Review
Prenatal environmental exposures, epigenetics, and disease

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Abstract

This review summarizes recent evidence that prenatal exposure to diverse environmental chemicals dysregulates the fetal epigenome, with potential consequences for subsequent developmental disorders and disease manifesting in childhood, over the lifecourse, or even transgenerationally. The primordial germ cells, embryo, and fetus are highly susceptible to epigenetic dysregulation by environmental chemicals, which can thereby exert multiple adverse effects. The data reviewed here on environmental contaminants have potential implications for risk assessment although more data are needed on individual susceptibility to epigenetic alterations and their persistence before this information can be used in formal risk assessments. The findings discussed indicate that identification of environmental chemicals that dysregulate the prenatal epigenome should be a priority in health research and disease prevention.

Introduction

Following a brief summary of the role of epigenetics in early development and disease, this review focuses on the evidence that the prenatal/fetal period is highly susceptible to epigenomic dysregulation with implications for health, both lifelong and transgenerationally. We then offer examples of developmental exposure to various environmental pollutants shown to induce epigenetic changes and neurodevelopmental deficits and diseases. Interactions between toxic and environmental exposures and genetic, nutritional and social factors that can exacerbate effects are then described. Finally, two case studies are provided to illustrate the strengths and limitations of available epigenetic data and the potential of using epigenetic markers to forge causal links between toxic environmental exposures and neurodevelopmental outcomes. In this section, we summarize evidence that epigenetic alterations in endocrine and immune pathways are directly involved in the adverse neurodevelopmental effects associated with in utero exposure to the two classic endocrine disruptors, polycyclic aromatic hydrocarbons (PAHs) and bisphenol A (BPA).

Section snippets

The role of epigenetics in early development and disease: the prenatal/fetal window of susceptibility

Epigenetics is the study of heritable changes in gene expression or phenotype occurring without changes in DNA sequence [1]. For general reviews, see [2], [3], [4]. The genetic information in DNA has been likened to the notes of an orchestral score and epigenetics to the conductor who interprets the score and controls the dynamics of the symphonic performance [5]. While new epigenetic mechanisms are being uncovered, the best characterized are DNA methylation, changes in histone proteins around

Prenatal exposure to environmental pollutants, related health effects, and epigenetic dysregulation

As reviewed by Baccarelli and Bollati [57], studies in adults have demonstrated epigenetic changes related to environmental exposure to metals, air pollution, benzene and persistent organic pollutants. For example, in a study of adult coke oven workers and controls, global and IL-6 hypermethylation and p53 hypomethylation were associated with PAH exposure [58]. In workers exposed to the leukemogen, benzene, epigenomic data showed effects of benzene on DNA methylation of a number of specific

Case studies: a proposed epigenetic mechanism for the neurodevelopmental effects of in utero exposure to PAHs and BPA

The prior section has reviewed the evidence that diverse prenatal environmental exposures increase risk of various diseases in the offspring and in some cases their grandchildren, that they also alter the epigenome, and that epigenetic dysregulation may mediate their adverse health effects. In contrast, in the following section we present two case studies in which we propose that epigenetic alterations in endocrine and immune pathways are directly involved in the neurodevelopmental effects

Transgenerational effects of prenatal exposures

As we have seen, the role of prenatally acquired somatic epigenetic alterations in disease has been quite widely studied, mostly in experimental models. Less well characterized are epigenetic events that are inherited through the germline from parent to child and transmitted to subsequent generations [181].

There is growing evidence that environmental variations experienced by both fathers and mothers may lead to phenotypic variation in the development and behavior of offspring resulting from

Emerging evidence that nutritional, genetic and psychosocial factors may influence DNA methylation by environmental toxicants

Experimental animal studies have shown that the epigenetic reprogramming by behavioral factors is reversible by nutritional factors. For example, Weaver and colleagues showed that the programming of the GR exon 1 promoter associated with low grooming maternal care, as well as the resulting stress response and behavioral phenotypes, were reversible by administration of a methyl donor precursor or a histone deacetylase (HDAC) inhibitor [189]. Other investigators have shown that the effects of

Implications for prevention of childhood, adult and multigenerational disease: conclusions

Most of the research to date has focused on the critical role of epigenetics in mediating the effects of social experience and nutrition [197], [198]. However, there is also compelling human and experimental evidence that prenatal environmental exposures to endocrine disruptors and other environmental xenobiotics, acting alone or in combination with genetic, nutritional, or psychosocial factors, adversely affect human development and health in childhood and possibly over the lifecourse, and

Conflict of interest statement

The authors have no conflicts of interest.

Acknowledgments

The Center's research is supported by NIEHS, US EPA, and several private foundations and donors including 5PO1ES009600 NIEHS; RD834509 EPA; and 1 P50 ES015905 NIEHS.

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