title: Reporter gene transgenic mice as a tool for analyzing the molecular mechanisms underlying experimental carcinogenesis.
abstract: Carcinogenic compounds are classified into 2 categories, genotoxic and non-genotoxic, which are basically judged from in vitro genotoxicity data. However, it is well documented that genotoxicants do not necessarily exert in vivo carcinogenicity in rodents, partly because of a discrepancy between in vitro and in vivo mutagenicities. Recently, transgenic animal models with reporter genes such as lacI, lacZ and gpt have been developed as a tool for assessing 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 lacI transgenic mice, dimethylnitrosamine (DMN) treatment significantly increased lacI mutant frequency (MF) in the liver, kidenys and lungs, but not in other non-target organs. Repeated dose ip administration of DMN was more effective than single dose treatment in the induction of lacI MF. The spectrum of mutant plaques induced by DMN was characterized by deletions as well as GC to AT base transitions. The remaining mice 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 (MelQx) significantly increased lacI and gpt MFs in the liver and colon. The characteristic spectrum of mutant plaques induced by MeIQx was a GC to TA base transversion in both the lacI and gpt mutations. Our results thus strongly suggest that these reporter gene transgenic animal models could offer a useful tool for analyzing molecular mechanisms underlying experimental carcinogenesis and for assessing the carcinogenic risk of environmental chemicals.
authors.affiliation: Division of Pathology, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nishikawa
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Masumura
authors.forename: F
authors.initials: F
authors.lastname: Furukawa
authors.forename: M
authors.initials: M
authors.lastname: Miyauchi
authors.forename: H
authors.initials: H
authors.lastname: Nakamura
authors.forename: H Y
authors.initials: HY
authors.lastname: Son
authors.forename: T
authors.initials: T
authors.lastname: Nohmi
authors.forename: M
authors.initials: M
authors.lastname: Hayashi
authors.forename: M
authors.initials: M
authors.lastname: Hirose
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D010582:Bacteriophage lambda; D015197:Carcinogenicity Tests / Q000379:methods*; D002273:Carcinogens / Q000633:toxicity; D002874:Chromosome Mapping; D004128:Dimethylnitrosamine / Q000633:toxicity*; D029968:Escherichia coli Proteins; D017930:Genes, Reporter; D016153:Genes, Suppressor; D056968:Lac Repressors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009152:Mutagenicity Tests / Q000379:methods; D009153:Mutagens / Q000633:toxicity; D010957:Plasmids; D011810:Quinoxalines / Q000633:toxicity*; D012343:RNA, Transfer / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D002273:Carcinogens; D029968:Escherichia coli Proteins; D056968:Lac Repressors; D009153:Mutagens; D011810:Quinoxalines; D012097:Repressor Proteins; C096275:supF tRNA; D012343:RNA, Transfer; D017855:Transferases (Other Substituted Phosphate Groups); C106504:UDP-GlcNAc-undecaprenyl phosphate N-acetylglucosaminyl 1-phosphate transferase; D001616:beta-Galactosidase; D004128:Dimethylnitrosamine; C045421:3,4,8-trimethylimidazo(4,5-f)quinoxalin-2-amine