Asbestos Damages

The first evidence indicating the DNA-damaging effect of asbestos was demonstrated in Chinese hamster and human cell lines exposed to asbestos.142 Further studies indicated that asbestos can induce large deletions of DNA and consequent failure of chromosomal segregation and cell mitosis.143 144 in workers exposed to asbestos, increased frequency of sister chromatid exchange and DNA double-strand breaks have been observed.145 146 The DNA-damaging effect of asbestos was enhanced in the presence of H2O2.147 The presence of surface-bound iron was considered a critical factor in the induction of •OH radicals and 8-OHdG DNA adduct formation.148149

Several studies suggested that cigarette smoking enhances the lifetime accumulation of asbestos in the lung and, consequently, increases the generation of ROS and the occurrence of lung cancer.150 It was shown in in vitro studies that asbestos fibers absorb and retain benzo(a)pyrene, and thereby enhance direct delivery of this carcinogen to the nucleus of the cells.151152 This mechanism may be a reasonable explanation for the increased G to T transversions at codon 12 of the k-ras gene and G:C to T:A mutations of the p53 gene in lung cancer resulting from combined exposure to asbestos and cigarette smoke.153154

Increased p53 expression or function has been frequently observed in the cellular response to DNA damage signals. If asbestos is capable of damaging DNA, one can speculate a change in p53 protein or its function following exposure to asbestos. Indeed, in an inhalation study of rats exposed to aerosolized asbestos, increases in the expression of p53 protein at the sites of asbestos fiber deposition were observed. The expression of p53 was detected by immunostaining after 24h of exposure and peaked at 8 days.155 A similar study reported on the accumulation of p53 in human lung cancer tissues, with a significant correlation with the asbestos content in the lung tissue.156 In addition, an increased level of serum p53 protein was reported to be present in patients with asbestos-associated lung cancer.157 The elevated level of p53 in asbestos-induced cancer is correlated with the enhanced downstream effects of p53, such as cell cycle arrest at G1 phase and expression of p53 target genes p21, gadd45, and gadd153.158 159 It was proposed that the increased level of p53 protein may be largely because of the increased p53 stability resulting from mutation or post-transcriptional modification rather than the increase of p53 mRNA expression. A recent study by Matsuoka et al.160 demonstrated that exposure of human pulmonary epithelial type II cells to asbestos increased the S15 phosphorylation of p53. This phosphorylation of p53 seems to be dependent on the activation PI3K family members, such as ATM, ATR, or DNA-PK, since the PI3K inhibitor wortmannin, but not MAPK inhibitors, blocked S15 phosphorylation induced by asbestos.160

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