Alteration of HOX Gene Expression by Endocrine Disrupting Chemicals

内分泌干​​扰物改变 HOX 基因表达

• 批准号: 7868034
• 负责人: Hugh Smith Taylor
• 金额: $ 34.12万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7868034
• 关键词: Acute; Affect; Binding; Binding Sites; Cells; Chemicals; CpG Islands; Data; Defect; Development; Diethylstilbestrol; Dose; Endocrine Disruptors; Endocrine disruption; Endocrine system; Endometrial; Environment; Epigenetic Process; Estradiol; Estrogen Receptors; Estrogens; Exposure to; Funding; Gene Expression; Gene Expression Regulation; Gene Mutation; Genes; HOXA10 gene; Health; Homeobox Genes; Human; Hypermethylation; In Vitro; Knowledge; Lead; Mediating; Methoxychlor; Methylation; Modeling; Modification; Molecular; Mus; Nucleic Acid Regulatory Sequences; Perinatal Exposure; Play; Regulation; Regulatory Element; Research Personnel; Response Elements; Rodent; Role; Signal Transduction; Testing; Time; Tissues; Trans-Activators; Transcriptional Regulation; Transgenic Mice; Undifferentiated; Uterus; Woman; base; bisphenol A; endocrine disruptor exposure; environmental chemical; hazard; imprint; in utero; in vivo; offspring; pregnant; programs; reproductive; reproductive development; research study; response; transcription factor; xenoestrogen

DESCRIPTION (provided by applicant): Humans and other species have suffered adverse health effects thought to result from exposure to environmental chemicals that interact with the endocrine system. A significant portion of these effects have been manifested as decreased reproductive potential - often through their effects in utero leading to abnormal development of the reproductive tract. In humans and rodents these effects have been clearly demonstrated with diethylstilbestrol (DES). HOX genes are highly evolutionary conserved and impart segmental tissue identity during the development of undifferentiated body axes. We have demonstrated that HOX genes play an essential role in reproductive tract development. In the prior funding period we have shown that HOX gene expression is altered in mice after in utero exposure to DES, methoxychlor or bisphenol A. We will continue to use DES as our model endocrine disrupter due to its well characterized effects, however will also include these additional agents in selected experiments. The objective of this proposal is to test the hypothesis that the mechanism by which endocrine disrupters affect the development of the reproductive tract is by altering the epigenetic regulation of HOX gene expression. While the initial regulation is mediated through the estrogen receptor (ER a or (b), persistent defects in HOX gene expression after exposure to endocrine disrupters suggests epigenetic alteration of HOX expression. In this application we will determine the molecular mechanisms that regulate HOXA10 and HOXA11 as well as identify epigenetic modifications that regulate HOX genes in both mice and humans. First we will characterize the 5' and intronic regulatory regions of HOXA10 and HOXA11 and identify transcription factor binding sites. Based on preliminary data, we hypothesize that these regulatory regions are methylated in response to xenoestrogen exposure. We will identify the potential impact of DES induced methylation on transcriptional regulation of these genes. Second, we will define the epigenetic changes that lead to persistent Hox gene alteration in the absence of continued exposure in mice. Finally, we will determine if the molecular mechanism by which endocrine disrupters alter HOX gene expression in mice is conserved in humans. We will examine uterine tissue from women with known in utero DES exposure. We have previously shown that Hox genes are necessary for reproductive tract development and that altered Hox expression leads to developmental or functional alterations. Here we expect to demonstrate that endocrine disrupters alter HOX gene expression and will determine the molecular mechanisms that mediate this regulation. No good model exists to explain the mechanism of both the acute and long term diminished HOX gene expression following endocrine disrupter exposure in utero. We hypothesize that the effects are maintained long after exposure through epigenetic mechanisms such as methylation of HOX genes.

描述（由申请人提供）：人类和其他物种遭受了不利的健康影响，认为是由于与内分泌系统相互作用的环境化学物质所造成的。这些作用的很大一部分已经表现为生殖潜力的降低 - 通常是由于它们在子宫内的作用而导致生殖道异常发育。在人类和啮齿动物中，这些作用已清楚地证明了二乙基甲虫（DES）。 HOX基因是高度进化保守的，并且在未分化的身体轴发展过程中赋予了节段组织的身份。我们已经证明HOX基因在生殖道发育中起着至关重要的作用。在以前的资金期间，我们已经表明，在子宫内暴露于DES，甲氧氯或双酚A后，HOX基因表达改变了小鼠。由于其表征良好的效果，我们将继续使用DES作为模型内分泌剂，但是在选定的实验中还将包括这些其他药物。该提案的目的是检验以下假设：内分泌dis分泌器影响生殖道的发展的机制是改变HOX基因表达的表观遗传调节。虽然最初的调节是通过雌激素受体（ER A或（B）介导的，但在暴露于内分泌disocrine discrupter的HOX基因表达中持久缺陷表明HOX表达的表观遗传变化。在本应用中，我们将确定分子机制，这些分子机制将HOXA10和HOXA11和HOXA11以及Shoice and veriention and Seperantized nigne nightize nigne nigne nignize nightized nightized nigutized nigution nightion nightized nigutized nignized ryans in n Morsy rys rys。 HOXA10和HOXA11的内在调节区域基于初步数据，我们假设这些调节区域是甲基甲基化的，响应于Xenoterogen的影响，我们将识别DES诱导的甲基化对二次转化的潜在影响。最终，我们将在人类中保守小鼠的分子机制改变了小鼠的HOX基因表达。我们将检查在暴露子宫内已知的女性的子宫组织。我们先前已经表明，HOX基因对于生殖道的发育是必要的，而HOX表达改变会导致发育或功能改变。在这里，我们期望表明内分泌diSRUPTERS改变了HOX基因的表达，并将确定介导该调节的分子机制。没有一个好的模型来解释子宫内分泌暴露后的急性和长期hox基因表达的机制。我们假设通过表观遗传机制（例如HOX基因的甲基化）暴露后很长时间维持该作用。