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-nitrosodimethylamine (NDMA) as single doses of 5 mg/kg or 10 mg/kg or as 10daily doses of 1 mg/kg and changes in DNA N7- or O6-methylguanine or therepair enzyme O6-alkylguanine-DNA alkyltransferase (AGT) were followed forup to 14 days in various tissues. Adduct induction in the liver exceeded byat least one order of magnitude than observed in the next nearest targettissue (lung), and was approximately linearly related to dose, except forO6-methylguanine after the first dose of 1 mg/kg which was lower thanexpected. Substantial induction of lambda lacZ mutagenesis was observedonly in the liver, where the mutant frequency was already maximal within 7days after 5 mg/kg NDMA and remained unchanged thereafter up to 49 days.Small but marginally significant increases in mutant frequency wereconsistently observed in the spleen after all three modes of treatment. Alack of proportionality between mutation induction and the administereddose or the corresponding adduct levels was observed, probably reflectingthe importance of toxicity-related cell proliferation caused by NDMA athigher doses. Twenty eight days after a dose of 10 mg/kg (causing a 3.6-fold increase in mutant frequency), NDMA was found to increase thefrequency of GC-->AT mutations (with a concomitant shift of theirpreferential location from CpG sites to GpG sites), which made upapproximately 60% of the induced mutations. Surprisingly, NDMA also causeda significant increase in deletions of a few (up to 11) base- pairs (22%).