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Quantitative assessment of the dose–response of alkylating agents in DNA repair proficient and deficient ames tester strains
Author(s) -
Tang Leilei,
Guérard Melanie,
Zeller Andreas
Publication year - 2014
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/em.21825
Subject(s) - ethyl methanesulfonate , ethylnitrosourea , ames test , genotoxicity , dna repair , methyl methanesulfonate , dna , mutagen , dna damage , clastogen , carcinogen , mutagenesis , biology , in vivo , chemistry , mutation , genetics , microbiology and biotechnology , toxicology , salmonella , toxicity , gene , organic chemistry , mutant , bacteria
Mutagenic and clastogenic effects of some DNA damaging agents such as methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS) have been demonstrated to exhibit a nonlinear or even “thresholded” dose–response in vitro and in vivo. DNA repair seems to be mainly responsible for these thresholds. To this end, we assessed several mutagenic alkylators in the Ames test with four different strains of Salmonella typhimurium : the alkyl transferases proficient strain TA1535 (Ogt+/Ada+), as well as the alkyl transferases deficient strains YG7100 (Ogt+/Ada−), YG7104 (Ogt−/Ada+) and YG7108 (Ogt−/Ada−). The known genotoxins EMS, MMS, temozolomide (TMZ), ethylnitrosourea (ENU) and methylnitrosourea (MNU) were tested in as many as 22 concentration levels. Dose–response curves were statistically fitted by the PROAST benchmark dose model and the Lutz‐Lutz “hockeystick” model. These dose–response curves suggest efficient DNA‐repair for lesions inflicted by all agents in strain TA1535. In the absence of Ogt, Ada is predominantly repairing methylations but not ethylations. It is concluded that the capacity of alkyl‐transferases to successfully repair DNA lesions up to certain dose levels contributes to genotoxicity thresholds. Environ. Mol. Mutagen. 55:15–23, 2014. © 2013 Wiley Periodicals, Inc.