Toxicological Sciences 62, 315-320 (2001)
Copyright © 2001 by the Society of Toxicology
REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY |
Effect of 4-Vinylcyclohexene Diepoxide Dosing in Rats on GSH Levels in Liver and Ovaries
,
,1
* Departments of Physiology and
Pharmacology and Toxicology, The University of Arizona, 1501 N. Campbell Ave., P.O. Box 245051, Tucson, Arizona 85724–5051; and
Southwest Environmental Health Sciences Center, The University of Arizona, Tucson, Arizona 85724–5051
Repeated daily dosing of rats with the occupational chemical 4- vinylcyclohexene or its diepoxide metabolite (VCD) for 15 days destroys the smallest ovarian follicles. VCD acutely reduced hepatic levels of the antioxidant, glutathione (GSH); therefore, these studies were designed to evaluate whether GSH concentrations mediate VCD-induced ovotoxicity. Immature female Fischer 344 rats were dosed once or daily for 15 days with VCD (0.57 mmol/kg, ip) or the GSH synthesis inhibitor buthionine sulfoximine (BSO, 2 mmol/kg, ip). Animals were euthanized 2, 6, or 26 h following a single dose, and 2 or 26 h following 15 days of daily dosing. Reduced (p < 0.05) hepatic GSH was seen within 2 h of a single dose of either VCD (51 ± 5% of control) or BSO (42 ± 9%), but only BSO reduced ovarian GSH (71 ± 5% at 6 h, p = 0.05) as measured by HPLC. Within 26 h, GSH levels had returned to control levels with either treatment. Hepatic GSH levels were reduced (< 0.05) 2 h after 15 daily doses with BSO (42 ± 5%) or VCD (70 ± 4%), but only BSO decreased ovarian GSH (64 ± 3%). GSH levels in 15-day tissues were similar to controls 26 h after the final dose. Neither BSO nor VCD increased hepatic or ovarian concentrations of the oxidized dimer of GSH (GSSG) or thiobarbituric acid-reactive substances (TBARS), indicators of oxidative stress. These results suggest these treatments did not cause an oxidative stress. Histological counts of ovarian small follicle numbers were reduced (p < 0.05) in 15-day VCD-treated rats, whereas BSO did not affect follicle numbers, even though BSO reduced ovarian GSH content. These results support the conclusion that alterations in ovarian GSH levels are not involved in VCD-induced ovotoxicity.
Key Words: 4-vinylcyclohexene diepoxide; ovarian follicle; glutathione; buthionine sulfoximine; ovary..
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