TRANSGENIC MODELS FOR DETECTION OF MUTATIONS IN TUMORS AND NORMAL-TISSUES OF RODENTS

Transgenic rodents that contain easily retrievable target genes allow the rapid quantitation of mutations in any tissue from which DNA can b e isolated. We are using the Stratagene Big Blue(TM) transgenic mouse system that contains a lacl target and an alacZ reporter gene to study the parameters that affect mutations. We have evaluated a number of c hemicals to determine mutant frequency (MF) in specific target tissues of C57Bl/6 and B6C3F1 mice. The correlation between mutagenesis and c arcinogenesis in this system is excellent. For example, the liver carc inogen dimethylnitrosamine produces significant increases in MF in mou se liver, whereas the nonhepatocarcinogenic mutagen methylmethane sulf onate does not. We have also evaluated the induction of mutations by r adiation and demonstrated that this system is suitable for the study o f agents that produce deletion mutations. This system is also useful f or studying changes in MF in developing tumors. We have used an initia tion-promotion protocol to induce hepatocellular carcinomas, and we th en measured MF in normal liver, tumors, and metastases from these mice . Animals initiated with diethylnitrosamine maintain an elevated MF in normal liver, even 1 year after initiation. This MF increases exponen tially in developing liver tumors, possibly owing to a breakdown in th e fidelity of DNA replication and DNA repair in tumors. This system of fers a unique tool for the study of mutations induced in specific targ et tissues of rodents and should become an important assay for evaluat ing the mutagenic risk of drugs and chemicals.