Dual protective role for Glutathione S-transferase class pi against VCD-induced ovotoxicity in the rat ovary

Aileen F. Keating, Nivedita Sen, I. Glenn Sipes, Patricia B Hoyer

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The occupational chemical 4-vinylcyclohexene diepoxide (VCD) selectively destroys ovarian small pre-antral follicles in rats and mice via apoptosis. Detoxification of VCD can occur through glutathione conjugation, catalyzed by glutathione S-transferase (GST) enzymes. Further, GST class pi (GSTp) can negatively regulate JNK activity through protein:protein interactions in extra-ovarian tissues. Dissociation of this protein complex in the face of chemical exposure releases the inhibition of pro-apoptotic JNK. Increased JNK activity during VCD-induced ovotoxicity has been shown in isolated ovarian small pre-antral follicles following in vivo dosing of rats (80. mg/kg/day; 15. days, i.p.). The present study investigated the pattern of ovarian GSTp expression during VCD exposure. Additionally, the effect of VCD on an ovarian GSTp:JNK protein complex was investigated. PND4 F344 rat ovaries were incubated in control medium ± VCD (30μM) for 2-8. days. VCD increased ovarian GSTp mRNA (P <0.05) relative to control on d4-d8; whereas GSTp protein was increased (P<0.05) on d6-d8. A GSTp:JNK protein complex was detected by immunoprecipitation and Western blotting in ovarian tissues. Relative to control, the amount of GSTp-bound JNK was increased (P=0.09), while unbound JNK was decreased (P<0.05) on d6 of VCD exposure. The VCD-induced decrease in unbound JNK was preceded by a decrease in phosphorylated c-Jun which occurred on d4. These findings are in support of a possible dual protective role for GSTp in the rat ovary, consisting of metabolism of VCD and inhibition of JNK-initiated apoptosis.

Original languageEnglish (US)
Pages (from-to)71-75
Number of pages5
JournalToxicology and Applied Pharmacology
Volume247
Issue number2
DOIs
StatePublished - Sep 2010

Fingerprint

Glutathione S-Transferase pi
Glutathione Transferase
Rats
Ovary
Proteins
4-vinyl-1-cyclohexene dioxide
Tissue
Apoptosis
Enzyme inhibition
Detoxification
Inbred F344 Rats
Immunoprecipitation
Metabolism
Glutathione
Western Blotting

Keywords

  • 4-vinylcyclohexene diepoxide
  • Glutathione S-transferase pi
  • Ovotoxicity

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Dual protective role for Glutathione S-transferase class pi against VCD-induced ovotoxicity in the rat ovary. / Keating, Aileen F.; Sen, Nivedita; Sipes, I. Glenn; Hoyer, Patricia B.

In: Toxicology and Applied Pharmacology, Vol. 247, No. 2, 09.2010, p. 71-75.

Research output: Contribution to journalArticle

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abstract = "The occupational chemical 4-vinylcyclohexene diepoxide (VCD) selectively destroys ovarian small pre-antral follicles in rats and mice via apoptosis. Detoxification of VCD can occur through glutathione conjugation, catalyzed by glutathione S-transferase (GST) enzymes. Further, GST class pi (GSTp) can negatively regulate JNK activity through protein:protein interactions in extra-ovarian tissues. Dissociation of this protein complex in the face of chemical exposure releases the inhibition of pro-apoptotic JNK. Increased JNK activity during VCD-induced ovotoxicity has been shown in isolated ovarian small pre-antral follicles following in vivo dosing of rats (80. mg/kg/day; 15. days, i.p.). The present study investigated the pattern of ovarian GSTp expression during VCD exposure. Additionally, the effect of VCD on an ovarian GSTp:JNK protein complex was investigated. PND4 F344 rat ovaries were incubated in control medium ± VCD (30μM) for 2-8. days. VCD increased ovarian GSTp mRNA (P <0.05) relative to control on d4-d8; whereas GSTp protein was increased (P<0.05) on d6-d8. A GSTp:JNK protein complex was detected by immunoprecipitation and Western blotting in ovarian tissues. Relative to control, the amount of GSTp-bound JNK was increased (P=0.09), while unbound JNK was decreased (P<0.05) on d6 of VCD exposure. The VCD-induced decrease in unbound JNK was preceded by a decrease in phosphorylated c-Jun which occurred on d4. These findings are in support of a possible dual protective role for GSTp in the rat ovary, consisting of metabolism of VCD and inhibition of JNK-initiated apoptosis.",
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