Hepatic lacI and cII mutation in transgenic (lambdaLIZ) rats treated with 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 data in this species. The utility of the Big Blue(R) rat for the detection of in vivo mutations was investigated by studying spontaneous and dimethylnitrosamine (DMN)-induced hepatic mutations. High molecular weight DNA isolated from Big Blue(R) rat livers typically yielded good transgene rescue efficiency of up to 5x105 plaque forming units per packaging reaction. DMN, when administered by oral gavage at dose levels of 0.2, 0.6, 2.0, and 6.0 mg kg-1 day-1, induced up to a 4.5-fold increase in mutations at the highest dose level. There was no apparent difference between the lacI vs. cII target genes of the shuttle vector in either the background or DMN-induced mutant frequencies. These results suggest that the transgenic rat model is a useful tool for studying potential genotoxicity in target organs and, with further validation, the selectable cII target could be an attractive alternative to the conventional lacI color screening method for the detection of mutations in the lambdaLIZ shuttle vector.
Gollapudi
B B
BB
The Dow Chemical, Health and Environmental Research Laboratory, 1803 Building, Midland, MI 48674, USA. bgollapudi@dow.com
Jackson
K M
KM
Stott
W T
WT
D000818:Animals; D030801:Animals, Genetically Modified; D010582:Bacteriophage lambda / Q000235:genetics; D004128:Dimethylnitrosamine / Q000633:toxicity*; D007786:Lactose Factors / Q000235:genetics*; D008099:Liver / Q000648:ultrastructure; D009152:Mutagenicity Tests; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344; D014157:Transcription Factors / Q000235:genetics*; D014764:Viral Proteins
D014157:Transcription Factors; D014764:Viral Proteins; C039000:cII protein, bacteriophage lambda; D004128:Dimethylnitrosamine