Effect of 4-vinylcyclohexene diepoxide dosing in rats on GSH levels in liver and ovaries

Patrick J. Devine, I. Glenn Sipes, Patricia B Hoyer

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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 (p < 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.

Original languageEnglish (US)
Pages (from-to)315-320
Number of pages6
JournalToxicological Sciences
Volume62
Issue number2
DOIs
StatePublished - 2001

Fingerprint

Liver
Rats
Ovary
Oxidative stress
Ovarian Follicle
Buthionine Sulfoximine
Oxidative Stress
Glutathione Disulfide
Thiobarbituric Acid Reactive Substances
Level control
Metabolites
Dimers
Glutathione
Inbred F344 Rats
Animals
Antioxidants
Tissue
High Pressure Liquid Chromatography
4-vinyl-1-cyclohexene dioxide
4-vinylcyclohexene

Keywords

  • 4-vinylcyclohexene diepoxide
  • Buthionine sulfoximine
  • Glutathione
  • Ovarian follicle
  • Ovary

ASJC Scopus subject areas

  • Toxicology

Cite this

Effect of 4-vinylcyclohexene diepoxide dosing in rats on GSH levels in liver and ovaries. / Devine, Patrick J.; Sipes, I. Glenn; Hoyer, Patricia B.

In: Toxicological Sciences, Vol. 62, No. 2, 2001, p. 315-320.

Research output: Contribution to journalArticle

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abstract = "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 (p < 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.",
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