Specific mutational spectrum of dimethylnitrosamine in the lad transgene of big blue® C57BL/6 mice

Abstract

Dimethylnitrosamine (DMN) produces tumors in mice predominantly in the liver, but also in the kidney and lung. It forms O6-methylguanine adducts in DNA, which induce G:C→A:T transitions, We have analyzed the spectra of spontaneous and DMN-induced mutations in the lacI transgene of the Big Blue® mouse (C57BL/6). In both cases, mutations in the liver, kidney and lung were predominantly base substitutions, among which G:C→A:T transitions were the most frequent. In contrast, a high incidence of short deletions (2-23 bp) was only found in the liver of treated mice. The deletions often occurred at direct repeat sequences. Single-base deletion incidence was also higher in the liver than in the kidney and lung. These results imply that accumulation of DNA lesions or their repair in liver is different from other organs. Spontaneous and induced base substitutions and deletions appeared to be randomly distributed in the lacI gene and an apparent hotspot was not observed, except for a 4 bp deletion of a (TGGC)3 sequence at positions 621-632. The present data demonstrate, for the first time, that DMN induces short deletions especially in the liver, although the mechanism involved needs further investigation.