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. ? ? ?
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