OVARIAN DIOXIN BINDING AND MODULATION OF STEROIDOGENESIS IN VITRO

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。以放射自显影技术定位二恶英与猴子卵巢内特定隔室的结合，作为女性生殖中断的潜在机制。2，3，7，8-四氯二苯并对二恶英(TCDD，典型的二恶英)通常被认为是已知的最有毒的物质。TCDD是在森林火灾中合成的，是某些塑料制造和各种氯化程序的副产品，是某些除草剂中的污染物。在发达国家，个人垃圾焚烧占TCDD产量的50%以上。TCDD的作用机制尚不完全清楚，但它是通过芳香烃受体(AHR)发挥作用的。TCDD是雌激素调节剂，因为它的受体通过共激活分子与雌激素受体(ER)α和β直接结合。1976年，在意大利塞维索的一次工厂爆炸中，接触到TCDD的女性患上了某些生殖癌。我们自己的数据显示，二恶英抑制人卵巢颗粒细胞的类固醇合成，AHR定位于这些细胞。我们以前已经证明AHR在整个恒河猴卵巢中都存在，但还没有建立其定位的特定区段。在这项研究中，我们首次证明了放射性标记的TCDD结合了恒河猴卵巢中的卵泡。我们发现TCDD与恒河猴卵巢有腔卵泡的特异性结合，而竞争性拮抗剂可显著降低这种结合。此外，结合的区域类似于我们之前在恒河猴卵巢中定位ER-α的区域。这些发现支持这样的假设，即二恶英通过卵泡中的受体直接影响灵长类卵巢功能，可能是通过ER调节。初步，我们还观察到暴露于TCDD的猴子卵巢片段雌激素分泌减少。这些研究构成了一种实验方法，旨在阐明环境污染物对人类女性生殖功能的不良影响的生物医学目标。这项研究使用了WNPRC病理服务。资金在本报告所述期间之前结束，但仍有出版物待定。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To localize autoradiographically dioxin binding to specific compartments within the monkey ovary as a potential mechanism of reproductive disruption in women. 2,3,7,8-Tetrachloro-dibenzo-p-dioxin (TCDD, the prototypical dioxin) is often considered to be the most poisonous substance known. TCDD is synthesized in forest fires, as a by-product of certain plastics manufacture and various chlorination procedures, and is a contaminant in certain herbicides. Personal waste incineration accounts for over 50% of TCDD production in developed countries. The mechanism of TCDD action is not entirely clear, but it acts via the aromatic hydrocarbon receptor (AHR). TCDD is estrogen modulatory as its receptor associates directly with estrogen receptors (ER) alpha and beta via co-activator molecules. TCDD was associated with certain reproductive cancers in women exposed to a factory explosion in Seveso, Italy in 1976. Our own data show that dioxin inhibits steroidogenesis in human ovarian granulosa cells and that AHR is localized to these cells. We previously demonstrated that AHR is found in whole rhesus ovary, but have not established specific compartments for its localization. In this research, we showed for the first time that radiolabeled TCDD binds ovarian follicles in rhesus monkey ovaries. We showed specific binding of TCDD to antral follicles of rhesus monkey ovaries, and this was drastically reduced with competitive antagonist. Additionally, the areas of binding were similar to those in which we previously localized ER-alpha in rhesus monkey ovaries. These findings support the hypothesis that dioxins directly affect primate ovarian function via receptors in ovarian follicles, possibly via ER modulation. Preliminarily, we also observe reduced estrogen secretion by monkey ovarian fragments exposed to TCDD. These studies constitute an experimental approach aimed at the biomedical goal of elucidating untoward effects of environmental contaminants on human female reproductive function. This research used WNPRC Pathology Services. Funding ended before this reporting period, but there are publications pending.