Evaluation of chlordecone in a two-stage model of hepatocarcinogenesis: a significant sex difference in the hepatocellular carcinoma incidence.
Evaluation of chlordecone in a two-stage model of hepatocarcinogenesis: a significant sex difference in the hepatocellular carcinoma incidence.
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十氯酮在肝癌两阶段模型中的评估：肝细胞癌发病率存在显着的性别差异。
DOI：
10.1093/carcin/10.6.1047
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发表时间：
1989
期刊：
影响因子：
4.7
通讯作者：
Guzelian,PS
中科院分区：
文献类型：
--
作者：
Sirica,AE;Wilkerson,CS;Wu,LL;Fitzgerald,R;Blanke,RV;Guzelian,PS
十氯酮（Kepone）对接触大量这种有机氯农药的男性生产工人的毒性进行了广泛研究。考虑到这些工人患肝癌的风险可能会增加，我们在肝癌发生的两阶段大鼠模型中测试了十氯酮。在雄性和雌性Sprague-Dawley大鼠中，十氯酮主要是作为肝脏肿瘤的促进剂而不是完全的肝癌致癌物。剂量反应实验表明，长期给予十氯酮的肝致癌性作用在未启动的大鼠肝脏中的浓度与从没有肝影响的暴露工人的人体活组织检查中测量的浓度相同的范围内无法检测到。虽然从未研究过十氯酮对女性的毒性，但我们发现十氯酮促进大鼠肝脏恶性肿瘤的发生率存在显著的性别差异。研究发现，63%的雌性大鼠的肝脏在部分肝切除术后24小时被给予亚致癌性剂量的二乙基亚硝胺“启动”，然后被给予27周的十氯酮“促进”。相比之下，即使在十氯酮“促进”44周后，接受同样治疗的男性也没有出现恶性肝脏肿瘤。在二乙基亚硝胺启动组/十氯酮促进组中，女性也含有γ-谷氨酰转肽酶阳性的“肿瘤前”肝细胞灶，其数量和面积比在同等处理的男性中观察到的要多。此外，由于在实验结束时，在两性的肝脏中测量到相似水平的十氯酮，二乙基亚硝胺引发的雌性大鼠的肝细胞癌的发展似乎是由于它们对促进治疗的敏感性增加。
Chlordecone (Kepone) has been extensively studied for its toxicity in male production workers who were exposed to large quantities of this organochlorine pesticide. Concern that these workers might be at an increased risk of developing liver cancer prompted us to test chlordecone in a two-stage rat model of hepatocarcinogenesis. Chlordecone acted largely as a liver tumor promoter rather than as a complete hepatic carcinogen in both male and female Sprague—Dawley rats. Dose—response experiments showed that the hepatocarcinogenic effects of long-term chlordecone administration became undetectable at concentrations in non-initiated rat liver in the same range as those measured in human biopsies taken from exposed workers who exhibited no liver effects. Although the toxicity of chlordecone in women has never been studied, we found a dramatic sex difference in the incidence of malignant liver tumors caused by chlordecone promotion in rats. Frank hepatocellular carcinomas were observed in up to 63% of female rats whose livers were previously ‘initiated’ with a subcarcinogenic dose of diethylnitrosamine given 24 h after partial hepatectomy, and then ‘promoted’ by 27 weeks of chlordecone administration. In contrast, none of comparably treated males had malignant liver tumors, even after 44 weeks of ‘promotion’ with chlordecone. Females in the diethylnitrosamine-initiated/chlordecone-promotion groups also contained γ-glutamyltranspeptidase-positive ‘preneoplastic’ hepatocellular foci that were more abundant and larger than those observed in comparably-treated males. Moreover, because similar levels of chlordecone were measured in the livers of both sexes at the end of the experimental period, the development of hepatocellular carcinomas in the diethylnitrosamine-initiated female rats appeared to be due to their increased sensitivity to the promotion treatment.