DNA adducts, mutant frequencies, and mutation spectra in various organs of λlacZ mice exposed to ethylating agents
article
To investigate tissue-specific relations between DNA adducts and mutagenesis in vivo, λlacZ transgenic mice were treated i.p. with N-ethyl-N-nitrosourea (ENU), diethylnitrosamine (DEN), and ethyl methanesulphonate (EMS). In liver, bone marrow, and brain DNA from mice sacrificed at several time points after treatment O6-ethylguanine (O6-EtG) and N7-ethylguanine (N7-EtG) levels were determined as well as the mutant frequency (MF) in lacZ. In liver DNA of ENU- and DEN-treated mice, the bulk of O6-EtG was removed at 3 days after treatment, while the MF continued to increase thereafter. This suggests that O6-EtG is not the major premutagenic lesion in the liver. Indeed, sequence analysis of mutants showed only 24% GC → AT transitions, consistent with the O6-EtG lesion, and 28% TA → AT transversions, expected from O2-ethylthymine. In bone marrow after ENU treatment, a maximum mutation induction occurred at 3 days post-treatment, of which 43% were GC → AT mutations and 22% were TA → AT mutations. This suggests that in bone marrow O6-EtG may be a major premutagenic lesion at the 3-day time point. In liver and bone marrow, EMS treatment gave rise to a high level of N7-EtG and a low level of O6-EtG but no increase in MF. No adducts or mutation induction were observed in bone marrow of DEN-treated mice. No MF increase was observed in the brain of either ENU- or EMS-treated mice, although O6- and N7-adducts were present.
Topics
λlacZ transgenic miceEthyl DNA adductsMuta(TM)MouseMutagenesisMutation spectraAlkylating agentDiethylnitrosamineEthylnitrosoureaGuanine derivativeMesylic acid ethyl esterAnimal experimentAnimal tissueBone marrowBrainControlled studyDna adductFemaleLiverMouseMutagenesisMutationMutation rateNonhumanSequence analysisTransgenic mouseAnimalsBone MarrowBrainDiethylnitrosamineDNA AdductsEthyl MethanesulfonateEthylnitrosoureaFemaleGuanineLac OperonLiverMiceMice, TransgenicMutagens
TNO Identifier
234397
ISSN
08936692
Source
Environmental and Molecular Mutagenesis, 31(1), pp. 18-31.
Pages
18-31
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