MECHANISMS OF HEPATIC TUMOR PROMOTION BY PCB'S

PCB促进肝肿瘤的机制

• 批准号: 6217744
• 负责人: HOWARD P GLAUERT
• 金额: $ 19.85万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217744
• 关键词: DNA damage; apoptosis; cell proliferation; chemical carcinogenesis; cytochrome P450; deoxyguanosine; environment related neoplasm /cancer; environmental toxicology; gene expression; halobiphenyl /halotriphenyl compound; liver cells; liver neoplasms; neoplasm /cancer genetics; preneoplastic state; tissue /cell culture; toxin metabolism; transcription factor; tumor promoters

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.

多氯联苯 (PCB) 在环境中无处不在 在实验动物模型中具有致癌性的污染物。 单独的 PCB 同系物以及商业 PCB 混合物 已被证明在两阶段中是有效的肝肿瘤促进剂 大鼠肝癌发生。 其生化机制 然而，多氯联苯会促进肝病灶和肿瘤，但从未被研究过。 决定。 此外，尚不清楚 PCB 同系物是否起作用 在两阶段肝癌发生过程中具有协同作用，这一点非常重要 因为人类会接触 PCB 混合物。 最后还是不知道 如何准确估算PCB的推广潜力 不是 Ah 受体的配体。 因此我们建议测试 假设 1)PCBs 通过以下方式促进两阶段肝癌发生： 诱导氧化DNA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估算 诱导细胞色素 P-450 2B1/2 的能力； 3) 多氯联苯法案 协同促进肝癌的发生。 在第一个 研究表明，多氯联苯将在不同的时间段内施用，并且 它们诱导 8-羟基鸟苷、增加细胞增殖的能力 在正常肝细胞中，并改变前列腺素的浓度 E2 和 F2alpha 以及其他类二十烷酸将被测定。 在 肿瘤促进研究，PCBs将在 二乙基亚硝胺管理，我们将确定他们的能力 1) 诱导肝脏病灶发生改变，正如其 2B1/2 诱导所预测的那样 活性和 2) 在诱导肝功能改变方面发挥协同作用 焦点。 这些研究将展示多氯联苯如何促进肝脏 致癌作用，它们是否协同作用，以及它们是否 促进能力可以很容易地预测。 这些信息将有帮助 理解和量化人类暴露于的风险 超级基金化学品。