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 (TiO(2)-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 TiO(2)-NPs exposure. In the present study, we investigated the cytotoxicity of TiO(2)-NPs using PC12 cells and intended to clarify the molecular mechanisms underlying the biological effects of TiO(2)-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 TiO(2)-NPs to the neurotoxicity were also investigated. The anatase TiO(2)-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 TiO(2)-NPs, the rutile TiO(2)-NPs showed moderately toxic effect on neuron cells. The micron-sized TiO(2) 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 TiO(2)-NPs can induce apoptosis and cell cycle arrest in PC12 cells. In addition, both the size and crystal structure of TiO(2)-NPs exposure contributed to the neurotoxicity. Nanoparticles were more toxic than micrometer-sized particles and the anatase form were more toxic than the rutile.
Wu
Jie
J
Shanghai Biomaterials Research & Testing Center, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, No. 427 Jumen Road, Shanghai 200023, China.
Sun
Jiao
J
Xue
Yang
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D053758:Nanoparticles / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress; D016716:PC12 Cells; D010316:Particle Size; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D014025:Titanium / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C009495:titanium dioxide; D014025:Titanium; D048031:JNK Mitogen-Activated Protein Kinases