Estrogens/Xenoestrogens and Epigenetic Regulation of Gene Expression

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DESCRIPTION (provide by applicant) Estrogens, in addition to androgen, are involved in the development, growth regulation and pathobiology of the prostate. Bisphenol A (BPA), a mimic of estrogen, is now used in the manufacture of polycarbonate plastics and epoxy resins contained in a variety of consumer products. Its estrogenic effects suggest it can reprogram developing human and animal tissues, specifically those sensitive to estrogens, and alter disease risk in later life. The investigators' previous studies demonstrated that a set of genes showed aberrant methylation status in rat prostates neonatally exposed to environmentally relevant, low dose of BPA or estradiol-17-beta (E2) when compared to oil-treated controls. Among them, they found that the promoter region of phosphodiesterase 4 variant 4 (PDE4D4), encoding a cAMP-degrading enzyme, was demethylated in the prostate of adult rats as a result of neonatal BPA/E2-exposure. More recently, the investigators found that neonatal BPA/E2 treatment exerted an opposite effect on the Hippocalcin-like protein 1 (HPCAL1) in the adult prostate and caused promoter hyper-methylation of this gene. Parallel studies of PDE4D4 and HPCAL1 will generate insightful data on how intracellular cAMP contributes to prostate carcinogenesis and thereby improve our understanding of the effects of early life exposure to BPA/E2 on prostate cancer risk. The investigators propose to study PDE4D4 promoter hypomethylation together with HPCAL1 promoter hypermethylation under BPA/E2 influences as a model system to ascertain the mechanisms underpinning BPA- or E2-induced epigenetic changes in the prostate genome. The investigators hypothesize that exposure of normal prostatic epithelial cells, to BPA or E2 induces long-lasting regulation changes in specific genes epigenetically by remodeling the chromatin state and altering promoter DNA methylation patterns, thus setting the stage for neoplastic transformation. The primary focus of this application will be on epigenetic changes occurring in PDE4D4 and HPCAL1 and their association with cAMP-regulated downstream effectors and early neoplastic transformation. Results from these studies will improve our understanding of how estrogens or environmental estrogens epigenetically modify the genome, leading to development of prostate disease and/or cancer. Establishment of specific estrogen-related "epigenetically reprogramming" mechanisms will facilitate future prevention of harmful effects of related endocrine disrupters on human health.