Gene-Environment Interactions

Many complex chronic diseases are influenced by gene-environment interactions. Genetic variation can influence the ways in which people respond to occupational or environmental exposures.

photo of coffee in a cup — People have different responses to caffeine depending on genetic variants.

For example, genetic variation can change how people are affected by drinking coffee. One person might drink a lot of coffee without feeling the effects, while another person cannot handle more than a cup. In this case, one person’s genetic variant of the enzyme that metabolizes caffeine is more efficient, while another variant is less efficient in the other person. Your ability to metabolize caffeine is dependent on which variant you carry.

Similarly, some people are less efficient at metabolizing environmental chemicals, putting them at a higher risk for disease. While these variants can create a genetic susceptibility to disease, the environmental exposure is still required for the disease to manifest.¹

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, result from the complex interactions between environmental exposures and gene variants.²

Open all

Examples of Gene-Environment Interactions

Epigenetics

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 surrounds the genome and controls what it does.

These tags turn genes on or off. It is through epigenetic mechanisms that cells become specialized.⁷ Your development from one fertilized egg into a collection of 200 cell types across 3 trillion cells occurs through epigenetic regulation.⁸ 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 whether cells need to repair themselves, fight off intruders, divide into two cells, or function as part of an organ. Epigenetic mechanisms allow this to happen.⁹

A queen bee, a drone, and a worker bee — A queen bee, drone, and worker. The differences between queens and workers are the result of epigenetic modification.

Bees illustrate an example of environmental exposure changing gene expression. A worker bee 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. Only developing bees fed royal jelly can grow into queen bees. Only these bees can reproduce. The genes are not changed, but their expression has.

Occupational and environmental exposures can change gene expression through epigenetic mechanisms. In humans, hormones circulating in a mother’s bloodstream affect the developing reproductive system of the fetus through epigenetic changes. Endocrine disrupting chemicals (EDCs) can mimic or disrupt the action of hormones and disrupt this natural process. For example, EDCs can alter gene function in pathways associated with infertility, obesity, cancer, and osteoporosis.¹⁰

Lifelong impacts

The epigenome is heritable between generations of cells. Each time a cell divides, not only is the DNA copied, but the epigenome around that DNA must also 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 is not enough folate to supply the dividing epigenome with the tags it needs, disorders such as spina bifida can result. This is one reason why doctors recommend folic acid supplements to pregnant women.¹¹ Maternal nutrition is especially important to ensuring there is enough folate, as well as other precursors, available for the epigenetic replication processes to occur accurately.¹²

One active area of epigenetic research is in cancer. Alterations in the epigenome can change whether genes are on or off. Those changes can affect uncontrolled cell growth and immune responses.¹³ Additionally, 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. In several types of cancer, those genes are active.

Studies in animals show that when developing young are exposed to the EDC bisphenol A (BPA), these silenced genes can turn on and disrupt normal genomic functioning. For example, rodents exposed to BPA in utero have a greater risk of developing cancer, along with obesity and diabetes. Interestingly, when the BPA-exposed pregnant rodent was also given a folic acid supplement, those risks were reduced.¹⁴

Windows of vulnerability

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. The epigenome is especially vulnerable to environmental exposures and toxicants during these developmental stages.

Because development is a period of rapid cell division, effects of epigenetic alteration can last a lifetime. 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. Establishing healthy epigenetic profiles across dividing cells is important for health in adulthood.

Transgenerational effects

Chart showing transgeneration inheritance — *Source: King S, Skinner M.*¹⁵

Chemical exposures can have transgenerational effects through epigenetics.

For example, when a person pregnant with a female fetus is exposed to EDCs, that represents three generations of exposures: The mother (F0), the fetus (F1), and the fetus’ already present germ cells and gametes (F2). If the 4^thgeneration (F3) – that is, the great-grandchild of the exposed mother – also shows effects, then those effects are considered transgenerational. This represents health effects in individuals who were never personally exposed. Instead, their exposures were ancestral.

One study found that exposure to DDT could have transgenerational effects on the epigenome, increasing a person’s great-grandchildren’s chances of having obesity.¹⁶

Another example of epigenetic information being 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 (F3) experienced reproductive and kidney abnormalities. The researchers believe this was mediated by epigenetic markers.¹⁷

Exposures that Alter Epigenetic Function

Laboratory and human epidemiologic data demonstrate that common exposures have the ability to alter the epigenome in ways that can increase risk of chronic diseases, including cancer. The exposures described here can be found in everyday products such as motor vehicle exhaust, foods, household furniture, children’s products, and electronics.

There is strong evidence connecting the following exposures with the listed health outcomes via epigenetic effects. These exposures can also have other health effects that are not mediated through epigenetic mechanisms.

Air Pollution	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. These effects can increase the risk for cardiopulmonary diseases, cancer, asthma, neurological diseases, and early aging. See our air pollution webpage.¹⁸
Endocrine Disrupting Chemicals (EDCs)	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.¹⁹ See our EDCs webpage.
Heavy Metals	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, alter gene expression, and alter neural growth expression. The resulting epigenetic alterations can increase the risk for poor birth outcomes, developmental abnormalities, cancer, and neurodegeneration.²⁰
Persistent Organic Pollutants	Many chemicals in this class can alter: Estrogen-responsive gene expression Epigenetic regulation Imprinted gene expression Expression in cardiac, ovarian, sperm, skeletal, and liver tissue. These changes increase the risk of cognitive developmental disabilities, reduced fetal growth, reproductive disorders, cancer, and autoimmune diseases.²¹
Stress	Environments that are threatening, uncontrollable, or unpredictable can stimulate a stress response in the body, and chronic stress can erode a person's overall health.²² When experienced early in life, stressors can alter the epigenetic markers 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. 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.²³

Our expanding appreciation of the environment’s ability to affect genomic function through epigenetic changes argues for a precautionary approach to chemical and other hazardous exposures 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 chemicals and other preventable exposures that cause adverse epigenetic changes.

This page was last revised in October 2024 by CHE’s Science Writer Matt Lilley, with input from Dr. Rachel Massey, and editing support from CHE Director Kristin Schafer.

CHE invites our partners to submit corrections and clarifications to this page. Please include links to research to support your submissions through the comment form on our Contact page.

National Institute of Environmental Health Sciences. Gene and Environment Interaction. September 12, 2023. Viewed October 27, 2024.
National Institute of Environmental Health Sciences. Gene and Environment Interaction. September 12, 2023. Viewed October 27, 2024.
Priyadarshi A, Khuder SA, et al. A meta-analysis of Parkinson's disease and exposure to pesticides. Neurotoxicology. 2000; 21(4):435-40; Hancock DB, Martin ER, et al. Pesticide exposure and risk of Parkinson's disease: a family-based case-control study. Neurology. 2008; 28(8).
Primo-Parmo, A., Sorensen, R., et al. The human serum Paraoxonase/Arylesterase Gene (PON1) is one member of a multigene family. Genomics. 1996; 33(3):498-507.
Manthripragada A, Costello S, et al. Paraoxonase 1 (PON1), agricultural organophosphate exposure, and Parkinson disease. Epidemiology. 2010; 21(1):87-94; Costa L, Cole T, et al. Review: Functional genomic of the paraoxonase (PON1) polymorphisms: effects on pesticide sensitivity, cardiovascular disease, and drug metabolism. Annual Review of Medicine. 2003; 54:371-392; Li W, Costa L et al. Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds. Pharmacogenetics. 2000; 10(9):767-779.
Salam MT, Lin PC, Avol EL, Gauderman WJ, Gilliland FD. Microsomal epoxide hydrolase, glutathione S-transferase P1, traffic and childhood asthma. Thorax. 2007 Dec;62(12):1050-7.
National Human Genome Research Institute. Epigenomics Fact Sheet. National Institutes of Health. August 16, 2020. Viewed October 27, 2024.
Alberts B, Bray D, et al. Cells of the adult human body: a catalogue. Molecular Biology of the Cell: NCBI. 1994. Viewed July 19, 2016.
National Human Genome Research Institute. Epigenomics Fact Sheet. National Institutes of Health. August 16, 2020. Viewed October 27, 2024.
Hiller-Sturmhöfel S, Bartke A. The endocrine system. Alcohol Health Research World. 1998; 22:153-164; Martinez-Arguelles D, Papadopoulos, V. Epigenetic regulation of the expression of genes involved in steroid hormone biosynthesis and action. Steroids. 2010;75:467–476.
Crider K, Yang T et al. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role. Advances in Nutrition: An International Review Journal. 2012;3:21-38; Meethal S, Hogan K et al. Folate and epigenetic mechanisms in neural tube development and defects. Child’s Nervous System. 2013;29:1427–1433.
Meethal S, Hogan K et al. Folate and epigenetic mechanisms in neural tube development and defects. Child’s Nervous System. 2013;29:1427–1433.
National Human Genome Research Institute. Epigenomics Fact Sheet. National Institutes of Health. August 16, 2020. Viewed October 27, 2024.
Dolinoy DC. The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome. Nutrition Reviews. 2008; 66(s1):S7–S11.
King S, Skinner M. Epigenetic Transgenerational Inheritance of Obesity Susceptibility. Trends Endocrinol Metab. 2020 Jul;31(7):478-494.
King S, Skinner M. Epigenetic Transgenerational Inheritance of Obesity Susceptibility. Trends Endocrinol Metab. 2020 Jul;31(7):478-494.
Guerrero-Bosagna C, Covert T, et al. Epigenetic transgenerational inheritance of vinclozolin induced mouse adult onset disease and associated sperm epigenome biomarkers. Reproductive Toxicology. 2012;34(4):694-707.
Jiménez-Chillarón J et al. Back to the future: transgenerational transmission of xenobiotic-induced epigenetic remodeling. Epigenetics. 2015;10(4):259-273.
Jiménez-Chillarón J et al. Back to the future: transgenerational transmission of xenobiotic-induced epigenetic remodeling. Epigenetics. 2015;10(4):259-273. Ho S, Johnson A et al. Environmental epigenetics and its implication on disease risk and health outcomes. Institute for Laboratory Research Journal. 2012;53:289–305; Hannon P, Flaws J. The effects of phthalates on the ovary. Frontiers in Endocrinology. 2015;6(8). Vaiserman A. Early-life exposure to endocrine disrupting chemicals and later-life health outcomes: an epigenetic bridge? Aging Disease. 2014;5:419-429; Vandenberg L, Colborn T et al. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocrine Reviews. 2012;33:378–455; Feinberg A. Phenotypic plasticity and the epigenetics of human disease. Nature. 2007;447:433–440.
Verma M. Cancer epigenetics: risk assessment, diagnosis, treatment, and prognosis. Humana Press; Springer, 2015; Jiménez-Chillarón J et al. Back to the future: transgenerational transmission of xenobiotic-induced epigenetic remodeling. Epigenetics. 2015;10(4):259-273; Bollati V, Baccarelli A. Environmental epigenetics. Heredity. 2010;105:105–112.
Verma M. Cancer epigenetics: risk assessment, diagnosis, treatment, and prognosis. Humana Press; Springer, 2015; Bollati V, Baccarelli A. Environmental epigenetics. Heredity. 2010;105:105–112; Jiménez-Chillarón J et al. Back to the future: transgenerational transmission of xenobiotic-induced epigenetic remodeling. Epigenetics. 2015;10(4):259-273; Ho S, Johnson A et al. Environmental epigenetics and its implication on disease risk and health outcomes. Institute for Laboratory Research Journal. 2012;53:289–305; Vandenberg L, Colborn T et al. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocrine Reviews. 2012;33:378–455; Öztürk B, Büyükgebiz A. Effects of environmental chemicals and drugs on reproductive endocrine system. Journal of Turgut Ozal Medical Center. 2015;22:66–72; Desaulniers D et al. Effects of mixtures of polychlorinated biphenyls, methylmercury, and organochlorine pesticides on hepatic DNA methylation in prepubertal female Sprague-Dawley rats. International Journal of Toxicology. 2009;28:294–307; Collotta M, Bertazzi P, Bollati V. Epigenetics and pesticides. Toxicology. 2013;307:35–41; Vaiserman A. Early-life exposure to endocrine disrupting chemicals and later-life health outcomes: an epigenetic bridge? Aging Disease. 2014;5:419-429; Heinde, J, Vandenberg L. Developmental origins of health and disease: a paradigm for understanding disease cause and prevention. Current Opinions in Pediatrics. 2015;1.
Del Giudice M, Ellis B, Shirtcliff E. The Adaptive Calibration Model of stress responsivity. Neuroscience Biobehavior Reviews. 2011;35:1562–1592.
Seckl J. Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. Molecular Cellular Endocrinology. 2001;185:61–71; Hunter R, McEwen B. Stress and anxiety across the lifespan: structural plasticity and epigenetic regulation. Epigenomics. 2013;5:177–194; Zhang T, Labonté B et al. Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacology. 2013;38:111–123; Meaney M. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annual Review of Neuroscience. 2001;24:1161–1192; Papaioannou A, Dafni U et al. Effects of neonatal handling on basal and stress-induced monoamine levels in the male and female rat brain. Neuroscience. 2002;114:195–206; Pérez-Ortiz J, García-Gutiérrez M et al. Gene and protein alterations of FKBP5 and glucocorticoid receptor in the amygdala of suicide victims. Psychoneuroendocrinology. 2013;38:1251–1258; Rice V. Handbook of Stress, Coping, and Health: Implications for Nursing Research, Theory, and Practice. 2^nd Edition. Thousand Oaks, Sage. 2012.

View All Footnotes