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Kinetics of induction of DNA damage and lacZ gene mutations in stomach mucosa of mice treated with β‐propiolactone and N ‐methyl‐ N ′‐nitro‐ N ‐nitrosoguanidine, using single‐cell gel electrophoresis and Muta TM Mouse models
Author(s) -
Brault Dominique,
Renault Dominique,
Tombolan Françoise,
Thybaud Véronique
Publication year - 1999
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(1999)34:2/3<182::aid-em17>3.0.co;2-y
Subject(s) - microbiology and biotechnology , methylnitronitrosoguanidine , mutant , gel electrophoresis , dna damage , stomach , dna , chemistry , gastric mucosa , gene , cell , biology , pharmacology , biochemistry
β‐Propiolactone (BPL) and N ‐methyl‐ N ′‐nitro‐ N ‐nitrosoguanidine (MNNG) are two direct alkylating agents that induce multiple genetic lesions and tumors in the rodent stomach. We measured the kinetics of the induction of DNA damage by using the single‐cell gel electrophoresis assay (SCGE) and the induction of gene mutations by using the Muta ™ Mouse model in the glandular stomach mucosa of mice exposed to a single oral administration of BPL or MNNG. The aims were to determine the optimal sampling time and to investigate the cause‐effect relationship between DNA damage and gene mutations. The induction of comets, evaluated in individual cells with the tail moment, was analyzed 1, 2, 4, 24, and 72 hr after a single oral administration of 25 mg/kg BPL or 20 mg/kg MNNG. The effects of both compounds were most intense at the earlier sampling times (1–2 hr), tailing off 4 hr after treatment and becoming undetectable at 72 hr. The lac Z mutant frequency (MF) was measured 3, 7, 14, 28, and 50 days after a single oral administration of 150 mg/kg BPL or 100 mg/kg MNNG, and 3 and 14 days after a single administration of 25 mg/kg BPL or 20 mg/kg MNNG. The MF was strongly enhanced at the highest doses and all sampling times, the most marked effects being observed 14 days (11.1‐fold) and 28 days (19.0‐fold) after BPL and MNNG administration, respectively. At the lowest doses, only a small increase in MF (∼2.5‐ to 3.5‐fold) was found at both sampling times. Primary DNA damage detected with SCGE shortly after treatment (1–2 hr) was rapidly (3 days) transformed into stable gene mutations that remained detectable for 50 days. These results illustrate the ability and complementarity of the SCGE and Muta ™ Mouse models to assess the genotoxicity of direct alkylating agents in the mouse gastric mucosa in vivo. Environ. Mol. Mutagen. 34:182–189, 1999 © 1999 Wiley‐Liss, Inc.