ENVIRONMENTAL CARCINOGENESIS

这项建议的重点是应用和继续 作为替代脊椎动物的虹鲑鱼模型的研究进展 用于研究遗传毒性，特别是致癌作用的物种 而肿瘤的调节，则受环境因素的影响。其目的是 是开发和开发鲑鱼模型的各个方面，例如 纳克致癌物质敏感性，这使它成为一种有价值的 用于致癌物生物检测和调节的附加系统 毒剂，以及一种重要的非哺乳动物物种 机理研究。拟议的项目将提供详细的 应该允许结果相关的机械性信息 很明显与哺乳动物的致癌有关。 涉及这一共同主题的六个项目概述如下 以下是： 1)基本模型改进(引发剂的亚微克生物测定， 抗癌物质、促进剂；创造完全纯合的克隆 鲑鱼线；肿瘤数据库扩展)； 2)异源代谢酶的特性及其相互作用 鲑鱼的发育规律； 3)非P450共氧化机理的表征 鲑鱼的致癌原激活和致癌作用； 4)温度对异源生物影响的研究 这类药物的药效学、代谢和致癌作用 变温模型； 5)鲑鱼胚胎显微注射模型的开发 探讨黄曲霉毒素相关物质之间的定量关系 相对致癌性，总体DNA结合和持久性， 形成加合物的化学，以及与序列相关的偏好 位点特异性癌基因的引入和转化； 6)染色质结构对基因影响的研究 靶点特定的黄曲霉毒素敏感性，使用均质 体外核小体和体内c-ras基因。

The focus of this proposal is the application and continued development of the rainbow trout model as an alternative vertebrate species for investigating genotoxicity, especially carcinogenesis and tumor modulation, by environmental agents an factors. The aim is to exploit and develop aspect of the trout model, such as nanogram carcinogen sensitivity, which make it a valuable additional system for bioassay of carcinogens and modulating agents, and an important non-mammalian species for comparative mechanism studies. The proposed projects will provide detailed mechanistic information which should allow results to be related clearly to mammalian carcinogenesis. The six projects which address this common theme are summarized as follows: 1) Basic model improvement (submicogram bioassay of initiators, anti-carcinogens, promoters; creation of totally homozygous cloned lines of trout; tumor data base expansion); 2) Characterization of xenobiotic metabolizing enzymes and their developmental regulation in trout; 3) Characterization on non-P450 co-oxidative mechanisms for procarcinogen activation and carcinogenesis in trout; 4) Investigation of temperature effects on xenobiotic pharmacodynamics, metabolism, and carcinogenesis in this poikilothermic model; 5) Exploitation of the trout embryo microinjection model to explore quantitative relationships among related aflatoxins in relative carcinogenicities, overall DNA binding and persistence, chemistry of adducts formed, and sequence-related preferences for site-specific oncogene adduction and transformation; 6) Investigation of the effects of chromatin structure on gene target site-specific aflatoxin susceptibility, using homogeneous nucleosomes in vitro and c-ras genes in vivo.