Open Access 7,12-Dimethylbenz[A]Anthracene Induces Sertoli–Leydig-Cell Tumors in the Follicle-Depleted Ovaries of Mice Treated with 4-Vinylcyclohexene Diepoxide

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Abstract:

Ovarian cancer is associated with high mortality due to its late onset of symptoms and lack of reliable screening methods for early detection. Furthermore, the incidence of ovarian cancer is higher in postmenopausal women. Mice rendered follicle-depleted through treatment with 4-vinylcyclohexene diepoxide (VCD) are a model of ovary-intact menopause. The present study was designed to induce ovarian neoplasia in this model by treating mice with 7,12-dimethylbenz[a]anthracene (DMBA). Female B6C3F1 mice (age, 28 d) received intraperitoneal sesame oil (vehicle; VCD– groups) as a control or VCD (160 mg/kg; VCD+ groups) daily for 20 d to cause ovarian failure. Four months after the onset of dosing, mice from each group received a single injection of DMBA (VCD–DMBA+ and VCD+DMBA+ groups, n = 15 per group) or vehicle control (VCD–DMBA–, n = 15; VCD+ DMBA–, n = 14) under the bursa of the right ovary. Ovaries were collected 3 or 5 mo after injection and processed for histologic evaluation. Immunohistochemistry was used to confirm classification of neoplasms. None of the animals in the VCD–DMBA– and VCD–DMBA+ groups (that is, mice still undergoing estrus) had tumors at either time point. At the 3-mo time point, 12.5% of the VCD+DMBA+ mice had ovarian tumors; at 5 mo, 57.1% of the VCD+DMBA+ and 14.3% of VCD+DMBA– ovaries had neoplasms. Neoplasms stained positively for inhibin α (granulosa cells) and negatively for keratin 7 (surface epithelium), thus confirming classification of the lesions as Sertoli–Leydig cell tumors. These findings provide evidence for an increased incidence of DMBA-induced ovarian neoplasms in the ovaries of follicle-depleted mice compared with that in age-matched cycling controls.

Document Type: Research Article

Affiliations: 1: Department of Veterinary Biosciences, University of Illinois, Urbana, Illinois 2: Department of Pathology, University Medical Center, University of Arizona, Tucson, Arizona 3: Department of Physiology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona 4: Department of Biomedical Engineering, BIO5 Institute, University of Arizona, Tucson, Arizona 5: Department of Physiology, Arizona Health Sciences Center, University of Arizona, Tucson, Arizona;, Email: hoyer@u.arizona.edu

Publication date: February 1, 2010

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  • Comparative Medicine (CM), an international journal of comparative and experimental medicine, is the leading English-language publication in the field and is ranked by the Science Citation Index in the upper third of all scientific journals. The mission of CM is to disseminate high-quality, peer-reviewed information that expands biomedical knowledge and promotes human and animal health through the study of laboratory animal disease, animal models of disease, and basic biologic mechanisms related to disease in people and animals.

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