DNA-ADDUCTS, MUTANT FREQUENCIES AND MUTATION SPECTRA IN LAMBDA-LACZ TRANSGENIC MICE TREATED WITH N-NITROSODIMETHYLAMINE

Groups of lambda lacZ transgenic mice were treated i.p. with N-nitroso dimethylamine (NDMA) as single doses of 5 mg/kg or 10 mg/kg or as 10 d aily doses of 1 mg/kg and changes in DNA N7- or O-6-methylguanine or t he repair enzyme O-6-alkylguanine-DNA alkyltransferase (AGT) were foll owed for up to 14 days in various tissues. Adduct induction in the liv er exceeded by at least one order of magnitude than observed in the ne xt nearest target tissue (lung), and was approximately linearly relate d to dose, except for O-6-methylguanine after the first dose of 1 mg/k g which was lower than expected. Substantial induction of lambda lacZ mutagenesis was observed only in the liver, where the mutant frequency was already maximal within 7 days after 5 mg/kg NDMA and remained unc hanged thereafter up to 49 days. Small but marginally significant incr eases in mutant frequency were consistently observed in the spleen aft er all three modes of treatment. A lack of proportionality between mut ation induction and the administered dose or the corresponding adduct levels was observed, probably reflecting the importance of toxicity-re lated cell proliferation caused by NDMA at higher doses. Twenty eight days after a dose of 10 mg/kg (causing a 3.6-fold increase in mutant f requency), NDMA was found to increase the frequency of GC-->AT mutatio ns (with a concomitant shift of their preferential location from CpG s ites to GpG sites), which made up similar to 60% of the induced mutati ons. Surprisingly, NDMA also caused a significant increase in deletion s of a few (up to 11) base-pairs (22%).