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）：美国每年花费超过 10 亿美元来诊断和治疗患有子宫内膜异位症的女性，这些女性经常遭受剧烈疼痛和不孕症的困扰。只有月经物种，包括人类和灵长类动物，才会表现出自然发生的子宫内膜异位症，并且在卵巢类固醇不产生的情况下，这种疾病很少持续存在。尽管子宫内膜异位症的确切发病率尚不清楚，但该疾病在工业化国家中发生得更为频繁，这可能反映了二恶英（TCDD；2,3,7,8 四氯二苯并-对二恶英）等内分泌干扰化学物质的环境污染。尽管流行病学数据相互矛盾，但大量研究表明接触 TCDD 与子宫内膜异位症的发生之间可能存在联系。我们的研究表明，子宫内膜黄体酮抵抗在子宫内膜异位症的发生和进展中起着重要作用。有趣的是，暴露于 TCDD 的正常子宫内膜模仿了子宫内膜异位症女性子宫内膜组织的几个关键特征，包括基质金属蛋白酶 (MMP) 表达增加。具体来说，我们发现 TCDD 激活细胞间通讯的上皮主导途径，从而降低子宫内膜对孕酮的敏感性，并促进裸鼠中 MMP 介导的实验性子宫内膜异位症的建立。人群中接触 TCDD 对子宫内膜功能的影响程度（与女性患子宫内膜异位症的风险相关）仍不清楚。为了解决这个问题，我们建议使用我们建立的细胞培养模型和裸鼠实验疾病模型来探索TCDD作为黄体酮干扰剂在人子宫内膜中的作用。我们还将利用我们的裸鼠模型来检查 TCDD 对人类子宫内膜组织侵袭行为的影响，这是子宫内膜异位症建立的必要条件。为了实现这些目标，我们提出以下具体目标：1) 确定子宫内膜异位症女性子宫内膜孕酮反应性降低是否会增加 TCDD 对 MMP 调节的毒性；2) 确定子宫内膜异位症女性子宫内膜孕酮敏感性降低是否会增加子宫内膜异位症增加了 TCDD 对体外基质蜕膜化过程中视黄酸合成的毒性影响，3) 与 TCDD 介导的视黄酸激活相关子宫内膜异位症实验模型中上皮优势细胞间通讯与基质细胞和上皮细胞的侵袭行为。