Mutant frequencies and mutation spectra of dimethylnitrosamine (DMN) at the lacI and cII loci in the livers of Big Blue (R) transgenic mice

The lacI gene in Big Blue(R) transgenic rodents has traditionally been used as a surrogate gene for in vivo mutations. Recently, a more efficient and less expensive assay involving direct selection in the smaller lambda cIIge ne has been developed. Little is known, however, about the comparative sens itivity of the two loci or their influence on the recovered mutation spectr um following mutagen treatment. We have compared the mutation frequency (MF ) and mutational spectrum (MS) of lacI and cII from the same DNA samples is olated from the liver of control and dimethylnitrosamine (DMN)-treated mice . A three-fold (p<0.01) increase in the MF was observed at both loci in the DMN-treated group compared to the corresponding control groups. While the DMN-induced mutation spectrum at lacI was significantly different: from its corresponding spontaneous mutation spectrum (p<0.001), the mutation spectr um at cII (p>0.28) was not. The mutation spectra at the two loci from the D MN-treated mice resembled each other but the 4, 2.5 and 12-fold increase in the mutation frequency of A:T>T:A transversions, single base deletions and deletions of more than four base pairs, respectively, at lacI, altered the spectra significantly (p<0.007). The number of mutations of these classes at cII was also increased, but the fractions were lower than at lacI. The s pontaneous mutation spectra at the cII and lacI loci resembled each other e xcept for the seven-fold increase in G:C<C:G transversions in the cII spect rum resulting in a significant difference (p<0.0001) between the spectra. O ur initial data indicates that although cII is as sensitive to mutation ind uction as lacI, fewer sites are available for certain classes of mutations to be manifest resulting in an apparent lack in change in the mutation spec trum. (C) 2000 Elsevier Science B.V. All rights reserved.