MECHANISTIC STUDIES OF OVARIAN TOXICITY

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Summary of Work: From Oct. 1996 to Sept. 1997, we determined by nonisotopic in situ hybridization studies that the tissue distributions of Brca1 and Brca2 expression correlates with the proliferating cell populations in embryos, in the developing and differentiating mammary gland and in adult tissues. However, in the ovary, the expression of these genes is independent of hormonal stimuli and/or the presence of a functional estrogen receptor. In the testes these genes are expressed in mitotic spermatogonia and early meitotic spermatocytes, but Brca1 is expressed prior to Brca2. We have described the development of ovarian tumors in adult female Sprague-Dawley rats exposed to TCDD (dioxin) and have localized the Ah receptor by RT-PCR, insitu hybridization and immunohistochemistry in rat and mouse ovaries, and in the TCDD-promoted rat ovarian tumors. We are defining the role of cyclooxygenase 1 and cycloxygenase 2 (COX 1 and COX 2) in the female using the mice deficient in these enzymes. Ovarian granulosa cell COX2 induction is essential for ovulation and release of the oocyte because mice without the enzyme can not initiate cumulus expanision and release the egg. The anovulation can be overriden by treatment with prostaglandins and specific cytokines.COX1 is necessary for initiation of parturition because the deficient mice have prolonged gestation and parturition can be initiated by supplementation with prostaglandins and specific steroid hormones. Thus, these studies identify critical roles and key signalling pathways of prostaglandins in female reproduction. We continue to evalute specific chemicals and their effect on ovarian function. We have finished studies that determined minimal effect on ovarian function from mercury vapor exposures. Additionaly, we are focusing on structure-activity relationships of the phthalates in their effect on ovarian function and endocrine disruption. Preliminary studies show a correlation between the compounds direct toxicity on the ovary and its ability to activiate the peroxisome proliferator activated receptors which we will pursue in the upcoming year.