Submission Number: PAT-4-34-15

Abstract Number: 455

GSH LEVELS IN LIVER AND OVARIES AFTER EXPOSURES OF RATS TO 4-VINYLCYCLOHEXENE DIEPOXIDE IN VIVO.

Patrick J Devine* ^1,3, I Glenn Sipes ^2,3 and Patricia B Hoyer* ^1,3

Department of Physiology, The University of Arizona, Tucson, AZ ¹
Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ ²
Center for Toxicology, The University of Arizona, Tucson, AZ, USA. ³

Abstract:
4-Vinylcyclohexene Diepoxide (VCD) is a known reproductive toxicant in both male and female rats and mice. This compound has been shown to deplete the ovarian follicle pool in females of both species. The mechanism by which this occurs is unknown, but may involve the breakdown of protective mechanisms within the ovary. In previous studies, metabolites assumed to be glutathione (GSH)-conjugated VCD were detected in rat urine 6 hours after administration of [¹⁴C] VCD. Therefore, GSH may be involved in the detoxification of VCD. The following study was designed to test whether liver or ovary participates in this detoxification. Day 28 Fischer 344 rats were treated either once or daily with vehicle (sesame oil) or VCD (80 mg/kg, ip). Homogenates were prepared from liver or ovarian tissue and GSH content was measured following derivatization with fluorodinitrobenzene, HPLC separation and UV detection. Two hours following a single dose of VCD, GSH levels were lower (p<0.05) than controls in liver (control, 8.90.4 moles/g tissue; VCD, 4.20.4, n=4/group), but not in whole ovary homogenates (control, 4.10.1 moles/g; VCD, 3.70.1, n=9/group). Hepatic GSH was restored to control levels 24 hours after a single dose of VCD (p>0.05). To determine whether GSH becomes irreversibly depleted in either tissue, samples were collected 24 hours after 5, 10, or 15 days of daily dosing with VCD. GSH was not affected in ovarian tissue at any time point (p>0.05). Hepatic GSH levels were unaltered on day 5 (p>0.05), increased (p<0.05) on day 10 (control, 6.90.7 moles/g; VCD, 9.20.5, n=7/group), and returned to control levels by day 15 (p>0.05). These findings provide evidence that GSH may participate in VCD metabolism in liver rather than ovaries in response to repeated daily dosing with VCD. Furthermore, no irreversible depletion of GSH occurred under these conditions in either tissue, indicating this protective mechanism was not compromised by repeated dosing with VCD. However, these results do not exclude the possibility that depletion of GSH is compartmentalized to target follicles within the ovary. (ESO06694, ESO8979).

Keywords: ovary, glutathione, VCD

This abstract is being presented at: 2:30 PM in session:
SESSION 19: ENDOCRINE DISRUPTION