Fetal Dioxin Exposure And The Pathology of Endometriosis

描述(申请人提供)：子宫内膜异位症是一种复杂而持久的疾病，通常发生在月经逆行和子宫内膜碎片异位形成之后。异位生长是一种侵袭性事件，类似于癌症转移，患有子宫内膜异位症的女性似乎有更高的患某些肿瘤的风险。雌激素暴露容易导致子宫内膜异位症的发生，而孕激素暴露，无论是在治疗过程中还是在怀孕期间，都可能降低女性患这种疾病的风险。接触二恶英(TCDD：2，3，7，8四氯二苯并对二恶英)，一种内分泌和免疫干扰毒素，会增加暴露在灵长类动物群体中的自发性子宫内膜异位症的发生率，尸检显示暴露在暴露动物中的侵袭性子宫内膜异位症。尽管TCDD与女性子宫内膜异位症的发展之间的联系仍是推测的，但我们使用子宫内膜异位症小鼠模型进行的研究表明，TCDD治疗与基质金属蛋白酶(MMPs)的表达增加和一种更具侵袭性的疾病有关。与子宫内膜异位症相关的TCDD作用的一个潜在机制是作为转化生长因子-132的抑制因子，转化生长因子-132是正常胚胎发育和成人组织中的基质金属蛋白酶调节所必需的组织因子。为了评估宫内或新生儿暴露于TCDD可能永久改变类固醇介导的MMPs调节的可能性，我们建议建立体内和体外小鼠(小鼠)模型来探索MMPs的调节。尽管小鼠不会自发发生子宫内膜异位症，但最近的数据表明，这种疾病可能源于子宫对类固醇的敏感性缺陷。确定胎儿/新生儿TCDD扰乱成年小鼠子宫中类固醇介导的基质金属蛋白酶调节的机制将有助于深入了解毒素暴露在子宫内膜异位症发展中的潜在作用。

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.