Chrysotile asbestos induces apoptosis via activation of the p53-regulated mitochondrial pathway mediated by ROS in A549 cells

Abstract Long-term exposure to chrysotile asbestos has been associated with an increased risk of pulmonary fibrosis, lung cancer, ovarian cancer and peritoneal mesothelioma. Although numerous pathophysiological mechanisms account for chrysotile asbestos-induced pulmonary toxicity, apoptosis has attracted considerable attention and has not yet been fully elucidated. Therefore, the goal of the current study was to determine whether chrysotile asbestos could cause oxidative stress and apoptosis in A549 cells and the potential mechanism of reactive oxygen species (ROS)-induced cell apoptosis. The experimental results showed that chrysotile asbestos significantly inhibited the proliferation of A549 cells. Additionally, chrysotile asbestos increased ROS in a dose-dependent manner. Excessive ROS injured the antioxidant defense system and caused lipid peroxidation, of which glutathione (GSH) and superoxide dismutase (SOD) were dramatically decreased while malondialdehyde (MDA) was significantly increased. Excessive production of ROS upregulated the expression of pro-apoptotic proteins p53 and Bax to depress the mitochondrial membrane potential (MMP) and promote cytochrome c (Cyt c) release into the cytosol, which triggered the downstream apoptotic protein cleave-caspase-3 to induce cell apoptosis. Furthermore, N-acetyl-L-cysteine (NAC) was applied to inhibit the production of ROS. NAC pretreatment hindered the decrease of MMP, reduced expression of p53, Bax and Cyt c, downregulated cleave-caspase-3 and reduced cellular apoptosis. In conclusion, chrysotile asbestos caused mitochondrial dysfunction and cell oxidative stress to induce apoptosis via the p53-regulated mitochondrial pathway. Our research results provided a fundamental basis for a toxicity discussion and rational utilization of chrysotile asbestos.