ENVIRONMENTAL CARCINOGENESIS

这一建议的重点是应用和继续 虹鳟鱼作为替代脊椎动物模型的开发 研究遗传毒性，尤其是致癌作用的物种 和肿瘤的调节。 目的 是开发和发展鳟鱼模型的各个方面，例如 纳克致癌物的敏感性，这使得它成为一个有价值的 致癌物生物测定和调节的附加系统 代理人，和一个重要的非哺乳动物物种的比较 机理研究 建议的项目将提供详细的 应允许结果相关的机械信息 对哺乳动物致癌作用的影响。 针对这一共同主题的六个项目概述如下： 如下所示： 1)基本模型改进（引发剂的亚微克生物测定， 抗癌物质，启动子;创建完全纯合的克隆 鳟鱼品系;肿瘤数据库扩展）; 2)异源生物质代谢酶的特性及其应用 鳟鱼的发育调控; 3)非P450共氧化机制的表征 原致癌物激活和鳟鱼致癌; 4)温度对外源性物质影响的研究 药效学、代谢和致癌作用 变温模型; 5)鳟鱼胚胎显微注射模型的建立 探讨相关黄曲霉毒素之间的定量关系， 相对致癌性，总体DNA结合和持久性， 形成的加合物的化学，以及 位点特异性癌基因内收和转化; 6)染色质结构对基因表达影响的研究 靶位点特异性黄曲霉毒素敏感性，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.