It is increasingly recognized that exposure to chemical, nutritional, and behavioral factors alters gene expression and affects health and disease by not only mutating promoter and coding regions of genes, but also by modifying the epigenome — modifications to DNA that confer an additional layer of heritable gene regulation that lead to disease when deregulated. Moreover, such exposures have been directly linked with subsequent disease formation through epigenetic mechanisms. Until recently, most attempts to elucidate the effects on the epigenome following nutritional and environmental exposures, including in utero
exposures, were either 1) candidate gene driven or based on epigenetic techniques with limited genome coverage/sensitivity, 2) restricted in dose-response assessment, or 3) confined to animal models. Emerging advances in epigenomic and high-throughput quantitative epigenetic technologies now allow for the identification of the constellation of genomic loci with altered epigenetic status following dose-dependent exposures. Thus, epigenomic profiling facilitates the identification of biomarkers of exposure, enabling clinicians to identify at-risk individuals prior to disease onset. Furthermore, unlike genetic mutations, epigenetic marks are potentially reversible. Therefore, epigenetic approaches for prevention and treatment, such as nutritional supplementation and/or pharmaceutical therapies, may be developed to counteract negative epigenomic profiles.
Drawing upon data from multiple epigenomics platforms and focusing on bisphenol A (BPA) as a representative environmental exposure, we will explore dose- and species-dependent methylation effects and associated perturbations in physiological and cellular endpoints. Epigenomic data from animal models, human clinical samples, and epidemiological studies now indicate that BPA-induced alterations vary between species and across dose, a revelation that should be considered in human health risk assessment. For example, Avy/a mouse offspring from maternal dietary exposure to 50 ng/kg or 50 mcg/kg BPA show a significant shift toward the pseudoagouti (p-value=0.03, and 0.04) coat color in comparison to the non-exposed control offspring. Conversely, maternal dietary exposure to 50 mg/kg BPA shows a shift towards yellow coat color (p-value=0.006). These preliminary data indicate that BPA is affecting epigenetic gene regulation across multiple dose levels and that these epigenetic effects are non-monotonic in dose response. Based on this observation we hypothesize that dose-dependent non-monotonic effects of BPA on life-course obesity and metabolic status may be observed.
This work was supported by NIH grant NIH-ES-017524.