Developmental Programming of Endometriosis Genes

子宫内膜异位症基因的发育编程

• 批准号: 7762851
• 负责人: SUSAN C NAGEL
• 金额: $ 18.02万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762851
• 关键词: Adult; Affect; Apoptosis; Candidate Disease Gene; Canned Foods; Cell Adhesion Molecules; Cell Proliferation; Cessation of life; Chemicals; Chronic Disease; Complement; CpG Islands; DNA Methylation; Data; Development; Diethylstilbestrol; Disease; Dizygotic Twins; Endometrial; Endometrium; Estrogens; Ethinyl Estradiol; Etiology; Exposure to; Extracellular Matrix; Fetal Tissues; Fetus; Future; Gene Expression; Genes; Genistein; Goals; Growth; Hormonal; Human; Infertility; Intervention; Lead; Lesion; Link; Mammary gland; Measures; Metals; Methods; Mothers; Mus; Operative Surgical Procedures; Oral Contraceptives; Pain; Perinatal Exposure; Pharmaceutical Preparations; Pharmacotherapy; Plant Resins; Plants; Predisposition; Pregnancy; Proteins; RNA; Relative (related person); Reporting; Restriction Mapping; Risk; Risk Factors; Severities; Signal Pathway; Smoke; Targeted Research; Therapeutic; Time; Tissues; Uterus; Variant; Weight; Woman; angiogenesis; bisphenol A; bisulfite; endometriosis; environmental chemical; exposed human population; fetal; mouse model; new therapeutic target; novel therapeutics; polycarbonate plastic; programs; public health relevance; research and development; soy; xenoestrogen

DESCRIPTION (provided by applicant): While the etiology of endometriosis is likely multifactorial, the long-range goal of this project is to understand a recently identified component to endometriosis due to developmental estrogen programming. The data linking developmental DES exposure in humans and our preliminary data in mice have led to the hypothesis: Developmental xenoestrogen exposure programs the fetus by altered DNA methylation and exacerbates endometriosis in adulthood. Three specific aims are proposed. Specific Aim 1. Does developmental exposure to bisphenol A, genistein and ethinyl estradiol at current human exposure levels exacerbate endometriosis in adulthood. We have shown that developmental DES exposure increases cell proliferation in endometriotic lesions in a mouse model of surgically induced endometriosis and results in larger lesions relative to control mice. After developmental exposure to bisphenol A, genistein, ethinyl estradiol or DES, we will surgically induce endometriosis in adult mice. Four weeks later, we will measure lesion weight, cell proliferation, apoptosis and angiogenesis. Specific Aim 2. Does developmental xenoestrogen exposure program gene expression in endometriotic lesions? We have shown that developmental DES exposure alters the expression of extracellular matrix and adhesion molecules in endometriotic lesions. After developmental xenoestrogen exposure and surgical induction of endometriosis in adulthood, we will use RNA isolated from endometriotic lesions to probe Illumina mouseref 8 microarrays. Specific Aim 3. Does developmental xenoestrogen exposure alter DNA methylation of genes in endometriotic lesions. Many genes in human endometriotic tissue have recently been identified with altered DNA methylation. In a preliminary study, we have shown that exposure to DES or ethinyl estradiol during development alters the DNA methylation profile in eutopic endometrium. We will use mouse methylated CpG island amplification (MCA) as a global approach to screen mouse CpG islands for altered DNA methylation. This project has the potential to lead to new therapeutics for treatment of endometriosis with drugs that alter DNA methylation. In a broader context, this project is likely to identify candidate genes and their proteins that can be used as targets for novel therapeutics. Further, a causal relationship between xenoestrogen exposure and exacerbation of endometriosis in adulthood represents a prime target for intervention by reducing exposure to these environmental chemicals. PUBLIC HEALTH RELEVANCE: A causal relationship between fetal exposure to estrogenic environmental chemicals and endometriosis in adulthood represents a prime target for intervention by reducing exposure to these environmental chemicals and to perhaps decrease the severity of endometriosis. Further, this project has the potential to lead to new therapeutics for treatment of endometriosis with drugs that alter DNA methylation. In a broader context, this project is likely to identify candidate genes and their proteins that can be used as targets for novel therapeutics in the treatment and possible cure of endometriosis.

描述（由申请人提供）：虽然子宫内膜异位症的病因可能是多因素的，但本项目的长期目标是了解由于发育雌激素编程导致的子宫内膜异位症的最近确定的组成部分。将人类发育中DES暴露与我们在小鼠中的初步数据联系起来的数据导致了以下假设：发育中的异种雌激素暴露通过改变DNA甲基化对胎儿进行编程，并加剧成年期的子宫内膜异位症。提出了三个具体目标。具体目标1。在目前人类暴露水平下，发育期暴露于双酚A、染料木黄酮和炔雌醇是否会加重成年期子宫内膜异位症？我们已经表明，在手术诱导的子宫内膜异位症小鼠模型中，发育期DES暴露增加了子宫内膜异位症病变中的细胞增殖，并导致相对于对照小鼠的更大病变。在发育暴露于双酚A、染料木黄酮、炔雌醇或DES后，我们将在成年小鼠中手术诱导子宫内膜异位症。四周后，我们将测量病变重量、细胞增殖、凋亡和血管生成。具体目标2。发育中的外源性雌激素暴露是否会导致增生性病变的基因表达？我们已经表明，DES暴露的发展改变了细胞外基质和粘附分子的表达在增生性病变。在成年期暴露于发育性异雌激素和手术诱导子宫内膜异位症后，我们将使用从子宫内膜异位症病变中分离的RNA来探测Illumina mouseref 8微阵列。具体目标3。发育中的外源性雌激素暴露是否改变了乳腺癌病变中基因的DNA甲基化？最近在人类乳腺癌组织中发现了许多基因的DNA甲基化改变。在一项初步研究中，我们发现在发育过程中暴露于DES或炔雌醇会改变在位子宫内膜的DNA甲基化谱。我们将使用小鼠甲基化CpG岛扩增（MCA）作为一种全球性的方法来筛选小鼠CpG岛的DNA甲基化改变。该项目有可能导致新的治疗方法，用于治疗子宫内膜异位症的药物，改变DNA甲基化。在更广泛的背景下，该项目可能会识别候选基因及其蛋白质，这些基因及其蛋白质可用作新疗法的靶点。此外，外源性雌激素暴露与成年期子宫内膜异位症恶化之间的因果关系代表了通过减少暴露于这些环境化学品进行干预的主要目标。公共卫生关系：胎儿暴露于雌激素环境化学物质和成年子宫内膜异位症之间的因果关系代表了通过减少暴露于这些环境化学物质和可能降低子宫内膜异位症的严重程度进行干预的主要目标。此外，该项目有可能导致新的治疗子宫内膜异位症的药物，改变DNA甲基化。在更广泛的背景下，该项目可能会确定候选基因及其蛋白质，可用作治疗和可能治愈子宫内膜异位症的新疗法的靶点。

项目成果

The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity.

• DOI: 10.1016/j.mce.2012.01.001
• 发表时间: 2012-05-06
• 期刊: MOLECULAR AND CELLULAR ENDOCRINOLOGY
• 影响因子: 4.1
• 作者: Saal, Frederick S. vom;Nagel, Susan C.;Coe, Benjamin L.;Angle, Brittany M.;Taylor, Julia A.
• 通讯作者: Taylor, Julia A.