Fetal Dioxin Exposure And The Pathology of Endometriosis

胎儿二恶英暴露与子宫内膜异位症的病理学

• 批准号: 6745175
• 负责人: KEVIN G OSTEEN
• 金额: $ 15.1万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-05 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6745175
• 关键词: cell cell interaction; cell population study; cytokine; dioxins; disease /disorder model; embryo /fetus toxicology; endometriosis; endometrium; environmental toxicology; enzyme activity; estrogens; gene expression; genetic regulation; hormone regulation /control mechanism; immunity; interleukin 1; laboratory mouse; leukocytes; metalloendopeptidases; microarray technology; model design /development; pesticide biological effect; progesterone; sex cycle; tissue inhibitor of metalloproteinases; transforming growth factors; tumor necrosis factor alpha

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.

描述（由申请人提供）：子宫内膜异位症是一种复杂而持久的疾病，最常发生在月经逆行和子宫内膜碎片异位建立之后。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患某些肿瘤的风险似乎更高。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，无论是在治疗中还是在怀孕期间，都可能降低妇女患这种疾病的风险。二恶英（TCDD:2,3,7,8四氯二苯并对二恶英）是一种内分泌和免疫干扰毒素，暴露于二恶英会增加暴露于灵长类动物群体中自发性子宫内膜异位症的发生率，并且在尸检中发现暴露于二恶英的动物具有侵袭性子宫内膜异位症。尽管TCDD与女性子宫内膜异位症之间的关系仍然是推测性的，但我们使用子宫内膜异位症小鼠模型的研究表明，TCDD治疗与基质金属蛋白酶（MMPs）表达增加和更具侵袭性的疾病有关。TCDD与子宫内膜异位症相关的潜在作用机制是作为转化生长因子-132的抑制剂，转化生长因子-132是正常胚胎发育和成人组织中MMP调节的必需组织因子。为了评估子宫或新生儿暴露于TCDD可能永久改变激素介导的mmmp调节的可能性，我们建议建立体内和体外小鼠模型来探索MMP调节。虽然小鼠不会自发发生子宫内膜异位症，但最近的数据表明，该疾病可能源于子宫中有缺陷的类固醇敏感性。确定胎儿/新生儿TCDD在成年小鼠子宫中破坏类固醇介导的MMP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。