Involvement of JNK and P53 activation in G2/M cell cycle arrest and apoptosis induced by titanium dioxide nanoparticles in neuron cells

Despite that applications of titanium dioxide nanoparticles (TiO2-NPs) have been developed in the fields of paints, waste water treatment, sterilization, cosmetics, food additive, bio-medical ceramic and implant biomaterials and so on, relatively few studies have been conducted to determine the neurotoxicity of TiO2-NPs exposure. In the present study, we investigated the cytotoxicity of TiO2-NPs using PC12 cells and intended to clarify the molecular mechanisms underlying the biological effects of TiO2-NPs. PC12 cell is a type of cells, which have been used as an in vitro model of dopaminergic neurons for neurodegenerative diseases research. In addition, the roles of the particle size and crystal structure of TiO2-NPs to the neurotoxicity were also investigated. The anatase TiO2-NPs displayed a dose-dependent behavior on decreasing cell viability, increasing levels of lactate dehydrogenase (LDH), activating oxidative stress, inducing apoptosis, disturbing cell cycle, triggering JNK- and p53-mediated signaling pathway. In comparison to anatase TiO2-NPs, the rutile TiO2-NPs showed moderately toxic effect on neuron cells. The micron-sized TiO2 did not exhibit any toxic response. It is suggested from our results that reactive oxygen species (ROS) have a mediation effect to oxidative stress and up-regulation of JNK and P53 phosphorylation involved in mechanistic pathways of TiO2-NPs can induce apoptosis and cell cycle arrest in PC12 cells. In addition, both the size and crystal structure of TiO2-NPs exposure contributed to the neurotoxicity. Nanoparticles were more toxic than micrometer-sized particles and the anatase form were more toxic than the rutile. Crown Copyright (C) 2010 Published by Elsevier Ireland Ltd. All rights reserved.