ENVIRONMENTAL CARCINOGENESIS

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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.