Nano-sized TiO2의 세포독성 유도기전 연구

Abstract

Titanium dioxide (TiO2) has been widely used in many areas including the biomedicine, cosmetics, and environmental engineering. Recently, it has become evident that some of TiO2 particles have shown considerable cytotoxic effect in human normal cells. However, the molecular basis for the cytotoxicity of TiO2 has yet to be defined. We demonstrated in this study that TiO2 induces cell growth inhibition, DNA damage, and mitochondrial dysfunction in human normal liver cells through intracellular ROS generation, and that ROS-dependent caspase 8 and Bcl-2-associated X protein (Bax) activation is involved in TiO2-induced mitochondrial dysfunction and cell death. Treatment of TiO2 induced an increase in intracellular ROS, caspase 8 activation, conformational change and mitochondrial redistribution of Bax, mitochondrial membrane potential loss, and cell death. Inhibition of Bax with siRNA of Bax significantly attenuated TiO2-induced mitochondrial membrane potential loss, but did not affect ROS generation. Moreover, inhibition of ROS generation with an antioxidant, N-acetyl-L-cysteine (NAC), clearly suppressed caspase 8 activation and conformational change and mitochondrial translocation of Bax and subsequent mitochondrial cell death. In addition, pretreatment of NAC completely blocked TiO2-induced cell growth inhibition and DNA damage. These results indicate that TiO2 induces cell growth inhibition, DNA damage and mitochondrial dysfunction through intracellular ROS generation, and that ROS-dependent activation of caspase 8 and Bax is critically required for mitochondrial cell death in response to TiO2 in human normal liver cells. Elucidating the molecular mechanisms utilized by nanomaterials to regulate DNA damage, mitochondrial dysfunction and cell death is critical for the development of prevention strategies to protect cytotoxicity of nanomaterials.