Estrogens/Xenoestrogens and Epigenetic Regulation of Gene Expression

雌激素/异雌激素和基因表达的表观遗传调控

基本信息

批准号：
8272637
负责人：
Wan-yee Tang
金额：
$ 24.89万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-10 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8272637
关键词：
Adult Androgens Animal Model Award Binding Proteins Biological Models Cancerous Cell Line Cell Proliferation Chemicals Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA Methylation Data Development Dose Elderly Endocrine Disruptors Environment Environmental Estrogen Enzymes Epigenetic Process Epithelial Cells Epoxy Resins Estradiol Estrogens Event Exposure to Faculty Future Gene Expression Regulation Genes Genome Goals Growth and Development function Head Start Program Health Human Hypermethylation In Vitro Life Malignant Neoplasms Malignant neoplasm of prostate Mediating Mentors Methylation Neonatal Neoplastic Cell Transformation Oils Pattern Phase Prevention Promoter Regions Prostate Prostatic Prostatic Diseases Proteins Rattus Regulation Research Research Personnel Role Signal Pathway Signal Transduction Staging Testing Translating Universities Variant animal tissue bisphenol A cancer risk career career development chromatin remodeling consumer product disorder risk early life exposure epigenomics hippocalcin human tissue improved in vivo member phosphodiesterase IV polycarbonate plastic promoter prostate carcinogenesis relating to nervous system visinin xenoestrogen

项目摘要

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.

描述（由申请人提供）除雄激素外，雌激素也参与前列腺的发育、生长调节和病理学。双酚 A (BPA) 是一种雌激素模拟物，目前用于制造各种消费品中所含的聚碳酸酯塑料和环氧树脂。它的雌激素作用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。研究人员之前的研究表明，与经过油处理的对照组相比，新生期暴露于环境相关的低剂量 BPA 或雌二醇 17-β (E2) 的大鼠前列腺中的一组基因显示出异常的甲基化状态。其中，他们发现，由于新生大鼠接触 BPA/E2，成年大鼠前列腺中编码 cAMP 降解酶的磷酸二酯酶 4 变体 4 (PDE4D4) 的启动子区域发生去甲基化。最近，研究人员发现新生儿 BPA/E2 治疗对成人前列腺中的喜马钙素样蛋白 1 (HPCAL1) 产生相反的作用，并导致该基因的启动子过度甲基化。 PDE4D4 和 HPCAL1 的并行研究将产生有关细胞内 cAMP 如何促进前列腺癌发生的深入数据，从而提高我们对生命早期接触 BPA/E2 对前列腺癌风险影响的理解。研究人员提议研究 BPA/E2 影响下的 PDE4D4 启动子低甲基化和 HPCAL1 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。研究人员推测，正常前列腺上皮细胞接触 BPA 或 E2 会通过重塑染色质状态和改变启动子 DNA 甲基化模式，在表观遗传上诱导特定基因发生持久的调控变化，从而为肿瘤转化奠定基础。该应用的主要重点是 PDE4D4 和 HPCAL1 中发生的表观遗传变化及其与 cAMP 调节的下游效应器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对基因组进行表观遗传修饰，从而导致前列腺疾病和/或癌症的理解。建立特定的与雌激素相关的“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。