcomes may have supportable legal claims against those responsible for those exposures.
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