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Activation of Mitogen-Activated Protein Kinases and AP-1 Transcription Factor in Ovotoxicity Induced by 4-Vinylcyclohexene Diepoxide in Rats¹

^a Departments of Physiology ^b Pharmacology and Toxicology, ^c Southwest Environmental Health Sciences Center, The University of Arizona, Tucson, Arizona 85724 ^d Department of Epidemiology/Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201

Previous studies have demonstrated that ovotoxicity induced in small preantral (primordial and primary) ovarian follicles by 4-vinylcyclohexene diepoxide (VCD) in rats is likely via acceleration of the normal process of atresia (apoptosis). This acceleration is associated with increased activities of caspase cascades, changes in subcellular distribution of Bcl-2 family members, and alteration of estrogen receptor-mediated signaling pathways. The present study was designed to investigate possible effects of VCD dosing on the mitogen-activated protein kinases (MAPK)/AP-1 signaling pathways in rat ovarian small follicles. Female F344 rats were given a single dose of VCD (80 mg/kg i.p., 1 day—a time when ovotoxicity has not been initiated) or dosed daily for 10 or 15 days (80 mg/kg i.p.; 10 days—a time when the earliest signs of impending follicular destruction is seen, 15 days—a time when significant ovotoxicity is underway). Four hours following the final dose, ovaries and livers were collected. Ovarian small (25–100 µm) and large (100–250 µm) preantral follicles were isolated, and cytosolic or nuclear extracts were prepared from follicles and livers for analyses. Activities of MAPKs, including extracellular signal-regulated kinase, c-Jun N-terminal protein kinase (JNK), and p38 kinase, were determined in follicular and liver cytosolic extracts, and AP-1 DNA binding activity was determined in follicular and liver nuclear extracts. Compared with control, a single dose of VCD caused a decrease in JNK activity and an increase of AP-1 binding activity in isolated small ovarian follicles. After repeated daily dosing with VCD for 10 or 15 days, JNK and p38 kinase activities in small ovarian follicles were increased (p38 kinase: 1.64 ± 0.14 for 10 days, 1.48 ± 0.11 for 15 days, VCD/control, P < 0.01; JNK: 1.44 ± 0.11 for 10 days, 1.37 ± 0.06 for 15 days, VCD/control, P < 0.01) and AP-1 binding activity in small ovarian follicles was decreased (10 days, 0.29 ± 0.04; 15 days, 0.51 ± 0.04, VCD/control, P < 0.01). VCD did not affect any of these measurements in large preantral follicles or liver. Phosphorylation status of c-Jun protein as measured by Western blotting was increased (1.22 ± 0.1, VCD/control, P < 0.05) after the 15-day daily dosing with VCD, but total c-Jun protein levels were unaffected. Using antibodies against c-Jun or phospho-c-Jun for supershift DNA binding assay, c-Jun and phospho-c-Jun were identified in the AP-1-DNA binding complex, and the binding activity was reduced in tissues with increased phospho-c-Jun protein levels. Taken together, these data provide evidence that accelerated atretic signals induced by VCD is associated with MAPK/AP-1 signaling pathways and phosphorylation of c-Jun plays a significant role in transmitting the apoptotic signals.

First decision: 5 March 2002.

¹ Supported by NIH Grant RO1-ESO9246 and Center Grant ESO6694.

² Correspondence: Patricia B. Hoyer, 1501 North Campbell Ave., Dept. of Physiology, The University of Arizona, P.O. Box 245051, Tucson, AZ 85724. FAX: 520 626 2382; hoyer{at}u.arizona.edu

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