Dioxin Exposure and the Invasive Pathogenesis of Endometriosis

二恶英暴露与子宫内膜异位症的侵袭性发病机制

基本信息

批准号：
7900906
负责人：
KEVIN G OSTEEN
金额：
$ 33.64万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900906
关键词：
Address Affect Behavior Belgium Biopsy Cell Communication Cell Culture Techniques Cells Coculture Techniques Collaborations Communication Complex Conflict (Psychology)Confocal Microscopy Data Decidua Decidual Cell Reactions Developed Countries Development Diagnosis Dioxins Disease Disease model Down-Regulation Endocrine Disruptors Endometrial Endometrial Stromal Cell Endometrium Environment Environmental Pollution Enzymes Epidemiology Epithelial Epithelial Cells Estrogens Exhibits Experimental Models Exposure to Fibroblasts Goals Growth Human In Vitro Incidence Infertility Inflammatory Laboratories Lead Link Malignant Neoplasms Matrilysin Matrix Metalloproteinases Mediating Mesothelium Messenger RNA Methodology Modeling Nude Mice Ovarian Pain Pathogenesis Pathway interactions Pattern Peritoneal Peritoneum Phenotype Play Population Pregnancy Preparation Primates Process Production Progesterone Proteins Proteomics Regulation Research Personnel Resistance Retrograde Menstruation Retrospective Studies Risk Role Serum Site Steroids Stromal Cells Stromelysin 1 Tetrachlorodibenzodioxin Tissues Toxic Environmental Substances Toxic effect Toxin Tretinoin Woman cytokine endometriosis epidemiologic data in vivo in vivo Model interest mouse model prevent progesterone receptor B programs prospective protein expression response theories wound

项目摘要

DESCRIPTION (provided by applicant): Upwards of 1 billion dollars are spent each year in the U.S. diagnosing and treating women with endometriosis who often suffer from both severe pain and infertility. Only menstruating species, including humans and primates, exhibit naturally occurring endometriosis and the disease rarely persists in the absence of ovarian steroid production. Although the exact incidence of endometriosis is unknown, the disease occurs more frequently in industrialized countries, likely reflecting environmental contamination with endocrine disrupting chemicals such as dioxin (TCDD; 2,3,7,8 tetrachlorodibenzo-p-dioxin). Numerous studies have suggested a possible link between exposure to TCDD and the development of endometriosis, although epidemiologic data has been conflicting. Our studies indicate that endometrial progesterone resistance plays a significant role in the establishment and progression of endometriosis. Intriguingly, normal endometrium that has been exposed to TCDD mimics several key features of endometrial tissue from women with endometriosis, including an increased expression of matrix metalloproteinases (MMPs). Specifically, we have found that TCDD activates an epithelial-dominant pathway of cell-cell communication which reduces endometrial sensitivity to progesterone and promotes MMP-mediated establishment of experimental endometriosis in nude mice. The extent to which exposure to TCDD in human populations affects endometrial function related to a woman's risk for developing endometriosis remains unknown. To address this issue, we propose to use our established cell culture models and nude mouse experimental disease model to explore the role of TCDD as a progesterone disrupter in the human endometrium. We will also utilize our nude mouse model to examine the affect of TCDD on the invasive behavior of human endometrial tissue, a requirement for the establishment of endometriosis. To accomplish these goals, we propose the following specific aims: 1) to determine whether reduced progesterone responsiveness in the endometrium of women with endometriosis increases the toxicity of TCDD on MMP regulation and 2) to determine whether reduced progesterone sensitivity in the endometrium of women with endometriosis increases the toxic impact of TCDD on the synthesis of retinoic acid during stromal decidualization in vitro and 3) to correlate TCDD-mediated activation of epithelial-dominant cell-cell communication with the invasive behavior of stromal and epithelial cells in an experimental model of endometriosis.

描述（由申请人提供）：每年在美国诊断和治疗子宫内膜异位症的妇女经常患有严重疼痛和不育。在包括人类和灵长类动物在内的月经物种只会出现自然发生的子宫内膜异位症，并且在没有卵巢类固醇产生的情况下，这种疾病很少持续存在。尽管子宫内膜异位症的确切发生率尚不清楚，但该疾病在工业化国家中更频繁地发生，这可能反映了内分泌污染的内分泌污染，而内分泌破坏了二恶英（TCDD; 2,3,7,8 tetrachlorodibenzo-p-Dioxin）。许多研究表明，尽管流行病学数据一直在冲突，但暴露于TCDD和子宫内膜异位症的发展之间可能存在联系。我们的研究表明，子宫内膜孕酮耐药性在子宫内膜异位症的建立和进展中起着重要作用。有趣的是，已暴露于TCDD的正常子宫内膜模仿子宫内膜异位女性子宫内膜组织的几个关键特征，包括增加基质金属蛋白酶（MMP）的表达增加。具体而言，我们发现TCDD激活了细胞 - 细胞通信的上皮主导途径，该途径降低了子宫内膜敏感性对孕酮的敏感性，并促进了MMP介导的裸鼠实验性子宫内膜异位症的建立。人群中接触TCDD的程度影响与女性患子宫内膜异位症风险有关的子宫内膜功能尚不清楚。为了解决这个问题，我们建议使用我们已建立的细胞培养模型和裸小鼠实验疾病模型来探索TCDD作为孕酮在人子宫内部中的作用。我们还将利用我们的裸小鼠模型来检查TCDD对人子宫内膜组织侵入性行为的影响，这是建立子宫内膜异位症的要求。要实现这些目标，我们提出以下具体目的：1）确定子宫内膜异位症女性子宫内膜子宫内膜的孕激素反应能力降低会增加TCDD对MMP调节的毒性是否会降低MMP调节的毒性以及2）确定在子宫内膜异位效果上，在毒性上降低了子宫内膜异位的子宫内膜内部酸度的质量纳入pctstd prots ration detcdd的侵害是否会降低质量的侵害。 3）在子宫内膜异位症的实验模型中，将TCDD介导的上皮细胞 - 细胞通信与基质和上皮细胞的侵入性行为相关联。