Different mutation frequencies and spectra among organs by N-methyl-N-nitrosourea in rpsL (strA) transgenic mice

The frequencies and spectra of N-methyl-N-nitrasourea (MNU)-induced in vivo somatic mutations were determined in rpsL (strA) transgenic mice. The wild -type rpsL gene, which exhibits a streptomycin-sensitive (Sm-S) phenotype, was used as the rescue marker gene, Studies of mutation spectra among diffe rent organs and tissues were simplified using this system because of the sh ort coding sequence (375 bp) of the rpsL gene. MNU administration to transg enic mice significantly elevated the mutation frequencies in various adult organs. Two distinctive patterns of mutation spectrum were observed, depend ing on the organs tested. Mutations derived from labile organs (spleen and thymus) mere predominantly G:C to A:T transitions, as expected for MNU muta genesis. Stable organs like the liver and brain, however, carried many fewe r G:C to A:T transitions but significantly more single base deletions, of w hich the spectrum was very similar to that of background mutations in the r psL transgenic mice. This spectrum difference among more and less prolifera ting organs was confirmed by the predominant occurrence of G:C to A:T trans itions in fetal liver cells exposed to transplacental MNU treatment. In add ition, most (approximately 90%) of the G:C to A:T transitions induced by MN U were detected in the first nucleotide of some 5'-G-(C or G)-3' sequences, many. of which corresponded to the middle guanine residue of 5'-purine-G-( C or G)-3' sequences. It is thus suggested that at particular sites, the ne ighboring bases in both the 5' side and 3' side seem to influence either th e susceptibility to DNA damage or the ability to repair MNU-induced lesions .