This application is made to support the transition to independence of Dr. Aileen Keating, a post-doctoral fellow in the Department of Physiology at the University of Arizona. Dr. Keating will be mentored through the first two years of the award by Dr. Patricia B. Hoyer and will be co-mentored by Dr. Donna Zhang (University of Arizona) and Dr. Jodi Flaws (University of Illinois). Dr. Hoyer's research focuses on the effects of environmental chemicals on small pre-antral ovarian follicles. Specifically, her laboratory has developed a model of environmental xenobiotic exposure in the ovary, using the occupational chemical 4-vinylcyclohexene diepoxide (VCD). VCD selectively destroys small pre-antral follicles in the ovaries of rats and mice. Destruction of the small, pre-antral pool of ovarian follicles can lead to premature ovarian failure (early menopause in women). The research outlined in this application will complement but not overlap with work carried out in Dr. Hoyer's laboratory. With the trend in recent years for women to have children later in life, environmental exposures that reduce the reproductive years are of concern. Additionally, menopause is known to be associated with increased risk for cardiovascular disease, osteoporosis, ovarian cancer and depression. Thus, chemicals that accelerate the onset of menopause are of concern in women. Previous research has investigated a role for ovarian metabolism in mediating the response to ovotoxic chemicals. VCD can be metabolized to an inactive form in the ovary through the action of the Glutathione S-transferase (GST) family of proteins. Additionally, 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 of the NRF2 protein in regulation of GSTpi and mu. The findings will demonstrate how GST might simultaneously protect against and enhance VCD-induced ovotoxicity.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Heindel, Jerrold
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Iowa State University
Veterinary Sciences
Schools of Earth Sciences/Natur
United States
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Madden, Jill A; Thomas, Porsha Q; Keating, Aileen F (2017) Phosphoramide mustard induces autophagy markers and mTOR inhibition prevents follicle loss due to phosphoramide mustard exposure. Reprod Toxicol 67:65-78
Ganesan, Shanthi; Nteeba, Jackson; Madden, Jill A et al. (2017) Obesity alters phosphoramide mustard-induced ovarian DNA repair in mice. Biol Reprod 96:491-501
Ganesan, Shanthi; Keating, Aileen F (2016) The ovarian DNA damage repair response is induced prior to phosphoramide mustard-induced follicle depletion, and ataxia telangiectasia mutated inhibition prevents PM-induced follicle depletion. Toxicol Appl Pharmacol 292:65-74
Ganesan, Shanthi; Nteeba, Jackson; Keating, Aileen F (2015) Impact of obesity on 7,12-dimethylbenz[a]anthracene-induced altered ovarian connexin gap junction proteins in female mice. Toxicol Appl Pharmacol 282:1-8
Ganesan, Shanthi; Keating, Aileen F (2015) Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells. Toxicol Appl Pharmacol 282:252-8
Ganesan, Shanthi; Nteeba, Jackson; Keating, Aileen F (2014) Enhanced susceptibility of ovaries from obese mice to 7,12-dimethylbenz[a]anthracene-induced DNA damage. Toxicol Appl Pharmacol 281:203-10
Madden, Jill A; Hoyer, Patricia B; Devine, Patrick J et al. (2014) Acute 7,12-dimethylbenz[a]anthracene exposure causes differential concentration-dependent follicle depletion and gene expression in neonatal rat ovaries. Toxicol Appl Pharmacol 276:179-87
Ganesan, Shanthi; Keating, Aileen F (2014) Impact of 7,12-dimethylbenz[a]anthracene exposure on connexin gap junction proteins in cultured rat ovaries. Toxicol Appl Pharmacol 274:209-14
Madden, Jill A; Keating, Aileen F (2014) Ovarian xenobiotic biotransformation enzymes are altered during phosphoramide mustard-induced ovotoxicity. Toxicol Sci 141:441-52
Nteeba, Jackson; Ganesan, Shanthi; Keating, Aileen F (2014) Progressive obesity alters ovarian folliculogenesis with impacts on pro-inflammatory and steroidogenic signaling in female mice. Biol Reprod 91:86

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