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New insight into intrachromosomal deletions induced by chrysotile in the gpt delta transgenic mutation assay
An Xu1, Lubomir B Smilenov, Peng He
1Center for Radiological Research, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Background:
Genotoxicity is often a prerequisite to the development of malignancy. Considerable evidence has shown that exposure to asbestos fibers results in the generation of chromosomal aberrations and multilocus mutations using various in vitro approaches. However, there is less evidence to demonstrate the contribution of deletions to the mutagenicity of asbestos fibers in vivo.
Objectives:
In the present study, we investigated the mutant fractions and the patterns induced by chrysotile fibers in gpt delta transgenic mouse primary embryo fibroblasts (MEFs) and compared the results obtained with hydrogen peroxide (H2O2) in an attempt to illustrate the role of oxyradicals in fiber mutagenesis.
Results:
Chrysotile fibers induced a dose-dependent increase in mutation yield at the redBA/gam loci in transgenic MEF cells. The number of lambda mutants losing both redBA and gam loci induced by chrysotiles at a dose of 1 microg/cm(2) increased by > 5-fold relative to nontreated controls (p < 0.005). Mutation spectra analyses showed that the ratio of lambda mutants losing the redBA/gam region induced by chrysotiles was similar to those induced by equitoxic doses of H2O2. Moreover, treatment with catalase abrogated the accumulation of y-H2AX, a biomarker of DNA double-strand breaks, induced by chrysotile fibers.
Conclusions:
Our results provide novel information on the frequencies and types of mutations induced by asbestos fibers in the gpt delta transgenic mouse mutagenic assay, which shows great promise for evaluating fiber/particle mutagenicity in vivo.
Insights
Chrysotile asbestos fibers cause DNA mutations in mouse cells, similar to hydrogen peroxide. This study highlights the gpt delta transgenic mouse assay for evaluating fiber mutagenicity in vivo.
Area of Science:
- Toxicology
- Genetics
- Molecular Biology
Background:
- Genotoxicity is a key factor in cancer development.
- Asbestos exposure is linked to chromosomal damage and mutations in vitro.
- In vivo evidence for asbestos-induced deletions is limited.
Purpose of the Study:
- Investigate mutation patterns from chrysotile fibers in mouse cells.
- Compare chrysotile-induced mutations with those from hydrogen peroxide (H2O2).
- Elucidate the role of oxyradicals in asbestos fiber mutagenesis.
Main Methods:
- Utilized gpt delta transgenic mouse primary embryo fibroblasts (MEFs).
- Exposed MEFs to varying doses of chrysotile fibers and H2O2.
- Analyzed mutation spectra and DNA double-strand breaks (y-H2AX).
Main Results:
- Chrysotile fibers induced a dose-dependent increase in mutation yield.
- Chrysotile-induced mutations (5-fold increase) were similar to H2O2.
- Catalase treatment reduced DNA double-strand breaks caused by chrysotile.
Conclusions:
- Asbestos fibers induce specific mutation frequencies and types in vivo.
- The gpt delta transgenic mouse assay is promising for in vivo fiber mutagenicity assessment.
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