Dioxin Exposure and the Invasive Pathogenesis of Endometriosis

描述（由申请人提供）：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。只有月经来期的物种，包括人类和灵长类动物，会表现出自然发生的子宫内膜异位症，而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。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为常见，这可能反映了环境受到二恶英等内分泌干扰化学物质的污染（TCDD; 2,3,7,8四氯二苯并-对二恶英）。尽管流行病学数据相互矛盾，但许多研究表明，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发展中起着重要作用。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（MMPs）的表达增加。具体来说，我们发现TCDD激活了细胞-细胞通讯的上皮显性通路，降低了子宫内膜对黄体酮的敏感性，促进了mmp介导的实验性子宫内膜异位症在裸鼠中的建立。人类接触TCDD对子宫内膜功能的影响程度与女性发生子宫内膜异位症的风险有关，目前尚不清楚。为了解决这一问题，我们建议利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作为黄体酮干扰物在人子宫内膜中的作用。我们还将利用我们的裸鼠模型来研究TCDD对人子宫内膜组织侵袭行为的影响，这是建立子宫内膜异位症的必要条件。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患者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患者子宫内膜孕酮敏感性降低是否会增加TCDD对体外间质脱胞过程中维甲酸合成的毒性影响；3)TCDD介导的上皮优势细胞-细胞通讯激活与子宫内膜异位症的侵袭行为之间的相关性子宫内膜异位症实验模型中的基质和上皮细胞。

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.