New insight into intrachromosomal deletions induced by chrysotile in the gpt delta transgenic mutation assay.
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.


OBJECTIVE
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.
Xu
An
A
Center for Radiological Research, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Smilenov
Lubomir B
LB
He
Peng
P
Masumura
Ken-ichi
K
Nohmi
Takehiko
T
Yu
Zengliang
Z
Hei
Tom K
TK
D000818:Animals; D017632:Asbestos, Serpentine / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002872:Chromosome Deletion; D029968:Escherichia coli Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009152:Mutagenicity Tests; D010430:Pentosyltransferases / Q000235:genetics*
D017632:Asbestos, Serpentine; D029968:Escherichia coli Proteins; D006657:Histones; D010430:Pentosyltransferases; C071962:Gpt protein, E coli; C475961:gamma-H2AX protein, mouse