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.
N1 - Funding Information:
The project described was supported by award number R00ES016818 to AFK and R01ES09246 to PBH from the National Institutes of Environmental Health Sciences . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences or the National Institutes of Health.
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 -