OVARIAN DIOXIN BINDING AND MODULATION OF STEROIDOGENESIS IN VITRO

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。定位放射自显影二恶英结合到猴子卵巢内的特定隔室，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，原型二恶英）通常被认为是已知毒性最大的物质。四氯二苯并对二恶英是在森林火灾中合成的，是某些塑料生产和各种氯化过程的副产品，也是某些除草剂的污染物。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，但它通过芳香烃受体（AHR）发挥作用。TCDD是雌激素调节剂，因为其受体通过辅激活分子直接与雌激素受体（ER）α和β结合。1976年，在意大利塞维索的一次工厂爆炸中，四氯二苯并对二恶英与妇女的某些生殖系统癌症有关。我们自己的数据表明，二恶英抑制类固醇在人类卵巢颗粒细胞和AHR是本地化这些细胞。我们以前证明，AHR被发现在整个恒河猴卵巢，但还没有建立具体的隔间，其本地化。在这项研究中，我们首次发现放射性标记的TCDD结合恒河猴卵巢的卵泡。我们发现，特异性结合的TCDD的恒河猴卵巢窦卵泡，这是急剧减少与竞争性拮抗剂。此外，结合区域与我们先前在恒河猴卵巢中定位ER-α的区域相似。这些发现支持了二恶英通过卵泡中的受体直接影响灵长类动物卵巢功能的假设，可能是通过ER调节。此外，我们还观察到雌激素分泌减少猴子卵巢碎片暴露于TCDD。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。本研究使用WNPRC病理学服务。在本报告所述期间之前，资金已经结束，但仍有一些出版物有待出版。

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.