PARENT SESSION
PLATFORM SESSION 14: REPRODUCTIVE TOXICOLOGY AND ENDOCRINE DISRUPTION
Chair: Hoyer, Patricia¹, ¹
Co-chair: Benedict, Jamie¹, ¹
Dover A-C
2:00 PM-4:00 PM

(249) INTERACTION BETWEEN ESTROGEN RECEPTOR AND ACTIVATOR PROTEIN-1 IN 4-VINYLCYCLOHEXENE DIEPOXIDE-INDUCED OVOTOXICITY IN RATS.

Hu, Xiaoming¹, Sipes, I^2,3, Hoyer, Patricia^1,3, ¹ Department of Physiology, The University of Arizona, Tucson, AZ² Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ³ Southwest Enviromental Health Sciences Center, The University of Arizona, Tucson, AZ

ABSTRACT- Repeated daily dosing of rats with 4-vinylcyclohexene diepoxide selectively destroys ovarian small pre-antral (primordial and primary) follicles. Previous studies indicate that the mechanism is via apoptosis and involves signaling pathways which include activation of MAPK and decreased activator protein-1 (AP-1) binding activity in small ovarian follicles. Additionally, 17-estradiol dosing has been shown to protect against VCD-induced ovotoxicity. Thus, the present study was designed to determine whether the estrogen receptor interacts with the nuclear complex involved in AP-1 binding in VCD-induced ovotoxicity. Female F344 rats were dosed daily for 15 days (80 mg/kg, i.p., 15d). Four hours following the final dose, ovaries and livers were collected. Ovarian small (25-100 m) and large (100-250 m) pre-antral follicles were isolated, and nuclear extracts were prepared from follicles and livers for analysis of electrophoretic mobility shift assay (EMSA). Compared with control, repeated daily dosing with VCD significantly decreased nuclear protein AP-1 DNA binding activity (0.54±0.04, VCD/Control, p<0.01) and increased estrogen response element (ERE) binding activity (3.25±0.42, VCD/Control, p<0.01). VCD did not affect any these measurements in large pre-antral follicles or liver. Pre-incubation of nuclear extracts from control follicles with anti-ER antibody increased nuclear protein AP-1 DNA binding activity (1.36±0.12, pre-incubation/non-incubation, p<0.05), whereas pre-incubation with anti-ER antibody decreased this binding activity (0.74±0.04, pre-incubation/non-incubation, p<0.05). Thus, the presence of ER in the nuclear complex decreases, whereas, ER enhances AP-1 activation. Taken together, these data provide evidence that VCD-induced ovotoxicity is associated with an alteration in ERE and AP-1 activation, and ER plays a significant role in transmitting VCD-activated apoptotic signals. (ES09246; ES06694).

KEY WORDS: Ovary follicle, Activator Protein - 1, Estrogen Receptor, VCD