Dioxin Exposure and the Invasive Pathogenesis of Endometriosis

描述（由申请人提供）：在美国，每年花费超过10亿美元用于诊断和治疗患有子宫内膜异位症的妇女，这些妇女经常遭受严重的疼痛和不孕症。只有生殖物种，包括人类和灵长类动物，表现出自然发生的子宫内膜异位症，这种疾病很少在没有卵巢类固醇产生的情况下持续存在。虽然子宫内膜异位症的确切发病率尚不清楚，但这种疾病在工业化国家更常见，可能反映了二恶英（TCDD; 2，3，7，8 tetrachlorodibenzo-p-dioxin）等内分泌干扰化学品的环境污染。尽管流行病学数据相互矛盾，但许多研究表明接触TCDD和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发展中发挥着重要作用。有趣的是，暴露于TCDD的正常子宫内膜与子宫内膜异位症患者子宫内膜组织的几个关键特征相似，包括基质金属蛋白酶（MMPs）表达增加。具体来说，我们发现，TCDD激活上皮细胞占主导地位的细胞-细胞通讯途径，降低子宫内膜对孕酮的敏感性，促进MMP介导的建立实验性子宫内膜异位症裸鼠。在人群中暴露于TCDD对子宫内膜功能的影响程度与妇女发生子宫内膜异位症的风险有关，目前尚不清楚。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，以探讨TCDD作为孕酮干扰剂在人类子宫内膜中的作用。我们还将利用我们的裸鼠模型来研究TCDD对人子宫内膜组织的侵袭行为的影响，这是建立子宫内膜异位症的一个必要条件。为实现这些目标，我们提出以下具体目标：1）确定子宫内膜异位症妇女子宫内膜中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妇女子宫内膜中孕酮敏感性降低是否会增加TCDD对体外基质蜕膜化过程中视黄酸合成的毒性影响，3）在子宫内膜异位症的实验模型中，将TCDD介导的上皮主导细胞间通讯的激活与基质和上皮细胞的侵袭行为相关联。

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.