Women are exposed daily in the workplace, as well as the environment (cigarette smoke, automobile exhaust) to chemicals that can damage small pre-antral (primordial) ovarian follicles. Damage to these follicles can result in early ovarian failure (menopause). Because menopause is associated with a variety of health disorders, this represents a plausible health risk. Dosing of mice and rats with the occupational chemical, 4-vinyl-cyclohexene diepoxide (VCD) destroys primordial follicles and early ovarian failure can be caused in rodents by repeated dosing. On-going mechanistic studies in rats have helped characterize VCD as a model chemical for the study of xenobiotic-induced destruction of primordial follicles. However, the exact mechanism, which initiates oocyte degeneration, remains unknown. Thus, it is proposed here to expand the base of mechanistic information obtained with VCD to further identify those mechanisms. Because a variety of environmental chemicals are known to destroy primordial follicles, VCD-related information will prove applicable to chemicals that are sources of greater exposure in the environment. Therefore, a comparison between selected parameters of VCD-induced ovotoxicity and another environmental chemical, 9,10-dimethylbeznanthracene, DMBA, present in cigarette smoke and automobile exhaust will also be made. The hypothesis to be tested is that VCD causes destruction of primordial follicles by upregulation of pre- and post-transcriptional intracellular pathways and DMBA initiates similar events.
The Specific Aims are to: 1) identify and characterize gene expression directly regulated by VCD dosing, 2) dissect signaling pathways involved in VCD-induced ovotoxicity 3) compare selected signaling events initiated by DMBA with those of VCD, and 4) characterize the ability of ovarian compartments to bioactivate and detoxify VCH, VCD, and DMBA. Specifically investigating the mechanism(s) by which VCD damages ovarian primordial follicles and comparing this with DMBA will provide a greater ability to predict potential risks for early menopause from environmental exposures in women. This greater awareness will lead to an appreciation of the global impact of the environment on age of menopause in women ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009246-08
Application #
7250171
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Heindel, Jerrold
Project Start
1999-08-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
8
Fiscal Year
2007
Total Cost
$272,033
Indirect Cost
Name
University of Arizona
Department
Physiology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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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
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
Kappeler, Connie J; Hoyer, Patricia B (2012) 4-vinylcyclohexene diepoxide: a model chemical for ovotoxicity. Syst Biol Reprod Med 58:57-62
Bhattacharya, Poulomi; Sen, Nivedita; Hoyer, Patricia B et al. (2012) Ovarian expressed microsomal epoxide hydrolase: role in detoxification of 4-vinylcyclohexene diepoxide and regulation by phosphatidylinositol-3 kinase signaling. Toxicol Appl Pharmacol 258:118-23
Lukefahr, A L; Frye, J B; Wright, L E et al. (2012) Decreased bone mineral density in rats rendered follicle-deplete by an ovotoxic chemical correlates with changes in follicle-stimulating hormone and inhibin A. Calcif Tissue Int 90:239-49
Frye, Jennifer B; Lukefahr, Ashley L; Wright, Laura E et al. (2012) Modeling perimenopause in Sprague-Dawley rats by chemical manipulation of the transition to ovarian failure. Comp Med 62:193-202
Keating, Aileen F; Fernandez, Shannon M; Mark-Kappeler, Connie J et al. (2011) Inhibition of PIK3 signaling pathway members by the ovotoxicant 4-vinylcyclohexene diepoxide in rats. Biol Reprod 84:743-51
Mark-Kappeler, Connie J; Hoyer, Patricia B; Devine, Patrick J (2011) Xenobiotic effects on ovarian preantral follicles. Biol Reprod 85:871-83
Mark-Kappeler, Connie J; Sen, Nivedita; Keating, Aileen F et al. (2010) Distribution and responsiveness of rat anti-Mullerian hormone during ovarian development and VCD-induced ovotoxicity. Toxicol Appl Pharmacol 249:1-7

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