SPECIFIC MUTATIONAL SPECTRUM OF DIMETHYLNITROSAMINE IN THE LACI TRANSGENE OF BIG BLUE(R) C57BL 6 MICE/

Dimethylnitrosamine (DMN) produces tumors in mice predominantly in the liver, but also in the kidney and lung. It forms O-6-methylguanine ad ducts in DNA, which induce G:C --> A:T transitions. We have analyzed t he spectra of spontaneous and DMN-induced mutations in the lacI transg ene of the Big Blue(R) mouse (C57BL/6), In both cases, mutations in th e liver, kidney and lung were predominantly base substitutions, among which G:C --> A:T transitions were the most frequent. In contrast, a h igh incidence of short deletions (2-23 bp) was only found in the liver of treated mice. The deletions often occurred at direct repeat sequen ces. Single-base deletion incidence was also higher in the liver than in the kidney and lung. These results imply that accumulation of DNA l esions or their repair in liver is different from other organs. Sponta neous and induced base substitutions and deletions appeared to be rand omly distributed in the lad gene and an apparent hotspot was not obser ved, except for a 4 bp deletion of a (TGGC)(3) sequence at positions 6 21-632, The present data demonstrate, for the first time, that DMN ind uces short deletions especially in the liver, although the mechanism i nvolved needs further investigation.