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（申请人提供）除雄激素外，雌激素还参与了前列腺的发育，生长调节和病理学。 Bisphenol A（BPA）是一种模仿雌激素，现在用于多种消费产品中包含的聚碳酸酯塑料和环氧树脂的生产。它的雌激素作用表明它可以重新编程开发人类和动物组织，特别是对雌激素敏感的组织，并改变后来的疾病风险。研究者先前的研究表明，与油处理的对照相比，一组基因在大鼠前列腺中表现出异常的甲基化状态。其中，他们发现，编码一种磷酸二酯酶4变体4（PDE4D4）的启动子区域在成年大鼠的前列腺中被脱甲基，这是新生儿BPA/E2-暴露的结果。最近，研究人员发现，新生儿BPA/E2治疗对成年前列腺中的河马样蛋白1（HPCAL1）产生了相反的作用，并引起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营地如何促进前列腺癌发生的有见地数据，从而提高了我们对BPA/E2早期寿命对前列腺癌风险的影响的理解。研究人员建议在BPA/E2下研究PDE4D4启动子的低甲基化以及HPCAL1启动子高甲基化，作为一种模型系统，以确定前列腺基因组中BPA-或E2诱导的表观遗传变化的机制。研究者假设正常前列腺上皮细胞暴露于BPA或E2会通过重塑染色质状态并改变启动子DNA甲基化模式，从而在特定基因上诱导特定基因的长期调节变化，从而为Neoplastic Transformiss创造了阶段。该应用的主要重点将放在PDE4D4和HPCAL1中发生的表观遗传变化以及它们与cAMP调节的下游效应子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遗传修饰基因组的理解，从而导致前列腺疾病和/或癌症的发展。建立与雌激素相关的特定“表观遗传重编程”机制将有助于未来预防相关内分泌的有害影响对人类健康的有害影响。