OVARIAN DIOXIN BINDING AND MODULATION OF STEROIDOGENESIS IN VITRO

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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.