ACTIVATION OF PCB'S TO GENOTOXINS IN VIVO

PCB 对体内基因毒素的激活

• 批准号: 6106436
• 负责人: LARRY W ROBERTSON
• 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/6106436
• 关键词: DNA; DNA damage; adduct; chemical carcinogenesis; environmental toxicology; gene environment interaction; halobiphenyl /halotriphenyl compound; halogenation; laboratory rat; oxidative stress; toxin metabolism; tumor promoters

Polychlorinated biphenyls (PCBs) are industrial chemicals which persist in our environment. They are found in Superfund sites including the sites in Kentucky and are the direct cause of 5 fish consumption advisories currently in place in Kentucky. The lipophilicy of PCBs and their tendency to bioaccumulate raise concern about the health risks associated with exposure to PCBs and related compounds. Commercial PCB mixtures are complete carcinogens, producing hepatocellular carcinomas in rats and mice, but the mechanisms by which they do so have not been determined. We and others have shown that higher halogenated PCBs (especially, tetra-, penta-, and hexa-chlorinated biphenyls) act as promoters of liver carcinogenesis, but their initiating or DNA damaging activity has not been conclusively demonstrated. Here we present considerable data to support the concept that the lower halogenated biphenyls (especially mono- and di-chlorobiphenyls) may be activated by hepatic enzymes. These PCBs are metabolized to oxygenated species which are electrophilic and which bind to DNA. Of particular interest are quinone metabolites which are oxidation products of dihyroxylated biphenyls. Our preliminary data were generated in in vitro systems. We propose to extend our studies to investigate these activation pathways in the rat. We propose 1) To determine if selected lower halogenated PCBs are metabolized (activated) in vivo to electrophilic species which interact with cellular DNA, forming adducts detectable by sensitive 32P-postlabeling methods, 2) To determine if PCBs activated in vitro and in vivo to electrophiles can act as initiators in an in vivo rat liver initiation model, a modified Solf-Farber protocol, and 3) To determine if those PCBs activated to electrophiles in vitro and in vivo and found positive in the Solt Farber protocol will initiate tow stage hepatocarcinogenesis. Specific lower halogenated PCB initiators and higher halogenated PCB promotors will be used. Jointly these activities may explain why PCB mixtures are complete rodent carcinogens. In these studies rats will be administered highly- purified synthetic PCB congeners. The number and volume of altered hepatic foci, putative preneoplastic lesions, and tumors will be determined. Our project therefore addresses the fundamental question of the mechanisms of toxicity, specifically, genotoxicity of individual PCBs. Clarification of these fundamental questions concerning PCBs as carcinogens, their metabolism in vivo, the nature of their interactions with cellular DNA, their ability to initiate hepatocarcinogenesis and cause liver tumors, will form a basis for the quantitative human health risk assessment for these Superfund Chemicals.

多氯联苯 (PCB) 是工业化学品， 坚持在我们的环境中。 它们可以在超级基金网站上找到 包括肯塔基州的地点，是 5 条鱼的直接原因 肯塔基州目前正在实施消费建议。 这 PCB 的亲脂性及其生物累积趋势 对与接触多氯联苯相关的健康风险的担忧 相关化合物。 商用 PCB 混合物已完成 致癌物质，在大鼠和小鼠中产生肝细胞癌， 但它们这样做的机制尚未确定。 我们和其他人已经证明，卤化多氯联苯含量较高（特别是， 四氯化联苯、五氯化联苯和六氯化联苯）作为促进剂 肝癌发生，但其起始或 DNA 损伤活性 尚未得到最终证明。 在这里我们介绍 大量数据支持低卤化的概念 联苯（尤其是一氯联苯和二氯联苯）可能会被活化 通过肝酶。 这些多氯联苯被代谢成含氧的 亲电性且与 DNA 结合的物种。 的 特别感兴趣的是氧化醌代谢物 二羟基联苯的产物。 我们的初步数据是 在体外系统中产生。 我们建议将我们的研究扩展到 研究大鼠中的这些激活途径。 我们建议 1) 确定选定的低卤化 PCB 是否被代谢 （激活）在体内与细胞相互作用的亲电子物质 DNA，形成可通过敏感 32P 后标记检测到的加合物 方法，2) 确定 PCB 是否在体外和体内激活 亲电子试剂可以作为体内大鼠肝脏启动的引发剂 模型、修改的 Sol-Farber 协议，以及 3) 确定这些是否 发现多氯联苯在体外和体内被亲电子试剂激活 Solt Farber 协议中的积极结果将启动两个阶段 肝癌发生。 特定的低卤 PCB 引发剂和 将使用更高卤化的 PCB 促进剂。 共同这些 活动可能解释了为什么多氯联苯混合物是完全啮齿动物 致癌物质。 在这些研究中，将对大鼠进行高度 纯化的合成 PCB 同系物。 数量和体积 改变的肝病灶、推定的癌前病变和肿瘤将 被确定。 因此，我们的项目解决了基本问题 毒性机制问题，特别是遗传毒性 单独的 PCB。 澄清这些基本问题 关于 PCB 作为致癌物、它们在体内的代谢、性质 它们与细胞 DNA 的相互作用，它们启动的能力 肝癌发生并引起肝脏肿瘤，将形成基础 这些超级基金的定量人类健康风险评估 化学品。