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DNA adducts, mutant frequencies, and mutation spectra in various organs of λ lac Z mice exposed to ethylating agents
Author(s) -
Mientjes Edwin J.,
Luitenschuite Anja,
van der Wolf Esmeralda,
Borsboom Yvonne,
Bergmans Angela,
Berends Frits,
Lohman Paul H. M.,
Baan Robert A.,
van Delft Joost H. M.
Publication year - 1998
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/(sici)1098-2280(1998)31:1<18::aid-em4>3.0.co;2-7
Subject(s) - mutagenesis , mutant , bone marrow , mutation , microbiology and biotechnology , mutagen , mutation frequency , ethyl methanesulfonate , chemistry , dna adduct , nitrosourea , point mutation , dna , lesion , biochemistry , biology , gene , genetics , immunology , pathology , medicine , chemotherapy
To investigate tissue‐specific relations between DNA adducts and mutagenesis in vivo, λ lac Z 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 O 6 ‐ethylguanine (O 6 ‐EtG) and N7‐ethylguanine (N7‐EtG) levels were determined as well as the mutant frequency (MF) in lac Z. In liver DNA of ENU‐ and DEN‐treated mice, the bulk of O 6 ‐EtG was removed at 3 days after treatment, while the MF continued to increase thereafter. This suggests that O 6 ‐EtG is not the major premutagenic lesion in the liver. Indeed, sequence analysis of mutants showed only 24% GC → AT transitions, consistent with the O 6 ‐EtG lesion, and 28% TA → AT transversions, expected from O 2 ‐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 O 6 ‐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 O 6 ‐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 O 6 ‐ and N7‐adducts were present. Environ. Mol. Mutagen. 31:18–31, 1998. © 1998 Wiley‐Liss, Inc.