MECHANISMS OF HEPATIC TUMOR PROMOTION BY PCB'S

多氯联苯（PCBs）是环境中普遍存在的污染物 在实验动物模型中致癌的污染物。 个别多氯联苯同系物以及商用多氯联苯混合物 在两个阶段中被证明是有效的肝肿瘤促进剂 大鼠肝癌发生。 生物化学机制， 多氯联苯促进肝脏病灶和肿瘤，然而，从来没有 测定 此外，尚不清楚多氯联苯同系物是否会 在两阶段肝癌发生中协同作用，这是重要的 因为人类会接触到多氯联苯混合物。 最后不得而知 如何准确估计多氯联苯的促进潜力， 不是Ah受体的配体。 因此，我们建议测试 假设：1）PCBs促进两阶段肝癌发生， 诱导DNA氧化损伤，增加长期细胞 增殖和/或改变类二十烷酸代谢; 2） 非Ah结合PCB的促进指数可以通过其 诱导细胞色素P-450 2B 1/2的能力; 3）多氯联苯作用 协同促进肝癌发生。 上 研究，多氯联苯将管理不同的时间段，和 它们诱导8-羟基鸟苷、增加细胞增殖 在正常的肝细胞中，并改变胰高血糖素的浓度 将测定E2和F2 α和其他类花生酸。 在 肿瘤促进研究，PCB将在 二乙基亚硝胺管理，我们将确定他们的能力， 1）诱导肝病灶改变，如2B 1/2诱导所预测 活性和2）在诱导改变的肝细胞中协同作用， 焦点 这些研究将显示多氯联苯如何促进肝脏 致癌作用，它们是否协同作用，如果它们 可以容易地预测提升能力。 这些信息将帮助 在了解和量化人类暴露于 超级基金化学品

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants which are carcinogenic in experiment animal models. Individual PCB congeners as well as commercial PCB mixtures have been shown to be efficacious hepatic tumor promoters in two-stage hepatocarcinogenesis in rats. The biochemical mechanisms by which PCBs promote hepatic foci and tumors, however, have never been determined. Additionally, it is not known if PCB congeners act synergistically in two-stage hepatocarcinogenesis, which is important since humans are exposed to PCB mixtures. Finally, it is not known how to accurately estimate the promoting potential of PCBs which are not ligands of the Ah receptor. We therefore propose to test the hypotheses that 1)PCBs promote two-stage hepatocarcinogenesis by inducing oxidative DNA damage, increasing long-term cell proliferation, and/or altering eicosanoid metabolism; 2) the promotion index of non-Ah binding PCBs can be estimated by their ability to induce cytochrome P-450 2B1/2; and 3) PCBs act synergistically in the promotion of hepatocarcinogenesis. In the first studies, PCBs will be administered for varying periods of time, and their ability to induce 8-hydroxyguanosine, increase cell proliferation in normal hepatocytes, and alter the concentrations of prostaglandins E2 and F2alpha and other eicosanoids will be determined. In the tumor promotion studies, PCBs will be administered after diethylnitrosamine administration, and we will determine their ability to 1) induce altered hepatic foci as predicted by their 2B1/2 inducing activity and 2) act synergistically in the induction of altered hepatic foci. These studies will show how PCBs promote hepatic carcinogenesis, whether they act synergistically, and if their promoting ability can be easily predicted. This information will help in understanding and quantifying the risks for humans exposed to Superfund chemicals.