Glutathione S-transferase class mu regulation of apoptosis signal-regulating kinase 1 protein during VCD-induced ovotoxicity in neonatal rat ovaries

Poulomi Bhattacharya, Jill A. Madden, Nivedita Sen, Patricia B Hoyer, Aileen F. Keating

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

4-Vinylcyclohexene diepoxide (VCD) destroys ovarian primordial and small primary follicles via apoptosis. In mice, VCD exposure induces ovarian mRNA expression of glutathione S-transferase (GST) family members, including isoform mu (Gstm). Extra-ovarian GSTM negatively regulates pro-apoptotic apoptosis signal-regulating kinase 1 (ASK1) through protein complex formation, which dissociates during stress, thereby initiating ASK1-induced apoptosis. The present study investigated the ovarian response of Gstm mRNA and protein to VCD. Induction of Ask1 mRNA at VCD-induced follicle loss onset was determined. Ovarian GSTM:ASK1 protein complex formation was investigated and VCD exposure effects thereon evaluated. Phosphatidylinositol-3 kinase (PI3K) regulation of GSTM protein was also studied. Postnatal day (PND) 4 rat ovaries were cultured in control media ± 1) VCD (30. μM) for 2-8. days; 2) VCD (30. μM) for 2. days, followed by incubation in control media for 4. days (acute VCD exposure); or 3) LY294002 (20. μM) for 6. days. VCD exposure did not alter Gstm mRNA expression, however, GSTM protein increased (P<0.05) after 6. days of both the acute and chronic treatments. Ask1 mRNA increased (0.33-fold; P<0.05) relative to control after 6. days of VCD exposure. Ovarian GSTM:ASK1 protein complex formation was confirmed and, relative to control, the amount of GSTM bound to ASK1 increased 33% (P<0.05) by chronic but with no effect of acute VCD exposure. PI3K inhibition increased (P<0.05) GSTM protein by 40% and 71% on d4 and d6, respectively. These findings support involvement of GSTM in the ovarian response to VCD exposure, through regulation of pro-apoptotic ASK1.

Original languageEnglish (US)
Pages (from-to)49-56
Number of pages8
JournalToxicology and Applied Pharmacology
Volume267
Issue number1
DOIs
StatePublished - Feb 5 2013

Fingerprint

MAP Kinase Kinase Kinase 5
Glutathione Transferase
Rats
Ovary
Proteins
Messenger RNA
Phosphatidylinositol 3-Kinase
4-vinyl-1-cyclohexene dioxide
Apoptosis
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one

Keywords

  • 4-Vinylcyclohexene diepoxide
  • Apoptosis
  • Glutathione S-transferase mu
  • Ovotoxicity

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Glutathione S-transferase class mu regulation of apoptosis signal-regulating kinase 1 protein during VCD-induced ovotoxicity in neonatal rat ovaries. / Bhattacharya, Poulomi; Madden, Jill A.; Sen, Nivedita; Hoyer, Patricia B; Keating, Aileen F.

In: Toxicology and Applied Pharmacology, Vol. 267, No. 1, 05.02.2013, p. 49-56.

Research output: Contribution to journalArticle

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abstract = "4-Vinylcyclohexene diepoxide (VCD) destroys ovarian primordial and small primary follicles via apoptosis. In mice, VCD exposure induces ovarian mRNA expression of glutathione S-transferase (GST) family members, including isoform mu (Gstm). Extra-ovarian GSTM negatively regulates pro-apoptotic apoptosis signal-regulating kinase 1 (ASK1) through protein complex formation, which dissociates during stress, thereby initiating ASK1-induced apoptosis. The present study investigated the ovarian response of Gstm mRNA and protein to VCD. Induction of Ask1 mRNA at VCD-induced follicle loss onset was determined. Ovarian GSTM:ASK1 protein complex formation was investigated and VCD exposure effects thereon evaluated. Phosphatidylinositol-3 kinase (PI3K) regulation of GSTM protein was also studied. Postnatal day (PND) 4 rat ovaries were cultured in control media ± 1) VCD (30. μM) for 2-8. days; 2) VCD (30. μM) for 2. days, followed by incubation in control media for 4. days (acute VCD exposure); or 3) LY294002 (20. μM) for 6. days. VCD exposure did not alter Gstm mRNA expression, however, GSTM protein increased (P<0.05) after 6. days of both the acute and chronic treatments. Ask1 mRNA increased (0.33-fold; P<0.05) relative to control after 6. days of VCD exposure. Ovarian GSTM:ASK1 protein complex formation was confirmed and, relative to control, the amount of GSTM bound to ASK1 increased 33{\%} (P<0.05) by chronic but with no effect of acute VCD exposure. PI3K inhibition increased (P<0.05) GSTM protein by 40{\%} and 71{\%} on d4 and d6, respectively. These findings support involvement of GSTM in the ovarian response to VCD exposure, through regulation of pro-apoptotic ASK1.",
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