Davis B J, Mccurdy E A, Miller B D, Lucier G W, Tritscher A M
Laboratory of Women's, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Cancer Res. 2000 Oct 1;60(19):5414-9.
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.
2,3,7,8-四氯二苯并对二恶英（TCDD）是一种多物种生殖毒物，最近被国际癌症研究机构（IARC）列为已知的人类致癌物。在此，我们报告TCDD在雌性斯普拉格-道利大鼠的启动-促进模型中促进卵巢肿瘤的发生。70日龄的大鼠用二乙基亚硝胺（DEN）或赋形剂启动。在启动后2周或18周开始，大鼠每两周接受一次TCDD暴露，日平均剂量为125 ng/kg/天，持续14、30或60周，或持续30周加16或30周的撤药期。76只接受DEN启动并用TCDD促进不同时间的大鼠中有15只（20%）发生了支持细胞类型的卵巢性索间质肿瘤，而86只用作赋形剂对照或仅接受DEN或仅接受TCDD的大鼠未发生卵巢肿瘤。在DEN启动后连续60周接受TCDD处理的14只大鼠中有6只（43%）肿瘤发生率最高。6只大鼠中有1只在暴露30周时发生了肿瘤。由于TCDD的大多数作用可归因于其对芳烃受体（AhR）的激活，通过逆转录聚合酶链反应（RT-PCR）、免疫组织化学和原位杂交在大鼠卵巢和卵巢肿瘤中确定了AhR的存在和定位。在成年对照斯普拉格-道利大鼠的卵巢中，AhR定位于卵母细胞、生长卵泡的颗粒细胞和膜细胞、表面上皮细胞以及单个小管内衬的上皮细胞。卵巢肿瘤中的肿瘤细胞AhR信息和蛋白也呈阳性。这些结果表明，TCDD导致卵巢肿瘤的能力取决于启动、促进时间长度以及暴露和评估时动物的年龄。在该实验系统中TCDD诱导的肿瘤类型与意大利塞韦索一次工业事故中暴露的年轻人早期研究报告的组织学亚型相同。
