Titanium dioxide (TiO2) has been vastly used commercially, especially as white pigment in paints, colorants, plastics, coatings, cosmetics. Certain industrial uses TiO2 in diameter <100 nm. There are three common exposure routes for TiO2: (i) inhalation exposure, (ii) exposure via gastrointestinal tract, (iii) dermal exposure. Inhalation and gastrointestinal exposure appear to be the most probable ways of exposure, although nanoparticle (NP) penetration is limited. However, the penetration rate may increase substantially when the tissue is impaired. When TiO2 NPs migrate into the circulatory system, they can be distributed into all tissues including brain. In brain, TiO2 lead to oxidative stress mediated by the microglia phagocytic cells which respond to TiO2 NPs by the production and release of superoxide radicals that convert to multiple reactive oxygen species (ROS). The ROS production may also cause the damage of blood-brain barrier which then becomes more permeable for NPs. Moreover, several studies have showed neuron degradation and the impairment of spatial recognition memory and learning abilities in laboratory rodent exposed to TiO2 NPs.

Center for Evidence based Health Care Taipei Medical University Shuang Ho Hospital No 291 Zhongzheng Road Zhonghe District New Taipei City 23561 Taiwan

Department of Clinical Biochemistry Jessenius Faculty of Medicine in Martin Kollárova 2 03659 Martin Slovak Republic

Laboratory of Neurobiology and Molecular Psychiatry Department of Biochemistry Faculty of Science Masaryk University Kotlářská 2 611 37 Brno Czech Republic

Laboratory of Neurobiology and Pathological Physiology Institute of Animal Physiology and Genetics Academy of Sciences of the Czech Republic Veveří 97 602 00 Brno Czech Republic

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Popov A.P. Priezzhev A.V. Lademann J. et al.: ‘TiO2 nanoparticles as an effective UV‐B radiation skin‐protective compound in sunscreens’, J. Phys. D Appl. Phys., 2005, 38, (15), pp. 2564 –2570

Shah S.N.A. Shah Z. Hussain M. et al.: ‘Hazardous effects of titanium dioxide nanoparticles in ecosystem’, Bioinorganic Chem. Appl., 2017, 4101735 PubMed PMC

Kreyling W.G. Semmler‐Behnke M. Takenaka S. et al.: ‘Differences in the biokinetics of inhaled nano‐ versus micrometer‐sized particles’, Acc. Chem. Res., 2013, 46, (3), pp. 714 –722 PubMed PMC

Grassian V.H. O'Shaughnessy P.T. Adamcakova‐Dodd A. et al.: ‘Inhalation exposure study of titanium dioxide nanoparticles with a primary particle size of 2 to 5 Nm’, Environ. Health Perspect., 2007, 115, (3), pp. 397 –402 PubMed PMC

Yu K.N. Sung J.H. Lee S. et al.: ‘Inhalation of titanium dioxide induces endoplasmic reticulum stress‐mediated autophagy and inflammation in mice’, Food Chem. Toxicol., 2015, 85, pp. 106 –113 PubMed

Bermudez E. Mangum J.B. Asgharian B. et al.: ‘Long‐term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles’, Toxicol. Sci., 2002, 70, (1), pp. 86 –97 PubMed

Bermudez E. Mangum J.B. Wong B.A. et al.: ‘Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles’, Toxicol. Sci., 2004, 77, (2), pp. 347 –357 PubMed

Oberdorster G. Ferin J. Soderholm S. et al.: ‘Increased pulmonary toxicity of inhaled ultrafine particles ‐ due to lung overload alone’, Inhaled Particles VII, 1994, 38, (1), pp. 295 –302

Nemmar A. Hoet P.H.M. Vanquickenborne B. et al.: ‘Passage of inhaled particles into the blood circulation in humans’, Circulation, 2002, 105, (4), pp. 411 –414 PubMed

Wiebert P. Sanchez‐Crespo A. Seitz J. et al.: ‘Negligible clearance of ultrafine particles retained in healthy and affected human lungs’, Eur. Respir. J., 2006, 28, (2), pp. 286 –290 PubMed

Geiser M. Rothen‐Rutishauser B. Kapp N. et al.: ‘Ultrafine particles cross cellular membranes by nonphagocytic mechanisms in lungs and in cultured cells’, Environ. Health Perspect., 2005, 113, (11), pp. 1555 –1560 PubMed PMC

Muhlfeld C. Geiser M. Kapp N. et al.: ‘Re‐evaluation of pulmonary titanium dioxide nanoparticle distribution using the ‘relative deposition index’: evidence for clearance through microvasculature’, Part Fibre Toxicol., 2007, 4, p. 7 PubMed PMC

Geiser M.: ‘Update on macrophage clearance of inhaled micro‐ and nanoparticles’, J. Aerosol. Med. Pulm. Drug Deliv., 2010, 23, (4), pp. 207 –217 PubMed

Li Y. Li J. Yin J. et al.: ‘Systematic influence induced by 3 Nm titanium dioxide following intratracheal instillation of mice’, J. Nanosci. Nanotechnol., 2010, 10, (12), pp. 8544 –8549 PubMed

Eydner M. Schaudien D. Creutzenberg O. et al.: ‘Impacts after inhalation of nano‐ and fine‐sized titanium dioxide particles: morphological changes, translocation within the rat lung, and evaluation of particle deposition using the relative deposition index’, Inhal. Toxicol., 2012, 24, (9), pp. 557 –569 PubMed

Liu H. Ma L. Zhao J. et al.: ‘Biochemical toxicity of nano‐anatase TiO2 particles in mice’, Biol. Trace Elem. Res., 2009, 129, (1–3), pp. 170 –180 PubMed

Chen J.Y. Dong X. Zhao J. et al.: ‘In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection’, J. Appl. Toxicol., 2009, 29, (4), pp. 330 –337 PubMed

Wang J. Liu Y. Jiao F. et al.: ‘Time‐dependent translocation and potential impairment on central nervous system by intranasally instilled TiO(2) nanoparticles’, Toxicology, 2008, 254, (1–2), pp. 82 –90 PubMed

Wang J. Chen C. Liu Y. et al.: ‘Potential neurological lesion after nasal instillation of TiO(2) nanoparticles in the anatase and rutile crystal phases’, Toxicol. Lett., 2008, 183, (1–3), pp. 72 –80 PubMed

Yah C.S. Simate G.S. Iyuke S.E.: ‘Nanoparticles toxicity and their routes of exposures’, Pak. J. Pharm. Sci., 2012, 25, (2), pp. 477 –491 PubMed

Martirosyan A. Polet M. Bazes A. et al.: ‘Food nanoparticles and intestinal inflammation: a real risk?’. InTech, 2012, Inflammatory Bowel Disease edition

Jani P.U. McCarthy D.E. Florence A.T.: ‘Titanium dioxide (rutile) particle uptake from the Rat Gi tract and translocation to systemic organs after oral administration’, Int. J. Pharm., 1994, 105, (2), pp. 157 –168

Wang J. Zhou G. Chen C. et al.: ‘Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration’, Toxicol. Lett., 2007, 168, (2), pp. 176 –185 PubMed

Janer G. Mas del Molino E. Fernandez‐Rosas E. et al.: ‘Cell uptake and oral absorption of titanium dioxide nanoparticles’, Toxicol. Lett., 2014, 228, (2), pp. 103 –110 PubMed

MacNicoll A. Kelly M. Aksoy H. et al.: ‘A study of the uptake and biodistribution of nano‐titanium dioxide using in vitro and in vivo models of oral intake’, J. Nanoparticle Res., 2015, 17, (2)

Tassinari R. Cubadda F. Moracci G. et al.: ‘Oral, short‐term exposure to titanium dioxide nanoparticles in Sprague‐Dawley rat: focus on reproductive and endocrine systems and spleen’, Nanotoxicology, 2014, 8, (6), pp. 654 –662 PubMed

Mohammadipour A. Fazel A. Haghir H. et al.: ‘Maternal exposure to titanium dioxide nanoparticles during pregnancy; impaired memory and decreased hippocampal cell proliferation in rat offspring’, Environ. Toxicol. Pharmacol., 2014, 37, (2), pp. 617 –625 PubMed

Powell J.J. Faria N. Thomas‐McKay E. et al.: ‘Origin and fate of dietary nanoparticles and microparticles in the gastrointestinal tract’, J. Autoimmunity, 2010, 34, (3), pp. J226 –J233 PubMed

Senzui M. Tamura T. Miura K. et al.: ‘Study on penetration of titanium dioxide (TiO2) nanoparticles into intact and damaged skin in vitro’, J. Toxicol. Sci., 2010, 35, (1), pp. 107 –113 PubMed

Tan M.H. Commens C.A. Burnett L. et al.: ‘A pilot study on the percutaneous absorption of microfine titanium dioxide from sunscreens’, Australas J. Dermatol., 1996, 37, (4), pp. 185 –187 PubMed

Lademann J. Weigmann H. Rickmeyer C. et al.: ‘Penetration of titanium dioxide microparticles in a sunscreen formulation into the horny layer and the follicular orifice’, Skin Pharmacol. Appl. Skin Physiol., 1999, 12, (5), pp. 247 –256 PubMed

Newman M.D. Stotland M. Ellis J.I.: ‘The safety of nanosized particles in titanium dioxide‐ and zinc oxide‐based sunscreens’, J. Am. Acad. Dermatol., 2009, 61, (4), pp. 685 –692 PubMed

Sadrieh N. Wokovich A.M. Gopee N.V. et al.: ‘Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano‐ and submicron‐size TiO2 particles’, Toxicol. Sci., 2010, 115, (1), pp. 156 –166 PubMed PMC

Bennat C. Muller‐Goymann C.C.: ‘Skin penetration and stabilization of formulations containing microfine titanium dioxide as physical UV filter’, Int. J. Cosmet. Sci., 2000, 22, (4), pp. 271 –283 PubMed

Wu J. Liu W. Xue C. et al.: ‘Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure’, Toxicol. Lett., 2009, 191, (1), pp. 1 –8 PubMed

Liu X. Sui B. Sun J.: ‘Size‐and shape‐dependent effects of titanium dioxide nanoparticles on the permeabilization of the blood–brain barrier’, J. Mater. Chem. B, 2017, 5, (48), pp. 9558 –9570 PubMed

Brun E. Carriere M. Mabondzo A.: ‘In vitro evidence of dysregulation of blood‐brain barrier function after acute and repeated/long‐term exposure to TiO2 nanoparticles’, Biomaterials, 2012, 33, (3), pp. 886 –896 PubMed

Chen I.C. Hsiao I.L. Lin H.C. et al.: ‘Influence of silver and titanium dioxide nanoparticles on in vitro blood‐brain barrier permeability’, Environ. Toxicol. Pharmacol., 2016, 47, pp. 108 –118 PubMed

Disdier C. Chalansonnet M. Gagnaire F. et al.: ‘Brain inflammation, blood brain barrier dysfunction and neuronal synaptophysin decrease after inhalation exposure to titanium dioxide nano‐Aerosol in aging rats’, Sci. Rep., 2017, 7, (1), p. 12196 PubMed PMC

Allouni Z.E. Hol P.J. Cauqui M.A. et al.: ‘Role of physicochemical characteristics in the uptake of TiO2 nanoparticles by fibroblasts’, Toxicol. In Vitro, 2012, 26, (3), pp. 469 –479 PubMed

Andersson‐Willman B. Gehrmann U. Cansu Z. et al.: ‘Effects of subtoxic concentrations of TiO2 and Zno nanoparticles on human lymphocytes, dendritic cells and exosome production’, Toxicol. Appl. Pharmacol., 2012, 264, (1), pp. 94 –103 PubMed

Halamoda Kenzaoui B. Chapuis Bernasconi C. Guney‐Ayra S. et al.: ‘Induction of oxidative stress, lysosome activation and autophagy by nanoparticles in human brain‐derived endothelial cells’, Biochem. J., 2012, 441, (3), pp. 813 –821 PubMed

Wang Y. Aker W.G. Hwang H.M. et al.: ‘A study of the mechanism of in vitro cytotoxicity of metal oxide nanoparticles using catfish primary hepatocytes and human Hepg2 cells’, Sci. Total Environ., 2011, 409, (22), pp. 4753 –4762 PubMed PMC

Long T.C. Tajuba J. Sama P. et al.: ‘Nanosize titanium dioxide stimulates reactive oxygen species in brain microglia and damages neurons in vitro’, Environ. Health Perspect., 2007, 115, (11), pp. 1631 –1637 PubMed PMC

Long T.C. Saleh N. Tilton R.D. et al.: ‘Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (Bv2): implications for nanoparticle neurotoxicity’, Environ. Sci. Technol., 2006, 40, (14), pp. 4346 –4352 PubMed

Rothen‐Rutishauser B.M. Schurch S. Haenni B. et al.: ‘Interaction of fine particles and nanoparticles with red blood cells visualized with advanced microscopic techniques’, Environ. Sci. Technol., 2006, 40, (14), pp. 4353 –4359 PubMed

Takeda K. Suzuki K.I. Ishihara A. et al.: ‘Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems’, J. Health Sci., 2009, 55, (1), pp. 95 –102

Afaq F. Abidi P. Matin R. et al.: ‘Cytotoxicity, pro‐oxidant effects and antioxidant depletion in rat lung alveolar macrophages exposed to ultrafine titanium dioxide’, J. Appl. Toxicol., 1998, 18, (5), pp. 307 –312 PubMed

Gurr J.R. Wang A.S. Chen C.H. et al.: ‘Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells’, Toxicology, 2005, 213, (1–2), pp. 66 –73 PubMed

Sayes C.M. Wahi R. Kurian P.A. et al.: ‘Correlating nanoscale titania structure with toxicity: a cytotoxicity and inflammatory response study with human dermal fibroblasts and human lung epithelial cells’, Toxicolog. Sci., 2006, 92, (1), pp. 174 –185 PubMed

Wang J.J. Sanderson B.J. Wang H.: ‘Cyto‐ and genotoxicity of ultrafine TiO2 particles in cultured human lymphoblastoid cells’, Mutat. Res., 2007, 628, (2), pp. 99 –106 PubMed

Zhang Y. Yu W. Jiang X. et al.: ‘Analysis of the cytotoxicity of differentially sized titanium dioxide nanoparticles in murine Mc3t3‐E1 preosteoblasts’, J. Mater. Sci. Mater. Med., 2011, 22, (8), pp. 1933 –1945 PubMed

Lee K.P. Trochimowicz H.J. Reinhardt C.F.: ‘Pulmonary response of rats exposed to titanium dioxide (TiO2) by inhalation for two years’, Toxicol. Appl. Pharmacol., 1985, 79, (2), pp. 179 –192 PubMed

Warheit D.B. Brock W.J. Lee K.P. et al.: ‘Comparative pulmonary toxicity inhalation and instillation studies with different TiO2 particle formulations: impact of surface treatments on particle toxicity’, Toxicol. Sci., 2005, 88, (2), pp. 514 –524 PubMed

Kwon S. Yang Y.S. Yang H.S. et al.: ‘Nasal and pulmonary toxicity of titanium dioxide nanoparticles in rats’, Toxicol. Res., 2012, 28, (4), pp. 217 –224 PubMed PMC

Iavicoli I. Leso V. Bergamaschi A.: ‘Toxicological effects of titanium dioxide nanoparticles: a review of in vivo studies’, J. Nanomater., 2012, 2012 PubMed

Grissa I. Guezguez S. Ezzi L. et al.: ‘The effect of titanium dioxide nanoparticles on neuroinflammation response in rat brain’, Environ. Sci. Pollut. Res., 2016, 23, (20), pp. 20205 –20213 PubMed

Jia X. Wang S. Zhou L. et al.: ‘The potential liver, brain, and embryo toxicity of titanium dioxide nanoparticles on mice’, Nanoscale Res. Lett., 2017, 12, (1), p. 478 PubMed PMC

Ma L.L. Liu J. Li N. et al.: ‘Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity’, Biomaterials, 2010, 31, (1), pp. 99 –105 PubMed

Umezawa M. Tainaka H. Kawashima N. et al.: ‘Effect of fetal exposure to titanium dioxide nanoparticle on brain development– brain region information’, J. Toxicol. Sci., 2012, 37, (6), pp. 1247 –1252 PubMed

Block M.L. Zecca L. Hong J.S.: ‘Microglia‐mediated neurotoxicity: uncovering the molecular mechanisms’, Nat. Rev. Neurosci., 2007, 8, (1), pp. 57 –69 PubMed

Xue Y. Wu J. Sun J.: ‘Four types of inorganic nanoparticles stimulate the inflammatory reaction in brain microglia and damage neurons in vitro’, Toxicol. Lett., 2012, 214, (2), pp. 91 –98 PubMed

Huerta‐Garcia E. Perez‐Arizti J.A. Marquez‐Ramirez S.G. et al.: ‘Titanium dioxide nanoparticles induce strong oxidative stress and mitochondrial damage in glial cells’, Free Radical Biol. Med., 2014, 73, pp. 84 –94 PubMed

Hu R.P. Gong X.L. Duan Y.M. et al.: ‘Neurotoxicological effects and the impairment of spatial recognition memory in mice caused by exposure to TiO2 nanoparticles’, Biomaterials, 2010, 31, (31), pp. 8043 –8050 PubMed

Irie T. Kawakami T. Sato K. et al.: ‘Sub‐toxic concentrations of nano‐ZnO and nano‐TiO2 suppress neurite outgrowth in differentiated PC12 cells’, J. Toxicolog. Sci., 2017, 42, (6), pp. 723 –729 PubMed

Zhou Y. Hong F. Tian Y. et al.: ‘Nanoparticulate titanium dioxide‐inhibited dendritic development is involved in apoptosis and autophagy of hippocampal neurons in offspring mice’, Toxicol. Res., 2017, 6, (6), pp. 889 –901 PubMed PMC

Shin J.A. Lee E.J. Seo S.M. et al.: ‘Nanosized titanium dioxide enhanced inflammatory responses in the septic brain of mouse’, Neuroscience, 2010, 165, (2), pp. 445 –454 PubMed

Hsiao I.L. Chang C.C. Wu C.Y.: ‘Indirect effects of TiO2 nanoparticle on neuron‐glial cell interactions’, Chemico‐Biolog. Interact., 2016, 254, pp. 34 –44 PubMed

Mohamed H.R. Hussien N.A.: ‘Genotoxicity studies of titanium dioxide nanoparticles (TiO2 NPs) in the brain of mice’, Scientifica, 2016. PubMed PMC

Shimizu M. Tainaka H. Oba T. et al.: ‘Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse’, Part Fibre Toxicol., 2009, 6, 6:20 doi:10.1186/1743‐8977‐6‐20 PubMed PMC

Mohammadipour A. Hosseini M. Fazel A. et al.: ‘The effects of exposure to titanium dioxide nanoparticles during lactation period on learning and memory of rat offspring’, Toxicol. Ind. Health, 2016, 32, (2), pp. 221 –228 PubMed

Cui Y. Chen X. Zhou Z. et al.: ‘Prenatal exposure to nanoparticulate titanium dioxide enhances depressive‐like behaviors in adult rats’, Chemosphere, 2014, 96, pp. 99 –104 PubMed

Hu Q. Guo F. Zhao F. et al.: ‘Effects of titanium dioxide nanoparticles exposure on parkinsonism in zebrafish larvae and PC12’, Chemosphere, 2017, 173, pp. 373 –379 PubMed

Milaneschi Y. Cesari M. Simonsick E.M. et al.: ‘Lipid peroxidation and depressed mood in community‐dwelling older men and women’, PLoS One, 2013, 8, (6), doi: 10.1371/journal.pone.0065406. Print 2013 PubMed PMC

Zhao Y. Zhao B.: ‘Oxidative stress and the pathogenesis of Alzheimer's disease’, Oxid. Med. Cell. Longev., 2013, 2013, p. 316523 PubMed PMC

Joshi Y.B. Pratico D.: ‘Lipid peroxidation in psychiatric illness: overview of clinical evidence’, Oxid. Med. Cell. Longev., 2014, 2014, p. 828702 PubMed PMC

Subchronic Inhalation of TiO2 Nanoparticles Leads to Deposition in the Lung and Alterations in Erythrocyte Morphology in Mice