OVARIAN DIOXIN BINDING AND MODULATION OF STEROIDOGENESIS IN VITRO

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。利用放射自显像技术定位二恶英与猴卵巢内特定腔室的结合，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）通常被认为是已知毒性最大的物质。TCDD是在森林火灾中合成的，是某些塑料制造和各种氯化过程的副产品，也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，但它是通过芳烃受体（AHR）起作用的。TCDD具有雌激素调节作用，其受体通过共激活剂分子直接与雌激素受体(ER) α和β结合。TCDD与1976年意大利塞韦索工厂爆炸中暴露的妇女的某些生殖癌症有关。我们自己的数据表明，二恶英抑制人卵巢颗粒细胞的甾体生成，并且AHR局限于这些细胞。我们之前证明AHR存在于整个恒河猴卵巢中，但没有确定其定位的特定腔室。在这项研究中，我们首次发现放射性标记的TCDD与恒河猴卵巢的卵泡结合。我们发现TCDD与恒河猴卵巢的腔卵泡特异性结合，并在竞争性拮抗剂的作用下显著降低这种结合。此外，结合区域与我们之前在恒河猴卵巢中定位的er - α相似。这些发现支持了二恶英通过卵巢卵泡中的受体，可能通过内质网调节，直接影响灵长类动物卵巢功能的假设。我们还初步观察到暴露于TCDD的猴子卵巢碎片雌激素分泌减少。这些研究构成了旨在阐明环境污染物对人类女性生殖功能不利影响的生物医学目标的实验方法。本研究使用WNPRC病理学服务。经费在本报告所述期间之前已结束，但仍有出版物有待出版。

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.