A review on potential neurotoxicity of titanium dioxide nanoparticles

As the rapid development of nanotechnology in the past three decades, titanium dioxide nanoparticles (TiO2 NPs), for their peculiar physicochemical properties, are widely applied in consumer products, food additives, cosmetics, drug carriers, and so on. However, little is known about their potential exposure and neurotoxic effects. Once NPs are unintentionally exposed to human beings, they could be absorbed, and then accumulated in the brain regions by passing through the blood–brain barrier (BBB) or through the nose-to-brain pathway, potentially leading to dysfunctions of central nerve system (CNS). Besides, NPs may affect the brain development of embryo by crossing the placental barrier. A few in vivo and in vitro researches have demonstrated that the morphology and function of neuronal or glial cells could be impaired by TiO2 NPs which might induce cell necrosis. Cellular components, such as mitochondrial, lysosome, and cytoskeleton, could also be influenced as well. The recognition ability, spatial memory, and learning ability of TiO2 NPs-treated rodents were significantly impaired, which meant that accumulation of TiO2 NPs in the brain could lead to neurodegeneration. However, conclusions obtained from those studies were not consistent with each other as researchers may choose different experimental parameters, including administration ways, dosage, size, and crystal structure of TiO2 NPs. Therefore, in order to fully understand the potential risks of TiO2 NPs to brain health, figure out research areas where further studies are required, and improve its bio-safety for applications in the near future, how TiO2 NPs interact with the brain is investigated in this review by summarizing the current researches on neurotoxicity induced by TiO2 NPs.

[1]  Kun Yang,et al.  Toxicity of TiO2 Nanoparticles to Escherichia coli: Effects of Particle Size, Crystal Phase and Water Chemistry , 2014, PloS one.

[2]  M. Setou,et al.  Method for simultaneous imaging of endogenous low molecular weight metabolites in mouse brain using TiO2 nanoparticles in nanoparticle-assisted laser desorption/ionization-imaging mass spectrometry. , 2011, Analytical chemistry.

[3]  Wenxin Li,et al.  Aerosol inhalation exposure study of respiratory toxicity induced by 20 nm anatase titanium dioxide nanoparticles , 2014 .

[4]  J. Bisquert,et al.  Titanium dioxide nanomaterials for photovoltaic applications. , 2014, Chemical reviews.

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

[6]  Xiaobo Chen,et al.  Titanium dioxide-based nanomaterials for photocatalytic fuel generations. , 2014, Chemical reviews.

[7]  Jing Bai,et al.  Titanium dioxide nanomaterials for sensor applications. , 2014, Chemical reviews.

[8]  M. Nedergaard,et al.  The blood–brain barrier: an overview Structure, regulation, and clinical implications , 2004, Neurobiology of Disease.

[9]  Armand Masion,et al.  Structural degradation at the surface of a TiO(2)-based nanomaterial used in cosmetics. , 2010, Environmental science & technology.

[10]  Masakazu Umezawa,et al.  Effect of fetal exposure to titanium dioxide nanoparticle on brain development - brain region information. , 2012, The Journal of toxicological sciences.

[11]  R. Shrivastava,et al.  Effects of sub-acute exposure to TiO2, ZnO and Al2O3 nanoparticles on oxidative stress and histological changes in mouse liver and brain , 2014, Drug and chemical toxicology.

[12]  K. Sugibayashi,et al.  Safety evaluation of titanium dioxide nanoparticles by their absorption and elimination profiles. , 2008, The Journal of toxicological sciences.

[13]  F. Goñi-de-Cerio,et al.  Nanoparticles and blood-brain barrier: the key to central nervous system diseases. , 2014, Journal of nanoscience and nanotechnology.

[14]  N. Burgess,et al.  The hippocampus and memory: insights from spatial processing , 2008, Nature Reviews Neuroscience.

[15]  D. Strayer,et al.  Relationship between the chemokine receptor CCR5 and microglia in neurological disorders: consequences of targeting CCR5 on neuroinflammation, neuronal death and regeneration in a model of epilepsy. , 2013, CNS & neurological disorders drug targets.

[16]  Jeffrey I Ellis,et al.  The safety of nanosized particles in titanium dioxide- and zinc oxide-based sunscreens. , 2009, Journal of the American Academy of Dermatology.

[17]  Chang-Mu Chen,et al.  Titanium nanoparticle inhalation induces renal fibrosis in mice via an oxidative stress upregulated transforming growth factor-β pathway. , 2015, Chemical research in toxicology.

[18]  Pilje Kim,et al.  Toxicity of Zinc Oxide Nanoparticles in Rats Treated by Two Different Routes: Single Intravenous Injection and Single Oral Administration , 2015, Journal of toxicology and environmental health. Part A.

[19]  P. Hayes,et al.  Toxicology of ZnO and TiO2 nanoparticles on hepatocytes: Impact on metabolism and bioenergetics , 2015, Nanotoxicology.

[20]  E. Barbu,et al.  The potential for nanoparticle-based drug delivery to the brain: overcoming the blood-brain barrier. , 2009, Expert opinion on drug delivery.

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

[22]  Yingjun Zhou,et al.  Suppression of neurite outgrowth of primary cultured hippocampal neurons is involved in impairment of glutamate metabolism and NMDA receptor function caused by nanoparticulate TiO2. , 2015, Biomaterials.

[23]  M. Scriba,et al.  Evaluation of the morphological changes in the lungs of BALB/c mice after inhalation of spherical and rod-shaped titanium nanoparticles. , 2012, Micron.

[24]  J. Berman,et al.  Myelin basic protein induces inflammatory mediators from primary human endothelial cells and blood–brain barrier disruption: implications for the pathogenesis of multiple sclerosis , 2013, Neuropathology and applied neurobiology.

[25]  Byeong-Cheol Kang,et al.  Comparative absorption, distribution, and excretion of titanium dioxide and zinc oxide nanoparticles after repeated oral administration , 2013, Particle and Fibre Toxicology.

[26]  Yi-sheng Liu,et al.  Probing the optical property and electronic structure of TiO2 nanomaterials for renewable energy applications. , 2014, Chemical reviews.

[27]  F. Hong,et al.  Molecular mechanism of hippocampal apoptosis of mice following exposure to titanium dioxide nanoparticles. , 2011, Journal of hazardous materials.

[28]  M. Catauro,et al.  TiO2/PCL hybrid materials synthesized via sol-gel technique for biomedical applications. , 2015, Materials science & engineering. C, Materials for biological applications.

[29]  W. Auttachoat,et al.  Route-dependent systemic and local immune effects following exposure to solutions prepared from titanium dioxide nanoparticles , 2014, Journal of immunotoxicology.

[30]  Manuela Semmler-Behnke,et al.  Supplementary information Size dependent translocation and fetal accumulation of gold nanoparticles from maternal blood in the rat , 2014 .

[31]  M. Radomski,et al.  CuO nanoparticles induce apoptosis by impairing the antioxidant defense and detoxification systems in the mouse hippocampal HT22 cell line: protective effect of crocetin. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[32]  Guping Tang,et al.  In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection , 2009, Journal of applied toxicology : JAT.

[33]  Edward A Gordon,et al.  Energy dispersive X‐ray analysis of titanium dioxide nanoparticle distribution after intravenous and subcutaneous injection in mice , 2009, Journal of applied toxicology : JAT.

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

[35]  Chao Liu,et al.  Neurotoxicological effects and the impairment of spatial recognition memory in mice caused by exposure to TiO2 nanoparticles. , 2010, Biomaterials.

[36]  Carsten Schilde,et al.  Biological Surface Coating and Molting Inhibition as Mechanisms of TiO2 Nanoparticle Toxicity in Daphnia magna , 2011, PloS one.

[37]  F. Hong,et al.  Neurotoxic characteristics of spatial recognition damage of the hippocampus in mice following subchronic peroral exposure to TiO2 nanoparticles. , 2014, Journal of hazardous materials.

[38]  T. Sasaki,et al.  Tissue distribution and clearance of intravenously administered titanium dioxide (TiO2) nanoparticles , 2014, Nanotoxicology.

[39]  Qiang Wu,et al.  Transfer of quantum dots from pregnant mice to pups across the placental barrier. , 2010, Small.

[40]  A. R. Kulkarni,et al.  Targeted nanoparticles for drug delivery through the blood-brain barrier for Alzheimer's disease. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[41]  F. Hong,et al.  Mechanisms of TiO2 nanoparticle-induced neuronal apoptosis in rat primary cultured hippocampal neurons. , 2015, Journal of biomedical materials research. Part A.

[42]  M. Iqbal,et al.  TGF-β1 regulation of multidrug resistance P-glycoprotein in the developing male blood-brain barrier. , 2014, Endocrinology.

[43]  M Laird Forrest,et al.  Effects of nanomaterial physicochemical properties on in vivo toxicity. , 2009, Advanced drug delivery reviews.

[44]  C. Chuang,et al.  Silver nanoparticles affect on gene expression of inflammatory and neurodegenerative responses in mouse brain neural cells. , 2015, Environmental research.

[45]  Wei Liu,et al.  Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure. , 2009, Toxicology letters.

[46]  J. Borrell,et al.  Anandamide inhibits Theiler's virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB1 receptors , 2011, Journal of Neuroinflammation.

[47]  E. Fabian,et al.  Tissue distribution and toxicity of intravenously administered titanium dioxide nanoparticles in rats , 2008, Archives of Toxicology.

[48]  Mahmoud Hosseini,et al.  Maternal exposure to titanium dioxide nanoparticles during pregnancy; impaired memory and decreased hippocampal cell proliferation in rat offspring. , 2014, Environmental toxicology and pharmacology.

[49]  L. Lehtonen,et al.  Prenatal smoking exposure and the risk of psychiatric morbidity into young adulthood. , 2010, Archives of general psychiatry.

[50]  Håkan Wallin,et al.  Correction: Effects of prenatal exposure to surface-coated nanosized titanium dioxide (UV-Titan). A study in mice , 2011, Particle and Fibre Toxicology.

[51]  T. Sandström,et al.  Genetic variation influences immune responses in sensitive rats following exposure to TiO2 nanoparticles. , 2014, Toxicology.

[52]  Wei Li,et al.  Potential neurological lesion after nasal instillation of TiO(2) nanoparticles in the anatase and rutile crystal phases. , 2008, Toxicology letters.

[53]  Y. Schneider,et al.  Engineered Nanomaterials in Food: Implications for Food Safety and Consumer Health , 2014, International journal of environmental research and public health.

[54]  Eran Perlson,et al.  Retrograde axonal transport: pathways to cell death? , 2010, Trends in Neurosciences.

[55]  Paul R. Lockman,et al.  Nanoparticle Surface Charges Alter Blood–Brain Barrier Integrity and Permeability , 2004, Journal of drug targeting.

[56]  S. Ahmadian,et al.  Toxicity and interaction of titanium dioxide nanoparticles with microtubule protein. , 2008, Acta biochimica et biophysica Sinica.

[57]  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.

[58]  R. Handy,et al.  Uptake of different crystal structures of TiO₂ nanoparticles by Caco-2 intestinal cells. , 2014, Toxicology letters.

[59]  F. Hong,et al.  Nano-sized titanium dioxide-induced splenic toxicity: a biological pathway explored using microarray technology. , 2014, Journal of hazardous materials.

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

[61]  Yasuo Yoshioka,et al.  Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. , 2011, Nature nanotechnology.

[62]  Tao Zhang,et al.  Effects of nanoparticle zinc oxide on spatial cognition and synaptic plasticity in mice with depressive-like behaviors , 2012, Journal of Biomedical Science.

[63]  C. Murphy,et al.  Anisotropic metal nanoparticles: Synthesis, assembly, and optical applications. , 2005, The journal of physical chemistry. B.

[64]  Dual regulation by ethanol of the inhibitory effects of ketamine on spinal NMDA-induced pressor responses in rats , 2012, Journal of Biomedical Science.

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

[66]  L. F. Espinosa-Cristóbal,et al.  Toxicity, distribution, and accumulation of silver nanoparticles in Wistar rats , 2013, Journal of Nanoparticle Research.

[67]  W. E. Ford,et al.  Optical and electrical properties of three-dimensional interlinked gold nanoparticle assemblies. , 2004, Journal of the American Chemical Society.

[68]  K. Jensen,et al.  Airway exposure to silica-coated TiO2 nanoparticles induces pulmonary neutrophilia in mice. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[69]  Navid B. Saleh,et al.  Nanosize Titanium Dioxide Stimulates Reactive Oxygen Species in Brain Microglia and Damages Neurons in Vitro , 2007, Environmental health perspectives.

[70]  Wenjie Zhang,et al.  Antibacterial property, angiogenic and osteogenic activity of Cu-incorporated TiO2 coating. , 2014, Journal of materials chemistry. B.

[71]  A. H. Maia,et al.  Biomarker Evaluation in Fish After Prolonged Exposure to Nano-TiO2: Influence of Illumination Conditions and Crystal Phase. , 2015, Journal of nanoscience and nanotechnology.

[72]  P. Westerhoff,et al.  Titanium dioxide nanoparticles in food and personal care products. , 2012, Environmental science & technology.

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

[74]  Yingjun Zhou,et al.  Chronic exposure to nanoparticulate TiO2 causes renal fibrosis involving activation of the Wnt pathway in mouse kidney. , 2015, Journal of agricultural and food chemistry.

[75]  J. O. Flores-Flores,et al.  Titanium dioxide nanoparticles induce an adaptive inflammatory response and invasion and proliferation of lung epithelial cells in chorioallantoic membrane. , 2015, Environmental research.

[76]  Yunman Li,et al.  Penetration of verapamil across blood brain barrier following cerebral ischemia depending on both paracellular pathway and P-glycoprotein transportation , 2013, Neurochemistry International.

[77]  Alex Weir,et al.  Biological Response to Nano-Scale Titanium Dioxide (TiO2): Role of Particle Dose, Shape, and Retention , 2013, Journal of toxicology and environmental health. Part A.

[78]  Yankai Xia,et al.  Titanium dioxide nanoparticles alter cellular morphology via disturbing the microtubule dynamics. , 2015, Nanoscale.

[79]  W. D. de Jong,et al.  Tissue distribution and elimination after oral and intravenous administration of different titanium dioxide nanoparticles in rats , 2014, Particle and Fibre Toxicology.

[80]  I. Parkin,et al.  TiO2-coated CoCrMo: improving the osteogenic differentiation and adhesion of mesenchymal stem cells in vitro. , 2015, Journal of biomedical materials research. Part A.

[81]  BIOLOGICAL EFFECT OF INTRANASALLY INSTILLED TITANIUM DIOXIDE NANOPARTICLES ON FEMALE MICE , 2008 .

[82]  M. O’Connor,et al.  Psychiatric conditions associated with prenatal alcohol exposure. , 2009, Developmental disabilities research reviews.

[83]  E. Candelario-Jalil,et al.  Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia , 2009, Neuroscience.

[84]  Lei Zhao,et al.  TiO2 nanoparticles promote beta-amyloid fibrillation in vitro. , 2008, Biochemical and biophysical research communications.

[85]  Ken Takeda,et al.  Prenatal exposure to titanium dioxide nanoparticles increases dopamine levels in the prefrontal cortex and neostriatum of mice. , 2010, The Journal of toxicological sciences.

[86]  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.

[87]  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.

[88]  J. Pedraza-Chaverri,et al.  Cell cycle synchronization reveals greater G2/M-phase accumulation of lung epithelial cells exposed to titanium dioxide nanoparticles , 2014, Environmental Science and Pollution Research.

[89]  Thomas E. Nichols,et al.  Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease , 2014, BMC Genomics.

[90]  Yonghua Cui,et al.  Prenatal exposure to nanoparticulate titanium dioxide enhances depressive-like behaviors in adult rats. , 2014, Chemosphere.

[91]  J. Kanno,et al.  Comparative study of toxic effects of anatase and rutile type nanosized titanium dioxide particles in vivo and in vitro. , 2014, Asian Pacific journal of cancer prevention : APJCP.

[92]  T. Sasaki,et al.  Dose-dependent clearance kinetics of intratracheally administered titanium dioxide nanoparticles in rat lung. , 2014, Toxicology.

[93]  Emilie Brun,et al.  In vitro evidence of dysregulation of blood-brain barrier function after acute and repeated/long-term exposure to TiO(2) nanoparticles. , 2012, Biomaterials.

[94]  Shean-Jen Chen,et al.  Running exercise delays neurodegeneration in amygdala and hippocampus of Alzheimer’s disease (APP/PS1) transgenic mice , 2015, Neurobiology of Learning and Memory.

[95]  K. Fujioka,et al.  Effects of Silica and Titanium Oxide Particles on a Human Neural Stem Cell Line: Morphology, Mitochondrial Activity, and Gene Expression of Differentiation Markers , 2014, International journal of molecular sciences.

[96]  A. Grierson,et al.  Role of axonal transport in neurodegenerative diseases. , 2008, Annual review of neuroscience.

[97]  Lixia Sang,et al.  TiO2 nanoparticles as functional building blocks. , 2014, Chemical reviews.

[98]  Tieqiao Wen,et al.  A protein interaction network for the analysis of the neuronal differentiation of neural stem cells in response to titanium dioxide nanoparticles. , 2010, Biomaterials.

[99]  Jian Ling,et al.  Nanotoxicity of silver nanoparticles to red blood cells: size dependent adsorption, uptake, and hemolytic activity. , 2015, Chemical research in toxicology.

[100]  Masato Saito,et al.  Nanomaterial-based electrochemical biosensors for medical applications , 2008 .

[101]  Ru Bai,et al.  Rutile TiO₂ particles exert size and surface coating dependent retention and lesions on the murine brain. , 2011, Toxicology letters.

[102]  Sumit Kumar,et al.  Titanium oxide (TiO2) nanoparticles in induction of apoptosis and inflammatory response in brain , 2015, Journal of Nanoparticle Research.

[103]  F. Hong,et al.  TiO2 Nanoparticles Induced Hippocampal Neuroinflammation in Mice , 2014, PloS one.

[104]  J. Teixeira,et al.  Comparative study on effects of two different types of titanium dioxide nanoparticles on human neuronal cells. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[105]  E. Park,et al.  Nanosized titanium dioxide enhanced inflammatory responses in the septic brain of mouse , 2010, Neuroscience.

[106]  L. Mir,et al.  Subacute toxicity of titanium dioxide (TiO2) nanoparticles in male rats: emotional behavior and pathophysiological examination , 2015, Environmental Science and Pollution Research.

[107]  J. Kelly,et al.  Effects of material morphology on the phototoxicity of nano-TiO2 to bacteria. , 2013, Environmental science & technology.

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

[109]  Jie Wu,et al.  Involvement of JNK and P53 activation in G2/M cell cycle arrest and apoptosis induced by titanium dioxide nanoparticles in neuron cells. , 2010, Toxicology letters.

[110]  S. Grandi,et al.  Comparative cellular toxicity of titanium dioxide nanoparticles on human astrocyte and neuronal cells after acute and prolonged exposure. , 2015, Neurotoxicology.

[111]  R. Ransohoff,et al.  A Protective Role for ELR+ Chemokines during Acute Viral Encephalomyelitis , 2009, PLoS pathogens.

[112]  G. Barucca,et al.  DNA damage and repair following In vitro exposure to two different forms of titanium dioxide nanoparticles on trout erythrocyte , 2014, Environmental toxicology.

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

[114]  F. Michetti,et al.  Increased expression of Aquaporin 4 in the rat hippocampus and cortex during trimethyltin-induced neurodegeneration , 2014, Neuroscience.

[115]  Yaolin Xu,et al.  Surface charge and dosage dependent potential developmental toxicity and biodistribution of iron oxide nanoparticles in pregnant CD-1 mice. , 2014, Reproductive toxicology.

[116]  Xiaobo Chen,et al.  Titanium dioxide nanomaterials: synthesis, properties, modifications, and applications. , 2007, Chemical reviews.

[117]  Yu Tian Wang,et al.  Synaptic plasticity in learning and memory: stress effects in the hippocampus. , 2008, Progress in brain research.

[118]  R. López-Marure,et al.  Titanium dioxide nanoparticles induce strong oxidative stress and mitochondrial damage in glial cells. , 2014, Free radical biology & medicine.

[119]  N. Wu,et al.  Particle length-dependent titanium dioxide nanomaterials toxicity and bioactivity , 2009, Particle and Fibre Toxicology.

[120]  G. Terentyuk,et al.  Penetration of Pegylated Gold Nanoparticles Through Rat Placental Barrier , 2014, Bulletin of Experimental Biology and Medicine.

[121]  Majid Montazer,et al.  Functionality of nano titanium dioxide on textiles with future aspects: focus on wool , 2011 .

[122]  Shunqing Xu,et al.  Apoptosis induced by titanium dioxide nanoparticles in cultured murine microglia N9 cells , 2009 .