Effects of fetal bisphenol A exposure on mouse epigenome

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DESCRIPTION (provided by applicant): Increasing evidence has shown that environmental exposures cause various developmental abnormalities. Elucidation of the relevant molecular pathways provides critical insights into risks management and preventative approaches. A compound that has created a great public health concern is bisphenol A (BPA), commonly used in various plastic products. Humans are widely exposed and exposure is linked to obesity, infertility, cancer, reduced immune system and behavior anomalies in model organisms. Despite the widely reported phenotypes induced by BPA exposure, the relevant molecular mechanisms are unclear. Recently, several laboratories have demonstrated the ability of BPA to alter DNA methylation, proposing that epigenetic mechanisms are involved in BPA developmental action. The candidate's work has found effects of BPA exposure on the expression and methylation of mouse imprinted loci. As imprinted loci are critical for fetal, placental and postnatal brain development, and disrupted functions are linked to human developmental disorders, work demonstrates that fetal BPA exposure has the potential to impact development through epigenetic perturbations of developmental genes. In the current application, genome wide methylation and expression studies in the embryonic and placental tissues of mice exposed prenatally to BPA will be undertaken using methylated DNA immunoprecipitation followed by sequencing and using microarrays, respectively. The goal is to identify the relevant epigenetic pathways. The candidate will include mice lacking the functional genes for estrogen receptor alpha and beta as BPA is an estrogen and the project aims to investigate if these receptors mediate BPA effects in the epigenome. Additionally, the candidate proposes to study the effects of BPA exposure in placental development as her previous studies revealed significant epigenetic dysregulation of the imprinted Cdkn1c gene. The cell cycle inhibitor Cdkn1c gene plays a critical role in mouse placental development and histological and immunohistochemical studies will be conducted to analyze placentas from BPA-exposed mice. The current application also proposes to investigate the genome wide and gene specific roles of the histone methyltransferase EZH2 and its relevant H3K27me3 histone mark in mediating BPA-induced developmental abnormalities as several laboratories have found aberrant expression of the proteins in various tissues from mice exposed in utero to BPA. These studies will utilize chromatin immunoprecipitation followed by sequencing or followed by qPCR. Public Health Relevance: The proposed studies aim to elucidate epigenetic mechanisms related to environmental exposures by investigating effects of bisphenol A exposure on the fetal epigenome and analyzing the consequences of epigenetic perturbations on mammalian development. The mouse will be used as a model system in the proposed studies to determine the potential etiology of human diseases with underlying environmental causes.