DNA Damage Caused by Metal Nanoparticles: Involvement of Oxidative Stress and Activation of ATM

Abstract

Nanotechnology is a fast growing emerging field, the benefits of which are widely publicized. Our current knowledge of the health effects of metal nanoparticles such as nano-sized cobalt (Nano-Co) and titanium dioxide (Nano-TiO2) is limited but suggests that metal nanoparticles may exert more adverse pulmonary effects as compared with standard-sized particles. To investigate metal nanoparticle-induced genotoxic effects and the potential underlying mechanisms, human lung epithelial cell lines A549 cells were exposed to Nano-Co and Nano-TiO2. Our results showed that exposure of A549 cells to Nano-Co caused reactive oxygen species (ROS) generation that was abolished by pretreatment of cells with ROS inhibitors or scavengers, such as catalase and N-acetyl-L(+)-cysteine (NAC). However, exposure of A549 cells to Nano-TiO2 did not cause ROS generation. Nano-Co caused DNA damage in A549 cells which was reflected by an increase in length, width, and DNA content of the comet tail by Comet assay. Exposure of A549 cells to Nano-Co also caused a dose-and a time- response increased expression of phosphorylated histone H2AX (γ-H2AX), Rad51 and phosphorylated p53. These effects were significantly attenuated when A549 cells were pre-treated with catalase or NAC. Nano-TiO2 did not show these effects. These results suggest that oxidative stress may be involved in Nano-Co-induced DNA damage. To further investigate the pathways involved in the Nano-Co-induced DNA damage, we measured the phosphorylation of ataxia telangiectasia mutant (ATM). Our results showed that phosphorylation of ATM was increased when A549 cells were exposed to Nano-Co, and this effect was attenuated when cells were pretreated with catalase or NAC. Pre-treatment of A549 cells with an ATM specific inhibitor, KU55933, significantly abolished Nano-Co-induced DNA damage. Furthermore, pre-treatment of A549 cells with ROS scavengers, such as catalase and NAC, significantly abolished Nano-Co-induced increased expression of phosphorylated ATM. Taken together, oxidative stress and ATM activation are involved in Nano-Co-induced DNA damage. These findings have important implications for understanding the potential health effects of metal nanoparticle exposure.

Release, Transport and Toxicity of Engineered Nanoparticles

“…In contrast, exposures to ENPs may cause upregulation of the p53 tumor suppressor gene and to DNA repair proteins. Wan et al (2012) showed that ENPs can induce DNA damage and cell death via up-regulation of phosphorylated p53, histone H2AX (γ-H2AX) and via an ataxia telangiectasia mutant (ATM).…”

Zinc oxide nanoparticles exhibit cytotoxicity and genotoxicity through oxidative stress responses in human lung fibroblasts and <em>Drosophila melanogaster</em>

“…21 The generation of free radicals is known to cause oxidative damages in DNA and subsequently produce the product 8-hydroxy-2′-deoxyguanosine , an established oxidative DNA damage marker. 22 An in vitro study demonstrated that ZnO NPs (#35 or 50-80 nm) are able to cause oxidative DNA damage and genotoxicity as revealed by the Comet assay in human lymphoblastoid cells. 23 Other studies using mammalian cultured cells have also shown the potential risk of ZnO NPs in the induction of genotoxicity.…”

Metal-Based Nanotoxicity and Detoxification Pathways in Higher Plants

“…14 The cytotoxicity of cobalt (Co) and CuO NPs to human lung epithelial A549 cells were reported recently. 15,16 Both of these studies concluded that reactive Plants, as an essential component in the environment, are critical to ecosystem function and food supply integrity. Based on the findings of recent laboratory studies, abiotic and oxidative stresses caused by NPs exposure in plants were described at both physiological and biochemical levels.…”