Glutathione S-Tranferase signaling in VCD-induced ovotoxicity.

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This application is made to support the transition of Dr. Aileen Keating, currently a post-doctoral fellow in the Department of Physiology at the University of Arizona to independence as an Assistant Professor in the Department of Animal Science at Iowa State University. Dr. Keating will be assigned two mentors in the Department of Animal Science and will work with them to develop her teaching and research activities. The research of Dr. Hoyer, her postdoctoral mentor, focuses on the effects of environmental chemicals on small pre-antral ovarian follicles. Dr. Hoyer uses the occupational chemical, 4-vinylcyclohexene diepoxide (VCD), as a model of ovarian environmental xenobiotic exposure. VCD selectively destroys small pre-antral follicles in rodent ovaries, leading to premature ovarian failure (analogous to early menopause in women). Dr. Keating's research will continue to complement but not overlap with that of Dr. Hoyer. Menopause is known to be associated with increased risk for cardiovascular disease, osteoporosis, ovarian cancer and depression. Thus, chemicals that reduce reproductive years and accelerate the onset of menopause, such as VCD, are of concern in women. VCD can be metabolized to an inactive form by the action of Glutathione S-transferase (GST) proteins. GSTs can also participate in regulating signaling pathways. The specific aims proposed in this application will investigate the role and regulation of GST signaling in the rat ovary in response to VCD exposure. Specific Aim 1 will investigate whether GSTpi/mu form protein:protein complexes with pro-apoptotic proteins and to determine if, in response to VCD, these protein:protein complexes dissociate and apoptosis occurs. Specific Aim 2 will determine if VCD-induced increased nuclear phosphorylated c-jun alters transcriptional activity of ovarian genes, while Specific Aim 3 will determine the role ofthe NRF2 protein in regulation of GSTpi and mu. Dr. Keating will expand specific aim 1 and 3 to include preliminary studies on the involvement of GST's in metabolism of two other chemicals that cause ovarian damage and follicle destruction, 7,12-dimethylbenz[a]anthracene (DMBA) and phosphoramide mustard (PM).