HEPATIC LACI AND CII MUTATION IN TRANSGENIC (LAMBDA-LIZ) RATS TREATEDWITH DIMETHYLNITROSAMINE

The recent introduction of a transgenic rat in vivo mutation assay is a much needed supplement to the transgenic mouse models and offers the tools necessary for collecting target tissue specific genotoxicity da ta in this species. The utility of the Big Blue(R) rat for the detecti on of in vivo mutations was investigated by studying spontaneous and d imethylnitrosamine (DMN)-induced hepatic mutations. High molecular wei ght DNA isolated from Big Blue(R) rat livers typically yielded good tr ansgene rescue efficiency of up to 5 x 10(5) plaque forming units per packaging reaction. DMN, when administered by oral gavage at dose leve ls of 0.2, 0.6, 2.0, and 6.0 mg kg(-1) day(-1), induced up to a 4.5-fo ld increase in mutations at the highest dose level. There was no appar ent difference between the lacI vs. cII target genes of the shuttle ve ctor in either the background or DMN-induced mutant frequencies. These results suggest that the transgenic rat model is a useful tool for st udying potential genotoxicity in target organs and, with further valid ation, the selectable cII target could be an attractive alternative to the conventional lad color screening method for the detection of muta tions in the lambda LIZ shuttle vector. (C) 1998 Elsevier Science B.V. All rights reserved.