Fetal Dioxin Exposure And The Pathology of Endometriosis

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DESCRIPTION (provided by applicant): Endometriosis is a complex and persistent disease, which most often develops following retrograde menstruation and ectopic establishment of endometrial fragments. Ectopic growth is an invasive event, which mimics cancer metastasis, and women with endometriosis appear to have an increased risk for the development of certain neoplasms. Estrogen exposure predisposes development of endometriosis, while progesterone exposure, either therapeutically or during pregnancy, may lower a woman's risk of the disease. Exposure to dioxin (TCDD:2,3,7,8 tetrachlorodibenzo-p-dioxin), an endocrine and immune disrupting toxin increased the rate of spontaneous endometriosis in an exposed primate colony and, at autopsy revealed aggressive endometriosis in exposed animals. Although an association between TCDD and the development of endometriosis in women remains speculative, our studies using a mouse model of endometriosis has revealed TCDD treatment is associated with increased expression of matrix metalloproteinases (MMPs) and a more aggressive disease. A potential mechanism of TCDD action associated with endometriosis is as an inhibitor of transforming growth factor-132, an essential tissue factor for normal embryonic development as well as MMP regulation in adult tissues. In order to assess the possibility that in utero or neonatal exposure to TCDD may permanently alter steroid-mediated regulation of MMPs later in life, we propose the development of in vivo and in vitro murine (mouse) models in which to explore MMP regulation. Although mice do not spontaneously develop endometriosis, recent data suggest the disease may have an origin in defective steroid sensitivity in the uterus. Identifying the mechanisms by which fetal/neonatal TCDD disrupts steroid-mediated MMP regulation in the adult mouse uterus will provide insight into the potential role of toxin exposure in the development of endometriosis.