INDUCTION OF CARCINOGEN BINDING PROTEINS IN FISH

描述(改编自申请人的摘要)：持久化 有机氯(OCS)和多环芳烃(PAHs)是 广泛存在的化学致癌物，经常在受污染的环境中共存 水生环境。肿瘤发病率增加和肿瘤积聚 栖息在这些地点的野生鱼类中的致癌物质残留向公众展示 很难评估的健康风险。这项提案的重点是 增加对肝脏摄取和细胞内转运的了解 和虹鲑鱼肝脏中的一种遗传毒性多环芳烃。比较研究 此外，还提出了使用RAT的建议。申请人假设业主立案法团 暴露诱导结合并可能运输致癌物的蛋白质 在肝细胞内。刺激细胞内结合和加工 通过这种诱导产生的致癌物至少在三个方面与健康风险有关 方式。(1)这些蛋白质可能在OCS的生物积累中发挥关键作用 和多环芳烃，可能会导致这些物质的营养转移 材料传给人类。对这些药物吸收的传统解释 通过专注于脂肪分配的鱼类。更好地理解 亲脂性致癌物在鱼类中的处置机制基础是 这对于开发适当的生物积累模型很重要。(2) 环境中的OCS和PAHs在野生鱼类肿瘤发病率中的作用可能是 随着相互作用机制的定义，更好地进行评估。申请人 建议对虹鲑鱼进行肿瘤研究，以检查其致癌性 OCS及其对多环芳烃致癌的影响 多环芳烃诱导的癌症运动/进展中的活性。这些措施的结果 肿瘤研究将根据我们所了解的情况进行解释 OC诱导的致癌物结合蛋白。(3)虹鲑鱼模型为 对化学致癌的基础研究具有重要价值。法律的有效性 鱼类致癌物质结合蛋白的信息外推 人类健康将通过在大鼠身上进行比较研究来直接评估。 虹鲑鱼研究致癌物质的一个重要属性 结合/运输蛋白是诱导这些蛋白的潜在因素 而不诱导细胞色素P450系统。这提供了一个机会 目的：研究致癌物的致瘤性和生化毒理学。 结合和/或运输，而不是生物转化的系统 优先调制的。

DESCRIPTION (Adapted from applicant's abstract): Persistent organochlorines (OCs) and polycyclic aromatic hydrocarbons (PAHs) are widespread chemical carcinogens which frequently co-occur in contaminated aquatic environments. Increased incidence of tumors and accumulation of carcinogen residues in feral fish inhabiting such sites presents a public health risk which is difficult to assess. This proposal focuses on increasing the understanding of hepatic uptake and intracellular transport of OCs and a genotoxic PAH in rainbow trout liver. Comparative studies using the rat are also proposed. The applicant hypothesizes that OC exposure induces proteins which bind and perhaps transport carcinogens within the hepatocyte. Stimulation of intracellular binding and processing of carcinogens by such induction relates to health risks in at least three ways. (1) These proteins likely play a key role in bioaccumulation of OCs and PAHs by fish which can presumably result in trophic transfer of these materials to humans. Traditional explanations for uptake of these agents by fish focused upon lipid partitioning. Improved understanding of the mechanistic basis for disposition of lipophilic carcinogens in fish is important for the development of adequate bioaccumulation models. (2) The role of environmental OCs and PAHs in tumor incidence in feral fish can be better assessed as mechanisms of interaction are defined. The applicant proposes rainbow trout tumor studies which will examine carcinogenity of OCs, their influence on initiation of PAH-induced cancer, and their activity in romotion/progression of PAH-induced cancer. Results of these tumor studies will be interpreted in light of what we learn about OC-induced carcinogen binding proteins. (3) The rainbow trout model is valuable for basic research on chemical carcinogenesis. The validity of the extrapolation of information on fish carcinogen binding proteins to human health will be directly assessed by comparative studies in the rat. An important attribute of the rainbow trout for studying carcinogen binding/transport proteins is the potential to induce these proteins without inducing the cytochrome P450 system. This provides an opportunity to study the tumorigenicity and biochemical toxicology of carcinogens in a system where binding and/or transport, rather than biotransformation, is preferentially modulated.