From Oct. 1998 to Sept. 1999, we continued efforts to understand the molecular and cell signaling pathways involved in chemically-mediated ovarian dysfunction to focus on defining the roles that phthalates and prostaglandins play in ovarian toxicity and cancer. One major research focus has been to define the mechanisms by which phthalates cause granulosa cell toxicity and anovulation, and examine structure-activity of phthalates. We observe that mono-2ethylhexyl phthalate downregulates aromatase message and therefore suppresses estradiol through transcriptional events. Phthalates such mono-hexyl phthalate which does not effect ovarian function in vivo or in vitro also does not affect aromatase message levels. We are currently evaluating mono butyl phthalate. Additionally, we continue to examine the roles of the isoforms of cyclooxygenases and related prostaglandins in ovarian and reproductive function using the cyclooxygenase-1 (COX-1)- and cyclooxygenase-2 (COX-2)-deficient mice. These studes show that COX-2 and not COX-1 is required for the gonadotropin-related surge in ovarian prostaglandin levels and that COX-2-induced prostaglandins is necessary for cumulus activation and ovulation. These are the first studies to show that ovulation can be restored in COX-2 (-/-) mice by simultaneous treatment with gonadotropins and PGE2 or the cytokine IL1b, and that IL1b can function independently of COX-2. In contrast, the COX-1 isoform is necessary for normal parturition and we show that both prostaglandins and estradiol are necessary for normal parturition in the COX-1 deficient mouse. Based on these studies the hypothesis is that the final pathway for parturition is COX-1-related prostaglandins are necessary to support an enhanced production of ovarian estradiol, and estradiol is necessary and required to up-regulate COX-2-related prostaglandins. - ovulation, granulosa cells, rodents, humans, phthalates - Human Tissues, Fluids, Cells, etc.
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