Aging, Environment, & DiseaseDNA Methylation and HydroxymethylationImprinting and Inheritance

Early-Life Epigenetic Programming by Endocrine Disrupting Chemicals

     shutterstock_305661503The ‘developmental origins of adult health and disease’ (DOHaD) hypothesis postulates that adverse influences early in development can program the risks for adverse health outcomes in adult life. In modern societies, exposure to man-made environmental contaminants is a potential risk factor for developmental programming of chronic disease. Endocrine-disrupting chemicals (EDCs) are of specific concern. EDCs act by mimicking or inhibiting the actions of endogenous hormones, and can have estrogenic, anti-estrogenic, or even anti-androgenic activity. Most EDCs are synthetic chemicals that enter the environment and persist for long periods of time. Among them are many substances that are in widespread use, including dioxin, plastic-softening chemicals, agricultural pesticides, polychlorinated biphenyls, industrial solvents, and pharmaceuticals. Some evidence suggest that exposure to EDCs during early development can cause long-term health outcomes via mechanisms of epigenetic memory.

     Bisphenol A(BPA), a man-made carbon-based synthetic compound with estrogenic activity which is widely used in the manufacture of polycarbonate plastics and epoxy resins, is one of the most studied EDCs in the epigenetic context. This xenoestrogen is present in food cans, bottle tops, food and drink packaging, such as plastic water containers and baby bottles, as well as in dental materials. Because this compound may mimic estrogen to interact with estrogen receptors α and β, causing alterations in cell proliferation, migration and apoptosis, and thereby, contributing to carcinogenesis, there is increasing concern  as to the health risks arising from exposure. There is increasing evidence that in-utero and/or neonatal exposure to BPA may promote various diseases, including impaired sexual behavior and reproductive function, immune system dysregulation, and hormone-associated tumors such as breast and prostate cancers. In several experimental studies, it has been found that in-utero BPA exposure may affect gene expression in different tissues, including brain and spleen, and these BPA-induced changes in gene expression may persist into adulthood. The developmental exposure of rats to low-dose BPA has been shown to cause increased prostate gland susceptibility to adult-onset precancerous lesions and hormonal carcinogenesis. These outcomes were accompanied by permanent alterations in the DNA methylation patterns of multiple cell signaling genes, e.g., by persistent promoter hypomethylation of gene encoding PDE4D4, an enzyme responsible for intracellular cyclic adenosine monophosphate breakdown. In humans, similar effects were also detected. Alterations in expression of genes coding xenobiotic metabolizing enzymes, induced by in-uterohigh-level BPA exposures, were obtained in three fetal tissues, namely, placenta, kidney and liver. Since epigenetic alterations triggered by early-life exposure to adverse environmental conditions, including BPA and other EDCs, are known to persist into adulthood and may be even transferred to the offspring, these findings raise concerns regarding epigenetic effects of endocrine disruption, not just to individuals who were directly exposed, but also to further generations.

As epigenetic marks are potentially reversible, a deeper understanding of mechanisms involved in the persisting effects of life-course environmental exposures may likely lead to the development of effective therapeutic approaches targeted to the removal of the undesirable epigenetic modifications. Data suggesting the possibility of such correction were obtained in a study by Dolinoy et al. (2007) where exposure of agouti (Avy) mice to BPA two weeks prior to mating withAvy/amales and throughout gestation and lactation resulted in shifting the coat color ofAvy/aoffspring toward yellow, as well as in obesity, diabetes, and tumorigenesis. Such changes were accompanied by hypomethylation and increased expression of the Avy gene. These deleterious effects of BPA on the fetal epigenome might be ameliorated by specific nutritional interventions, for example, by maternal dietary supplementation with some methyl donors, including folic acid, betaine, vitamin B12, and choline.

Original Article:
Vaiserman A (2014). Early-life Exposure to Endocrine Disrupting Chemicals and Later-life Health Outcomes: An Epigenetic Bridge? Aging and disease, 5 (6), 419-29 PMID: 25489493

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Alexander Vaiserman

Alexander Vaiserman