Estrogens/Xenoestrogens and Epigenetic Regulation of Gene Expression

描述（由申请人提供） 除了雄激素之外，雌激素还参与前列腺的发育、生长调节和病理生物学。 双酚A（BPA）是一种雌激素的模拟物，现在用于制造各种消费品中含有的聚碳酸酯塑料和环氧树脂。它的雌激素效应表明它可以重新编程发育中的人类和动物组织，特别是那些对雌激素敏感的组织，并改变晚年的疾病风险。 研究人员先前的研究表明，与油处理的对照组相比，一组基因在大鼠前列腺中显示出异常的甲基化状态，这些大鼠前列腺暴露于环境相关的低剂量BPA或雌二醇-17-β（E2）。 其中，他们发现，由于新生儿BPA/E2暴露，成年大鼠前列腺中编码cAMP降解酶的磷酸二酯酶4变体4（PDE 4D 4）的启动子区发生去甲基化。 最近，研究人员发现，新生儿BPA/E2治疗对成年前列腺中的Hippocalcin样蛋白1（HPCAL 1）产生了相反的影响，并导致该基因的启动子超甲基化。 PDE 4D 4和HPCAL 1的平行研究将产生关于细胞内cAMP如何促进前列腺癌发生的有见地的数据，从而提高我们对早期生活暴露于BPA/E2对前列腺癌风险的影响的理解。 研究人员建议研究BPA/E2影响下的PDE 4D 4启动子低甲基化和HPCAL 1启动子高甲基化，作为模型系统，以确定BPA或E2诱导的前列腺基因组表观遗传变化的机制。 研究人员假设，正常前列腺上皮细胞暴露于BPA或E2通过重塑染色质状态和改变启动子DNA甲基化模式诱导特定基因表观遗传学上的长期调节变化，从而为肿瘤转化奠定基础。本申请的主要重点是PDE 4D 4和HPCAL 1中发生的表观遗传变化及其与cAMP调节的下游效应子和早期肿瘤转化的相关性。这些研究的结果将提高我们对雌激素或环境雌激素如何表观遗传修饰基因组，导致前列腺疾病和/或癌症发展的理解。 建立特定的雌激素相关的“表观遗传重编程”机制将有助于未来预防相关内分泌干扰物对人类健康的有害影响。

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.