The rapidly growing field of toxicoepigenetics seeks to understand how toxicant exposures interact with the epigenome to influence disease risk. Toxicoepigenetics is a promising field of environmental health research, as integrating epigenetics into the field of toxicology will enable a more thorough evaluation of toxicant-induced disease mechanisms as well as the elucidation of the role of the epigenome as a biomarker of exposure and disease and possible mediator of exposure effects. Likewise, toxicoepigenetics will enhance our knowledge of how environmental exposures, lifestyle factors, and diet interact to influence health. Ultimately, an understanding of how the environment impacts the epigenome to cause disease may inform risk assessment, permit noninvasive biomonitoring, and provide potential opportunities for therapeutic intervention. However, the translation of research from this exciting field into benefits for human and animal health presents several challenges and opportunities. Here, we describe four significant areas in which we see opportunity to transform the field and improve human health by reducing the disease burden caused by environmental exposures. These include (1) research into the mechanistic role for epigenetic change in environment-induced disease, (2) understanding key factors influencing vulnerability to the adverse effects of environmental exposures, (3) identifying appropriate biomarkers of environmental exposures and their associated diseases, and (4) determining whether the adverse effects of environment on the epigenome and human health are reversible through pharmacologic, dietary, or behavioral interventions. We then highlight several initiatives currently underway to address these challenges.

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Introduction: The developing epigenome changes rapidly, potentially making it more sensitive to toxicant exposures. DNA modifications, including methylation and hydroxymethylation, are important parts of the epigenome that may be affected by environmental exposures. However, most studies do not differentiate between these two DNA modifications, possibly masking significant effects.Methods: To investigate the relationship between DNA hydroxymethylation and developmental exposure to common contaminants, a collaborative, NIEHS-sponsored consortium, TaRGET II, initiated longitudinal mouse studies of developmental exposure to human-relevant levels of the phthalate plasticizer di(2-ethylhexyl) phthalate (DEHP), and the metal lead (Pb). Exposures to 25 mg DEHP/kg of food (approximately 5 mg DEHP/kg body weight) or 32 ppm Pb-acetate in drinking water were administered to nulliparous adult female mice. Exposure began 2 weeks before breeding and continued throughout pregnancy and lactation, until offspring were 21 days old. At 5 months, perinatally exposed offspring blood and cortex tissue were collected, for a total of 25 male mice and 17 female mice (n = 5–7 per tissue and exposure). DNA was extracted and hydroxymethylation was measured using hydroxymethylated DNA immunoprecipitation sequencing (hMeDIP-seq). Differential peak and pathway analysis was conducted comparing across exposure groups, tissue types, and animal sex, using an FDR cutoff of 0.15.Results: DEHP-exposed females had two genomic regions with lower hydroxymethylation in blood and no differences in cortex hydroxymethylation. For DEHP-exposed males, ten regions in blood (six higher and four lower) and 246 regions (242 higher and four lower) and four pathways in cortex were identified. Pb-exposed females had no statistically significant differences in blood or cortex hydroxymethylation compared to controls. Pb-exposed males, however, had 385 regions (all higher) and six pathways altered in cortex, but no differential hydroxymethylation was identified in blood.Discussion: Overall, perinatal exposure to human-relevant levels of two common toxicants showed differences in adult DNA hydroxymethylation that was specific to sex, exposure type, and tissue, but male cortex was most susceptible to hydroxymethylation differences by exposure. Future assessments should focus on understanding if these findings indicate potential biomarkers of exposure or are related to functional long-term health effects.