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 language | English (US) |
|---|---|
| Pages (from-to) | 49-56 |
| Number of pages | 8 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 267 |
| Issue number | 1 |
| DOIs | |
| State | Published - Feb 5 2013 |
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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 journal › Article
}
TY - JOUR
T1 - Glutathione S-transferase class mu regulation of apoptosis signal-regulating kinase 1 protein during VCD-induced ovotoxicity in neonatal rat ovaries
AU - Bhattacharya, Poulomi
AU - Madden, Jill A.
AU - Sen, Nivedita
AU - Hoyer, Patricia B
AU - Keating, Aileen F.
PY - 2013/2/5
Y1 - 2013/2/5
N2 - 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.
AB - 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.
KW - 4-Vinylcyclohexene diepoxide
KW - Apoptosis
KW - Glutathione S-transferase mu
KW - Ovotoxicity
UR - http://www.scopus.com/inward/record.url?scp=84872362413&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872362413&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2012.12.013
DO - 10.1016/j.taap.2012.12.013
M3 - Article
C2 - 23274565
AN - SCOPUS:84872362413
VL - 267
SP - 49
EP - 56
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 1
ER -