DNA adducts, mutant frequencies, and mutation spectra in various organs of λlacZ mice exposed to ethylating agents

Mientjes, Edwin; Luiten-Schuite, A.; Wolf, E.; Borsboom, Y.; Bergmans, Angela; Berends, Frits J.; Lohman, P.H.M.; Baan, R.A.; Delft, J.H.M. van

doi:10.1002/(sici)1098-2280(1998)31:1<18::aid-em4>3.0.co;2-7

Cited by 40 publications

(34 citation statements)

References 40 publications

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“…This conspicuous difference in CD59 − cells generated by radiation and EMS is likely due to the way each agent acts on DNA. Radiation is known to cause double strand breaks leading to deletions [5,21], leading to the complete loss of CD59 expression on the cell surface while EMS is an alkylating agent often generating base substitutions [12,13], which could lead to changes in protein folding and in turn antibody affinity for CD59 on the protein surface. This in turn would lead to varying levels of expression of fluorescence in this flow cytometry based assay.…”

Section: Discussionmentioning

confidence: 99%

“…In this report we investigate CD59 − populations and clones generated by exposure to the known alkylating agent ethylmethanesulfonate (EMS) [12,13] that are believed to be mostly point mutations. Point mutations allow for mutated conformations of CD59 on the cell surface and in turn intermediate staining, suggesting that a larger region should be used for mutant detection.…”

Section: Introductionmentioning

confidence: 99%

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EMS mutant spectra generated by multi-parameter flow cytometry

Keysar

Fox

2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The CHO AL cell line contains a single copy of human chromosome 11 that encodes several cell surface proteins including glycosyl phosphatidylinositol (GPI) linked CD59 and CD90, as well as CD98, CD44 and CD151 which are not GPI-linked. The flow cytometry mutation assay (FCMA) measures mutations of the CD59 gene by the absence of fluorescence when stained with antibodies against the CD59 cell surface protein. We have measured simultaneous mutations in CD59, CD44, CD90, CD98 and CD151 to generate a mutant spectrum for ionizing radiation. After treatment with ethyl methanesulfonate (EMS) many cells have an intermediate level of CD59 staining. Single cells were sorted from CD59− regions with varying levels of fluorescence and the resulting clonal populations had a stable phenotype for CD59 expression. Mutant spectra were generated by flow cytometry using the isolated clones and nearly all clones were mutated in CD59 only. Interestingly, about 60% of the CD59 negative clones were actually GPI mutants determined by staining with the GPI specific fluorescently labeled bacterial toxin aerolysin (FLAER). The GPI negative cells are most likely caused by mutations in the X-linked pigA gene important in GPI biosynthesis. Small mutations of pigA and CD59 were expected for the alkylating agent EMS and the resulting spectra are significantly different than the large deletions found when analyzing radiation mutants. After analyzing the CD59− clonal populations we have adjusted the FCMA mutant regions from 1% to 10% of the mean of the CD59 positive peak to include the majority of CD59 mutants.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

EMS mutant spectra generated by multi-parameter flow cytometry

Keysar

Fox

2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…EMS and MNU are DNA alkylating agents; 1,6-DNP and BP are mutagens typically generated during combustion; NNN is a mutagen typically found in cigarette smoke; and BCNU is a drug used in treating brain cancer. These mutagens were chosen because they are known to induce point mutation (Kunz & Mis, 1989;Watanabe et al, 1997;Mientjes et al, 1998;Fujita & Kamataki, 2001;Yim & Hee, 2001;Jemnitz et al, 2004;Vlasakova et al, 2005;Saito et al, 2006). Except for BP, all of the mutagens tested are direct mutagens that do not require metabolic activation.…”

Section: Chemicals and Antibacterial Agentsmentioning

confidence: 99%

Environmental mutagens may be implicated in the emergence of drug-resistant microorganisms

Miyahara

Nishie

Takumi

et al. 2011

FEMS Microbiology Letters

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The emergence of drug-resistant microorganisms is an important medical and social problem. Drug-resistant microorganisms are thought to grow selectively in the presence of antibiotics. Most clinically isolated drug-resistant microorganisms have mutations in the target genes for the drugs. While any of the many mutagens in the environment may cause such genetic mutations, no reports have yet described whether these mutagens can confer drug resistance to clinically important microorganisms. We investigated how environmental mutagens might be implicated in acquired resistance to antibiotics in clinically important microorganisms, which causes human diseases. We selected mutagens found in the environment, in cigarette smoke, or in drugs, and then exposed Pseudomonas aeruginosa to them. After exposure, the incidence of rifampicin- and ciprofloxacin-resistant P. aeruginosa strains markedly increased, and we found mutations in genes for the antibiotic-target molecule. These mutations were similar to those found in drug-resistant microorganisms isolated from clinical samples. Our findings show that environmental mutagens, and an anticancer drug, are capable of inducing drug-resistant P. aeruginosa similar to strains found in clinical settings.

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“…As expected, mutagenic effects were detected in the liver of the Muta™mouse, but none in the bone marrow [104,106,149,150]. The same mice showed also no micronuclei at these dose levels [104].…”

Section: Resultsmentioning

confidence: 59%

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et al. 2005

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As part of a larger literature study on transgenic animals in mutagenicity testing, test results from the transgenic mutagenicity assays (lacI model; commercially available as the Big Blue® mouse, and the lacZ model; commercially available as the Muta™Mouse), were compared with the results on the same substances in the more traditional mouse bone marrow micronucleus test. 39 substances were found which had been tested in the micronucleus assay and in the above transgenic mouse systems. Although, the transgenic animal mutation assay is not directly comparable with the micronucleus test, because different genetic endpoints are examined: chromosome aberration versus gene mutation, the results for the majority of substances were in agreement. Both test systems, the transgenic mouse assay and the mouse bone marrow micronucleus test, have advantages and they complement each other. However, the transgenic animal assay has some distinct advantages over the micronucleus test: it is not restricted to one target organ and detects systemic as well as local mutagenic effects.

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DNA adducts, mutant frequencies, and mutation spectra in various organs of λlacZ mice exposed to ethylating agents

Cited by 40 publications

References 40 publications

EMS mutant spectra generated by multi-parameter flow cytometry

EMS mutant spectra generated by multi-parameter flow cytometry

Environmental mutagens may be implicated in the emergence of drug-resistant microorganisms

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