The primary emphasis of this research group is to understand environmental influences on ovarian function and disease. Using ovarian toxicants such as the phthalates and glycol ethers, and ovarian carcinogens such as dioxins and other furans, the cellular and molecular pathologies are defined that contribute to fundamental lesions in ovarian function and towards the development of cancer. Using genetically altered animal models, the roles of genes and signaling molecules in ovarian, breast and uterine function and disease are also determined. Previous studies demonstrated that MEHP suppresses granulosa cell estradiol production independent of an effect on FSH-stimulated cAMP by affecting the amount of aromatase, the rate-limiting enzyme that converts testosterone to estradiol. The hypothesis was tested that MEHP affects aromatase trasncription, and MEHP was compared to several structurally related phthalates (0-200 microM) and Wy-14,643 (0-100 microM) in rat granulosa cell cultures. RNA was measured by fluorescent RT-PCR, and protein by western analysis. MEHP (0-200 mM) was unique among the phthalates in its ability to decrease estradiol production and was also found to significantly decrease aromatase RNA levels. The decrease in transcription was paralleled by a decrease in aromatase protein. Wy-14,643 had effects similar to MEHP at 100 microM. MEHP decreased transcription of aromatase specifically, and did not alter levels of P450scc. Treatment with a cAMP analogue increased expression of P450scc, while the decrease in aromatase remained. Thus, these studies are the first to show that MEHP decreases estradiol production in ovarian granulosa cells by decreasing transcription of aromatase specifically. Research efforts also continue to determine how prostaglandins function in reproductive health and disease. Specically, the expression of cyclooxygenase 1 and 2 in human ovarian cancers and ovarain cancer cell lines were examined. COX-2 is up-redulated in metastatic tumors, but not seen expressed in primary ovarian cancers (40 cases examined by immunohistochemistry). We are also confirming preliminary data that COX-1 is inhibited and COX-2 is up-regulated in nitrofurazone-induced ovarian tumors in mice. COX-2 is also overexpressed in mammary gland tumors of wnt-1 transgenics however, indomethacin does not seem to inhibit the development of tumors in these mice.
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