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).

Public Health Relevance

Female reproductive health can be negatively impacted by exposure to environmental chemicals. This project will investigate the ability of ovarian Glutathione S-Transferase proteins to detoxify chemicals as well as activate follicle death. Understanding these dual abilities will potentially aid in preventing ovarian follicle loss and early menopause in females.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Transition Award (R00)
Project #
5R00ES016818-05
Application #
8272625
Study Section
Special Emphasis Panel (NSS)
Program Officer
Heindel, Jerrold
Project Start
2010-05-10
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$248,999
Indirect Cost
$77,513
Name
Iowa State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011
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) Involvement of a volatile metabolite during phosphoramide mustard-induced ovotoxicity. Toxicol Appl Pharmacol 277:1-7
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
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
Nteeba, Jackson; Ganesan, Shanthi; Keating, Aileen F (2014) Impact of obesity on ovotoxicity induced by 7,12-dimethylbenz[a]anthracene in mice. Biol Reprod 90:68
Madden, Jill A; Keating, Aileen F (2014) Ovarian xenobiotic biotransformation enzymes are altered during phosphoramide mustard-induced ovotoxicity. Toxicol Sci 141:441-52
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
Abhilash, P A; Harikrishnan, R; Indira, M (2014) Ascorbic acid suppresses endotoxemia and NF-*B signaling cascade in alcoholic liver fibrosis in guinea pigs: a mechanistic approach. Toxicol Appl Pharmacol 274:215-24
Bhattacharya, Poulomi; Madden, Jill A; Sen, Nivedita et al. (2013) Glutathione S-transferase class ýý regulation of apoptosis signal-regulating kinase 1 protein during VCD-induced ovotoxicity in neonatal rat ovaries. Toxicol Appl Pharmacol 267:49-56
Nteeba, J; Ross, J W; Perfield 2nd, J W et al. (2013) High fat diet induced obesity alters ovarian phosphatidylinositol-3 kinase signaling gene expression. Reprod Toxicol 42:68-77

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