Frequency and Spectrum of lacI Mutations in the Liver of Big Blue Mice Following the Administration of Genotoxic Carcinogens Singly and in Series

Abstract

Transgenic mouse models offer a unique opportunity to study in vivo mutagenicity in any tissue of interest. In this study, the authors have determined the liver mutant frequency (MF) and mutational spectra (MS) of 12 week-old male Big Blue B6C3F1 transgenic mice exposed to the genotoxic carcinogens benzo[a]pyrene (B[a]P; 250 mg/kg/day), N-nitrosodimethylamine (NDMA; 7 mg/kg/day), or N-ethyl-1-nitrosourea (ENU; 50 mg/kg/day) singly (3 daily oral doses) or in series (B[a]P on day 1, NDMA on day 2, and ENU on day 3). All genotoxic agents, alone or in series, increased MF in the liver (three-to sixfold). MS analyses of liver DNA revealed a high percentage of G:C → A:T transitions in the control (88%) and the NDMA (64%) groups. In contrast, B[a]P, ENU, and the series treatment induced a high percentage (≥50%) of transversions. Significantly, 46% (19 out of 41) of the mutations in the series treatment group occurred at CpG dinucleotides, compared to less than 22% in the other treatment groups. The MS from the series exposure was most similar to B[a]P with a high percentage of transversion mutations occurring at guanine nucleotides (36%). These preliminary data suggest that genotoxic carcinogens, when exposed in series, produce a unique MS profile characterized not only by shifts in mutation class but also sequence context.