Titanium dioxide nanoparticles induce strong oxidative stress and mitochondrial damage in glial cells.

Titanium dioxide nanoparticles (TiO2 NPs) are widely used in the chemical, electrical, and electronic industries. TiO2 NPs can enter directly into the brain through the olfactory bulb and can be deposited in the hippocampus region; therefore, we determined the toxic effect of TiO2 NPs on rat and human glial cells, C6 and U373, respectively. We evaluated some events related to oxidative stress: (1) redox-signaling mechanisms by oxidation of 2',7'-dichlorodihydrofluorescein diacetate; (2) peroxidation of lipids by cis-parinaric acid; (3) antioxidant enzyme expression by PCR in real time; and (4) mitochondrial damage by MitoTracker Green FM staining and Rh123. TiO2 NPs induced a strong oxidative stress in both glial cell lines by mediating changes in the cellular redox state and lipid peroxidation associated with a rise in the expression of glutathione peroxidase, catalase, and superoxide dismutase 2. TiO2 NPs also produced morphological changes, damage of mitochondria, and an increase in mitochondrial membrane potential, indicating toxicity. TiO2 NPs had a cytotoxic effect on glial cells; however, more in vitro and in vivo studies are required to ascertain that exposure to TiO2 NPs can cause brain injury and be hazardous to health.

[1]  A. Landar,et al.  Cell signalling by oxidized lipids and the role of reactive oxygen species in the endothelium. , 2005, Biochemical Society transactions.

[2]  G. Oberdörster,et al.  Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles , 2005, Environmental health perspectives.

[3]  S. Sollott,et al.  Mitochondrial ROS-induced ROS release: an update and review. , 2006, Biochimica et biophysica acta.

[4]  Qing Huang,et al.  Systematic influence induced by 3 nm titanium dioxide following intratracheal instillation of mice. , 2010, Journal of nanoscience and nanotechnology.

[5]  Ian J. Reynolds,et al.  MitoTracker labeling in primary neuronal and astrocytic cultures: influence of mitochondrial membrane potential and oxidants , 2001, Journal of Neuroscience Methods.

[6]  Kent D. Sugden,et al.  Hypervalent chromium mimics reactive oxygen species as measured by the oxidant-sensitive dyes 2',7'-dichlorofluorescin and dihydrorhodamine. , 1998, Chemical research in toxicology.

[7]  Ran Liu,et al.  Small-sized titanium dioxide nanoparticles mediate immune toxicity in rat pulmonary alveolar macrophages in vivo. , 2010, Journal of nanoscience and nanotechnology.

[8]  Yanfei Liu,et al.  Cytotoxicity of titanium dioxide nanoparticles in rat neuroglia cells , 2013, Brain injury.

[9]  Jie Wu,et al.  Four types of inorganic nanoparticles stimulate the inflammatory reaction in brain microglia and damage neurons in vitro. , 2012, Toxicology letters.

[10]  J. Lemasters,et al.  Imaging of mitochondrial polarization and depolarization with cationic fluorophores. , 2007, Methods in cell biology.

[11]  Raj Acharya,et al.  Erratum to “Unsupervised Two-Way Clustering of Metagenomic Sequences” , 2012, Journal of Biomedicine and Biotechnology.

[12]  G. Bartosz,et al.  2,7‐DICHLOROFLUORESCIN OXIDATION AND REACTIVE OXYGEN SPECIES: WHAT DOES IT MEASURE? , 2000, Cell biology international.

[13]  Madhu Rani,et al.  Nano-TiO2-Induced Apoptosis by Oxidative Stress-Mediated DNA Damage and Activation of p53 in Human Embryonic Kidney Cells , 2012, Applied Biochemistry and Biotechnology.

[14]  A. Zanotto-Filho,et al.  Proteasome inhibitor MG132 induces selective apoptosis in glioblastoma cells through inhibition of PI3K/Akt and NFkappaB pathways, mitochondrial dysfunction, and activation of p38-JNK1/2 signaling , 2012, Investigational New Drugs.

[15]  S. Ojeda,et al.  A rapid microprocedure for isolating RNA from multiple samples of human and rat brain , 1985, Journal of Neuroscience Methods.

[16]  R. P. Rastogi,et al.  Detection of reactive oxygen species (ROS) by the oxidant-sensing probe 2',7'-dichlorodihydrofluorescein diacetate in the cyanobacterium Anabaena variabilis PCC 7937. , 2010, Biochemical and biophysical research communications.

[17]  V. Kagan,et al.  The role of nanotoxicology in realizing the ‘helping without harm’ paradigm of nanomedicine: lessons from studies of pulmonary effects of single‐walled carbon nanotubes , 2010, Journal of internal medicine.

[18]  D. González-Espinosa,et al.  Progesterone effects on cell growth of U373 and D54 human astrocytoma cell lines , 2007, Endocrine.

[19]  R. López-Marure,et al.  TiO₂ nanoparticles induce dysfunction and activation of human endothelial cells. , 2012, Chemical research in toxicology.

[20]  Helinor J Johnston,et al.  Air Pollution, Ultrafine and Nanoparticle Toxicology: Cellular and Molecular Interactions , 2007, IEEE Transactions on NanoBioscience.

[21]  Navid B. Saleh,et al.  Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity. , 2006, Environmental science & technology.

[22]  J. Pairon,et al.  A comparative transmission electron microscopy study of titanium dioxide and carbon black nanoparticles uptake in human lung epithelial and fibroblast cell lines. , 2012, Toxicology in vitro : an international journal published in association with BIBRA.

[23]  A. Siomek NF-κB signaling pathway and free radical impact. , 2012, Acta biochimica Polonica.

[24]  Tao Zhang,et al.  Oxidative stress and apoptosis induced by nanosized titanium dioxide in PC12 cells. , 2010, Toxicology.

[25]  V. Pentreath,et al.  Astrocyte phenotype and prevention against oxidative damage in neurotoxicity , 2000, Human & experimental toxicology.

[26]  A. Gramowski,et al.  Nanoparticles Induce Changes of the Electrical Activity of Neuronal Networks on Microelectrode Array Neurochips , 2010, Environmental health perspectives.

[27]  Minling Gao,et al.  Cytotoxicity of different sized TiO2 nanoparticles in mouse macrophages , 2013, Toxicology and industrial health.

[28]  E. Dopp,et al.  Titanium dioxide nanoparticles induce oxidative stress and DNA-adduct formation but not DNA-breakage in human lung cells , 2009, Particle and Fibre Toxicology.

[29]  Richard P. Haugland,et al.  Handbook of fluorescent probes and research chemicals , 1996 .

[30]  D. Drobne,et al.  The importance of a validated standard methodology to define in vitro toxicity of nano-TiO2 , 2012, Protoplasma.

[31]  Jianjie Ma,et al.  Mitochondrial Depolarization Accompanies Cytochrome cRelease During Apoptosis in PC6 Cells* , 1999, The Journal of Biological Chemistry.

[32]  Su Jin Kang,et al.  Titanium dioxide nanoparticles trigger p53‐mediated damage response in peripheral blood lymphocytes , 2008, Environmental and molecular mutagenesis.

[33]  A. Alfadda,et al.  Reactive Oxygen Species in Health and Disease , 2012, Journal of biomedicine & biotechnology.

[34]  Jie Liu,et al.  Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. , 2010, Biomaterials.

[35]  B. Ekstrand-Hammarström,et al.  Polymorph- and size-dependent uptake and toxicity of TiO₂ nanoparticles in living lung epithelial cells. , 2011, Small.

[36]  D. Warheit,et al.  Inhalation of high concentrations of low toxicity dusts in rats results in impaired pulmonary clearance mechanisms and persistent inflammation. , 1997, Toxicology and applied pharmacology.

[37]  Thomas Kuhlbusch,et al.  Particle and Fibre Toxicology BioMed Central Review The potential risks of nanomaterials: a review carried out for ECETOC , 2006 .

[38]  Il Je Yu,et al.  Biopersistence of silver nanoparticles in tissues from Sprague–Dawley rats , 2013, Particle and Fibre Toxicology.

[39]  Masakazu Umezawa,et al.  Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse , 2009, Particle and Fibre Toxicology.

[40]  Lucienne Juillerat-Jeanneret,et al.  Induction of oxidative stress, lysosome activation and autophagy by nanoparticles in human brain-derived endothelial cells. , 2012, The Biochemical journal.

[41]  J. Pedraza-Chaverri,et al.  Titanium dioxide nanoparticles impair lung mitochondrial function. , 2011, Toxicology letters.

[42]  Wei Liu,et al.  Nano titanium dioxide induces the generation of ROS and potential damage in HaCaT cells under UVA irradiation. , 2010, Journal of nanoscience and nanotechnology.

[43]  David B Warheit,et al.  Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[44]  Dragan Uskoković,et al.  DNA damage and alterations in expression of DNA damage responsive genes induced by TiO2 nanoparticles in human hepatoma HepG2 cells , 2011, Nanotoxicology.

[45]  R. López-Marure,et al.  Titanium dioxide nanoparticles inhibit proliferation and induce morphological changes and apoptosis in glial cells. , 2012, Toxicology.

[46]  Z. Chai,et al.  [Influence of intranasal instilled titanium dioxide nanoparticles on monoaminergic neurotransmitters of female mice at different exposure time]. , 2007, Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine].

[47]  Joshua A. Smith,et al.  Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration , 2013, Neurochemistry International.

[48]  F. Hong,et al.  Molecular mechanism of titanium dioxide nanoparticles-induced oxidative injury in the brain of mice. , 2013, Chemosphere.

[49]  Nianqiang Wu,et al.  Interlaboratory Evaluation of in Vitro Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials: The NIEHS Nano GO Consortium , 2013, Environmental health perspectives.

[50]  J. Andersen,et al.  Oxidative stress in neurodegeneration: cause or consequence? , 2004, Nature Reviews Neuroscience.

[51]  K. Jan,et al.  Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells. , 2005, Toxicology.

[52]  P. Borm,et al.  Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: role of the specific surface area and of surface methylation of the particles. , 2007, Toxicology and applied pharmacology.

[53]  F. Hong,et al.  Pulmotoxicological effects caused by long-term titanium dioxide nanoparticles exposure in mice. , 2012, Journal of hazardous materials.

[54]  Q. Lu,et al.  Cytotoxicity of titanium dioxide nanoparticles in mouse fibroblast cells. , 2008, Chemical research in toxicology.

[55]  Balaraman Kalyanaraman,et al.  Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations. , 2012, Free radical biology & medicine.

[56]  I. Iavicoli,et al.  Toxicological effects of titanium dioxide nanoparticles: a review of in vitro mammalian studies. , 2011, European review for medical and pharmacological sciences.

[57]  Ralf Kriehuber,et al.  Oxidative stress-induced cytotoxic and genotoxic effects of nano-sized titanium dioxide particles in human HaCaT keratinocytes. , 2012, Toxicology.

[58]  Y. Wang,et al.  Neurotoxicity and gene-expressed profile in brain-injured mice caused by exposure to titanium dioxide nanoparticles. , 2014, Journal of biomedical materials research. Part A.

[59]  Wei Li,et al.  Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO(2) nanoparticles. , 2008, Toxicology.