Epidemiological studies and animal experiments have now firmly established that environmental exposures during early embryonic development play a critical role in disease susceptibility in later life. Moreover, such exposures during gestation have been directly linked with subsequent disease formation through epigenetic mechanisms. Bisphenol A (BPA) is a high-production volume chemical used in the manufacture of polycarbonate plastic and epoxy resins. Rodent studies have associated pre- or perinatal BPA exposure with liver damage, insulin resistance, decreased sperm production, and altered prostate and mammary gland development, and recent human epidemiological data have linked BPA with increased risk of metabolic disorders and altered liver function. The proposed work presents a unique opportunity to combine state-of-the- art unbiased epigenomic approaches with specific quantitative epigenetic techniques to identify dose- dependent alterations in the fetal epigenome following in utero BPA exposure in both animal model and human samples. First, we will advance understanding of fetal epigenomic patterning of adult disease by identifying dose-dependent alterations in coat color distribution, adult body weight, and epigenome-wide methylation of viable yellow agouti (Avy) mouse offspring following maternal dietary exposure to environmentally relevant levels of BPA. Second, in a parallel human approach, we will characterize fetal BPA exposure by measuring total BPA (free plus conjugated species) concentrations in human fetal placenta and liver samples. We will apply methylated DNA immunoprecipitation deep-sequencing (mDIP-seq) to identify epigenome-wide methylation patterns in the human genome associated with low versus high gestational BPA exposure. Finally, we will utilize tissue specific expression profiling and high-throughput quantitative methylation sequencing to map and categorize metastable epiallelic loci in the mouse and human genomes that cannot be detected using currently available epigenome-wide DNA assay technologies due to the highly repetitive content of their regulatory and coding regions. Genomic loci identified through this approach will be assessed for altered methylation following in utero BPA exposure. The successful completion of this project will result in the first unbiased epigenome-wide experimental characterization of the repertoire of developmentally labile epigenetic loci following BPA exposure - in both mice and humans. Identifying these loci in both the mouse and human genomes will elucidate not only the similarities but also the differences between species-dependent environmental epigenetic regulation, allowing for the development of more relevant risk assessment strategies for protecting human populations. Knowledge generated from the proposed studies is crucial for deciphering the role of early epigenetic programming in the pathogenesis of adult disease and for the development of novel epigenetic-based diagnostic, screening, and therapeutic strategies for human diseases and disorders.

Public Health Relevance

It is increasingly recognized that environmental 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. The overall objective of this grant application is to identify epigenome-wide alterations following gestational exposure to bisphenol a (BPA), a high production volume chemical used in the manufacturing of polycarbonate plastics and epoxy resins, and to map developmentally labile epigenetic genes in order to facilitate human health risk assessment and human disease prevention, diagnosis, and treatment.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZES1-JAB-G (R3))
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Mcallister, Kimberly A
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University of Michigan Ann Arbor
Public Health & Prev Medicine
Schools of Public Health
Ann Arbor
United States
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