Carcinogenicity and mutagenicity of heterocyclic amines in transgenic mouse models

Double transgenic mice bearing fusion genes consisting of mouse albumin enh ancer/promoter-mouse c-myc cDNA and mouse metallothionein1 promoter-human T GF alpha cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing both the interaction of nuclear oncogenes and growth factors in tumorigene sis. In addition, these mice provide an experimental model to test how envi ronmental chemicals might interact with the c-myc and TGF alpha transgenes during the neoplastic process. Treatment of the double transgenic mice with both genotoxic agents such as diethylnitrosamine and 2-amino-3-methylimida zo-[4,5-f]quinoline (IQ) as well as the tumor promoter phenobarbital greatl y accelerated the neoplastic process. To investigate the role of mutagenesi s in the carcinogenic process, 2-amino-3,8-dimethyl-imidazo [4,5-f]quinoxal ine (MeIQx) induced mutagenesis and hepatocarcinogenicity was examined in C 57BL/lacZ (Muta(TM)Mice) and double transgenic c-myc/lacZ mice that carry t he lacZ mutation reporter gene. The MelQx hepatocarcinogenicity was associa ted with an increase in in vivo mutagenicity as scored by mutations in the lacZ reporter gene. These results suggest that transgenic mouse models may provide important tools for testing both the carcinogenic potential of envi ronmental chemicals and the interaction/cooperation of these compounds with specific genes during the neoplastic process. (C) 1999 Published by Elsevi er Science Ireland Ltd.