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Ovarian Tumors in Rats Induced by Chronic 2,3,7,8-Tetrachlorodibenzo-p- Dioxin Treatment

Laboratory of Women’s Health [B. J. D., E. A. M.] and Laboratory of Computational Biology and Risk Analysis [B. D. M., G. W. L.], National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, and Nestlé Research Center, CH-1000 Lausanne 26, Switzerland [A. M. T.]

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a multispecies reproductive toxicant, and it has been recently classified by IARC as a known human carcinogen. Here, we report that TCDD promotes the development of ovarian tumors in an initiation-promotion model in female Sprague Dawley rats. Rats were initiated with diethylnitrosamine (DEN) or vehicle at 70 days of age. Starting 2 or 18 weeks after initiation, rats were exposed biweekly to TCDD at a daily average dose of 125 ng/kg/day for 14, 30, or 60 weeks continuously or for 30 weeks plus withdrawal periods of 16 or 30 weeks. Fifteen of 76 (20%) rats initiated with DEN and promoted with TCDD for various lengths of time developed ovarian sex cord-stromal tumors of Sertoli cell type, whereas no ovarian tumors developed in 86 rats used as vehicle controls or that received DEN alone or TCDD alone. The highest tumor incidence occurred in 6 of 14 rats (43%) after 60 weeks of continuous TCDD after DEN initiation. One of six rats developed a tumor by 30 weeks of exposure. Because most effects of TCDD can be attributed to its activation of the aryl hydrocarbon receptor (AhR), the presence and localization of AhR was determined in the rat ovary and in the ovarian tumors by reverse transcription-PCR, immunohistochemistry, and in situ hybridization. AhR was localized to oocytes, granulosa and thecal cells of growing follicles, surface epithelial cells, and epithelial cells lining single tubules in ovaries from adult control Sprague Dawley rats. Neoplastic cells in the ovarian tumors were also positive for both AhR message and protein. These results indicate that the ability of TCDD to cause ovarian tumors is dependent on initiation, length of promotion, and age of the animal when exposed and evaluated. The tumor type induced by TCDD in this experimental system is the same histological subtype as that reported from an early study of youngsters exposed during an industrial accident in Seveso, Italy.

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