| New Insight into Intrachromosomal Deletions Induced by Chrysotile in the gpt delta Transgenic Mutation Assay An Xu,1,2 Lubomir B. Smilenov,1 Peng He,1 Ken-ichi Masumura,3 Takehiko Nohmi,3 Zengliang Yu,2 and Tom K. Hei1,4 1Center for Radiological Research, College of Physicians & Surgeons, Columbia University, New York, New York, USA; 2Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei, Anhui, People's Republic of China; 3Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, Japan; 4Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA Abstract
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  mutants losing both redBA and gam loci induced by chrysotiles at a dose of 1 µg/cm2 increased by > 5-fold relative to nontreated controls (p < 0.005) . Mutation spectra analyses showed that the ratio of 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  -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. Key words: chrysotile asbestos, gpt delta transgenic mutation system, kilobase-sized mutation, oxyradicals, -H2AX. Environ Health Perspect 115:87–92 (2007) . doi:10.1289/ehp.9425 available via http://dx.doi.org/ [Online 6 September 2006]
Address correspondence to T.K. Hei, Center for Radiological Research, Columbia University, New York, NY 10032 USA. Telephone: (212) 305-8462. Fax: (212) 305-3229. E-mail: TKH1@Columbia.edu We thank M. Partridge and V. Ivanov for their critical reading of the manuscript and R. Baker for his technical assistance with Spi– detection. Work was supported in part by National Institutes of Health grant ES 05786, Superfund grant ES 10349, National Institute of Environmental Health Sciences Center grant ES 09089, and National Nature Science Foundation of China grant 20322202. The authors declare they have no competing financial interests. Received 14 June 2006 ; accepted 6 September 2006.
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