Reporter gene transgenic mice as a tool for analyzing the molecular mechanisms underlying experimental carcinogenesis

Carcinogenic compounds are classified into 2 categories, genotoxic and non- genotoxic, which are basically judged from in vitro genotoxicity data. Howe ver, it is well documented that genotoxicants do not necessarily exert in v ivo carcinogenicity in rodents, partly because of a discrepancy between in vitro and in vivo mutagenicities. Recently, transgenic animal models with r eporter genes such as lad, lacZ and gpt have been developed as a tool for a ssessing in vivo mutagenicity as well as carcinogenicity. In this article, data using lacI transgenic mice and gpt delta mice are presented and their application is discussed. In lad transgenic mice, dimethylnitrosamine (DMN) treatment significantly increased lad mutant frequency (MF) in the liver, kidenys and lungs, but not in other non-target organs. Repeated dose ip adm inistration of DMN was more effective than single dose treatment in the ind uction of lacI MF. The spectrum of mutant plaques induced by DMN was charac terized by deletions as well as GC to AT base transitions. The remaining mi ce receiving DMN proved to have liver adenomas at a high frequency after 78 weeks. Meanwhile, dietary 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline ( MeIQx) significantly increased lad and gpt MFs in the liver and colon. The characteristic spectrum of mutant plaques induced by MeIQx was a GC to TA b ase transversion in both the lad and gpt mutations. Our results thus strong ly suggest that these reporter gene transgenic animal models could offer a useful tool for analyzing molecular mechanisms underlying experimental carc inogenesis and for assessing the carcinogenic risk of environmental chemica ls.