Estrogens/Xenoestrogens and Epigenetic Regulation of Gene Expression

描述(由申请人提供) 除了雄激素外，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，现在用于制造聚碳酸酯塑料和各种消费品中包含的环氧树脂。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，并改变以后生活中的疾病风险。研究人员之前的研究表明，与石油处理的对照组相比，暴露于环境相关的低剂量BPA或17-雌二醇(E2)的新生大鼠前列腺中的一组基因显示异常甲基化状态。其中，他们发现编码cAMP降解酶的磷酸二酯酶4变异体4(PDE4D4)的启动子区域在成年大鼠的前列腺中因新生BPA/E2暴露而去甲基化。最近，研究人员发现，新生儿BPA/E2治疗对成人前列腺中的Hippocalin-like Protein 1(HPCAL1)产生了相反的影响，并导致该基因的启动子超甲基化。对PDE4D4和HPCAL1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洞察力的数据，从而提高我们对早期暴露于BPA/E2对前列腺癌风险的影响的理解。研究人员建议在BPA/E2影响下研究PDE4D4启动子低甲基化和HPCAL1启动子高甲基化作为一个模型系统，以确定BPA或E2诱导的前列腺癌基因组表观遗传学变化的机制。研究人员假设，正常前列腺上皮细胞暴露于BPA或E2后，通过重塑染色质状态和改变启动子DNA甲基化模式，从表观上诱导特定基因的长期调控变化，从而为肿瘤转化奠定基础。这一应用的主要焦点将是在PDE4D4和HPCAL1中发生的表观遗传学变化，以及它们与cAMP调节的下游效应和早期肿瘤转化的关联。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改变基因组，导致前列腺癌和/或癌症的理解。建立特定的雌激素相关的“表观基因重新编程”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.