Abstract
Titanium dioxide nanoparticles (TiO2 NPs) are widely used for their whiteness and opacity in several applications such as food colorants, drug additives, biomedical ceramic, and implanted biomaterials. Research on the neurobiological response to orally administered TiO2 NPs is still limited. In our study, we investigate the effects of anatase TiO2 NPs on the brain of Wistar rats after oral intake. After daily intragastric administration of anatase TiO2 NPs (5–10 nm) at 0, 50, 100, and 200 mg/kg body weight (BW) for 60 days, the coefficient of the brain, acethylcholinesterase (AChE) activities, the level of interleukin 6 (IL-6), and the expression of glial fibrillary acidic protein (GFAP) were assessed to quantify the brain damage. The results showed that high-dose anatase TiO2 NPs could induce a downregulated level of AChE activities and showed an increase in plasmatic IL-6 level as compared to the control group accompanied by a dose-dependent decrease inter-doses, associated to an increase in the cerebral IL-6 level as a response to a local inflammation in brain. Furthermore, we observed elevated levels of immunoreactivity to GFAP in rat cerebral cortex. We concluded that oral intake of anatase TiO2 NPs can induce neuroinflammation and could be neurotoxic and hazardous to health.
Similar content being viewed by others
References
An L, Liu S, Yang Z, Zhang T (2012) Cognitive impairment in rats induced by nano-CuO and its possible mechanisms. Toxicol Lett 213:220–227
Bai R, Zhang L, Liu Y, Li B, Wang L, Wang P, Autrup H, Beer C, Chen C (2014) Integrated analytical techniques with high sensitivity for studying brain translocation and potential impairment induced by intranasally instilled copper nanoparticles. Toxicol Lett 226:70–80
Banks CN, Lein PJ (2012) A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation. Neurotoxicology 33:575–584
Belaid-Nouira Y, Bakhta H, Samoud S, Trimech M, Haouas Z, Ben Cheikh H (2013) A novel insight on chronic AlCl3 neurotoxicity through IL-6 and GFAP expressions: modulating effect of functional food fenugreek seeds. Nutr Neurosci 16:218–224
Booth GE, Kinrade EF, Hidalgo A (2000) Glia maintain follower neuron survival during drosophila CNS development. Development 127:237–244
Campbell A, Yang EY, Tsai-Turton M, Bondy SC (2002) Pro-inflammatory effects of aluminum in human glioblastoma cells. Brain Res 933:60–65
Chen Z, Wang Y, Zhuo L, Chen S, Zhao L, Luan X, Wang H, Jia G (2015) Effect of titanium dioxide nanoparticles on the cardiovascular system after oral administration. Toxicol Lett 239:123–130
Cho WS, Kang BC, Lee JK, Jeong J, Che JH, Seok SH (2013) Comparative absorption, distribution, and excretion of titanium dioxide and zinc oxide nanoparticles after repeated oral administration. Part Fibre Toxicol 10:9
Czajka M, Sawicki K, Sikorska K, Popek S, Kruszewski M, Kapka-Skrzypczak L (2015) Toxicity of titanium dioxide nanoparticles in central nervous system. Toxicol in Vitro 29:1042–1052
Delgado M, Jonakait GM, Ganea D (2002) Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit chemokine production in activated microglia. Glia 39:148–161
Deng ZJ, Mortimer G, Schiller T, Musumeci A, Martin D, Minchin RF (2009) Differential plasma protein binding to metal oxide nanoparticles. Nanotechnology 20
Disdier C, Devoy J, Cosnefroy A, Chalansonnet M, Herlin-Boime N, Brun E, Lund A, Mabondzo A (2015) Tissue biodistribution of intravenously administrated titanium dioxide nanoparticles revealed blood-brain barrier clearance and brain inflammation in rat. Part Fibre Toxicol 12:27
Duncan TV (2011) Applications of nanotechnology in food packaging and food safety: barrier materials, antimicrobials and sensors. J Colloid Interface Sci 363:1–24
Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdörster G (2006) Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect 114:1172–1178
Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95
Erickson MA, Dohi K, Banks WA (2012) Neuroinflammation: a common pathway in CNS diseases as mediated at the blood-brain barrier. Neuroimmunomodulation 19:121–130
Erta M, Quintana A, Hidalgo J (2012) Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 8:1254–1266
Grissa I, Elghoul J, Ezzi L, Chakroun S, Kerkeni E, Hassine M, El Mir L, Mehdi M, Ben Cheikh H, Haouas Z (2015) Anemia and genotoxicity induced by sub-chronic intragastric treatment of rats with titanium dioxide nanoparticles. Mutat Res Genet Toxicol Environ Mutagen 794:25–31
Guizzetti M, Moore NH, Giordano G, Costa LG (2008) Modulation of neuritogenesis by astrocyte muscarinic receptors. J Biol Chem 283:31884–31897
Hanada S, Fujioka K, Inoue Y, Kanaya F, Manome Y, Yamamoto K (2014) Cell-based in vitro blood-brain barrier model can rapidly evaluate nanoparticles’ brain permeability in association with particle size and surface modification. Int J Mol Sci 15:1812–1825
Hu R, Gong X, Duan Y, Li N, Che Y, Cui Y, Zhou M, Liu C, Wang H, Hong F (2010) Neurotoxicological effects and the impairment of spatial recognition memory in mice caused by exposure to TiO2 nanoparticles. Biomaterials 31:8043–8050
Hu R, Zheng L, Zhang T, Gao G, Cui Y, Cheng Z, Cheng J, Hong M, Tang M, Hong F (2011) Molecular mechanism of hippocampal apoptosis of mice following exposure to titanium dioxide nanoparticles. J Hazard Mater 191:32–40
Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH (2000) Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley neuropathology consortium. Mol Psychiatry 5:142–149
Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81:302–313
Leite PE, Pereira MR, Granjeiro JM (2015) Hazard effects of nanoparticles in central nervous system: searching for biocompatible nanomaterials for drug delivery. Toxicol in Vitro 29:1653–1660
Long TC, Tajuba J, Sama P, Saleh N, Swartz C, Parker J, Hester S, Lowry GV, Veronesi B (2007) Nanosize titanium dioxide stimulates reactive oxygen species in brain microglia and damages neurons in vitro. Environ Health Perspect 115:1631–1637
Ma L, Liu J, Li N, Wang J, Duan Y, Yan J, Liu H, Wang H, Hong F (2010) Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. Biomaterials 31:99–105
McCall MA, Gregg RG, Behringer RR, Brenner M, Delaney CL, Galbreath EJ, Zhang CL, Pearce RA, Chiu SY, Messing A (1996) Targeted deletion in astrocyte intermediate filament (Gfap) alters neuronal physiology. Proc Natl Acad Sci U S A 93:6361–6366
Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C (2004) Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol 16:437–445
Ozawa A, Kadowaki E, Haga Y, Sekiguchi H, Hemmi N, Kaneko T, Maki T, Sakabe K, Hara S, Yamamoto M, Arishima K, Sakaue M (2013) Acetylcholine esterase is a regulator of GFAP expression and a target of dichlorvos in astrocytic differentiation of rat glioma C6 cells. Brain Res 1537:37–45
Ramesh G, MacLean AG, Philipp MT (2013) Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediat Inflamm 2013:480739
Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C (1997) Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature 389:725–730
Rotundo RL (2003) Expression and localization of acetylcholinesterase at the neuromuscular junction. J Neurocytol 32:743–766
Shi H, Magaye R, Castranova V, Zhao J (2013) Titanium dioxide nanoparticles: a review of current toxicological data. Part Fibre Toxicol 10
Shin JA, Lee EJ, Seo SM, Kim HS, Kang JL, Park EM (2010) Nanosized titanium dioxide enhanced inflammatory responses in the septic brain of mouse. Neuroscience 165:445–454
Skalska J, Frontczak-Baniewicz M, Strużyńska L (2015) Synaptic degeneration in rat brain after prolonged oral exposure to silver nanoparticles. Neurotoxicology 46:145–154
Song B, Liu J, Feng X, Wei L, Shao L (2015) A review on potential neurotoxicity of titanium dioxide nanoparticles. Nanoscale Res Lett 10:1042
Song B, Zhang Y, Liu J, Feng X, Zhou T, Shao L (2016) Unraveling the neurotoxicity of titanium dioxide nanoparticles: focusing on molecular mechanisms Beilstein J. Nanotechnology 7:645–654
Sousa F, Mandal S, Garrovo C, Astolfo A, Bonifacio A, Latawiec D, Menk RH, Arfelli F, Huewel S, Legname G, Galla HJ, Krol S (2010) Functionalized gold nanoparticles: a detailed in vivo multimodal microscopic brain distribution study. Nanoscale 2:2826–2834
Spooren A, Kolmus K, Laureys G, Clinckers R, De Keyser J, Haegeman G, Gerlo S (2011) Interleukin-6, a mental cytokine. Brain Res Rev 67:157–183
Stasiuk M, Bartosiewicz D, Kozubek A (2008) Inhibitory effect of some natural and semisynthetic phenolic lipids upon acetylcholinesterase activity. Food Chem 108:996–1001
Takanaga H, Yoshitake T, Yatabe E, Hara S, Kunimoto M (2004) Beta-naphthoflavone disturbs astrocytic differentiation of C6 glioma cells by inhibiting autocrine interleukin-6. J Neurochem 90:750–757
Wang J, Zhou G, Chen C, Yu H, Wang T, Ma Y, Jia G, Gao Y, Li B, Sun J, Li Y, Jiao F, Zhao Y, Chai Z (2007) Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 168:176–185
Wang J, Chen C, Liu Y, Jiao F, Li W, Lao F, Li Y, Li B, Ge C, Zhou G, Gao Y, Zhao Y, Chai Z (2008a) Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anatase and rutile crystal phases. Toxicol Lett 183:72–80
Wang J, Liu Y, Jiao F, Lao F, Li W, Gu Y, Li Y, Ge C, Zhou G, Li B, Zhao Y, Chai Z, Chen C (2008b) Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO(2) nanoparticles. Toxicology 254:82–90
Wang Z, Zhao J, Li F, Gao D, Xing B (2009) Adsorption and inhibition of acetylcholinesterase by different nanoparticles. Chemosphere 77:67–73
Worek F, Reiter G, Eyer P, Szinicz L (2002) Reactivation kinetics of acetylcholinesterase from different species inhibited by highly toxic organophosphates. Arch Toxicol 76:523–529
Wu J, Ding T, Sun J (2013) Neurotoxic potential of iron oxide nanoparticles in the rat brain striatum and hippocampus. Neurotoxicology 34:243–253
Xue Y, Wu J, Sun J (2012) Four types of inorganic nanoparticles stimulate the inflammatory reaction in brain microglia and damage neurons in vitro. Toxicol Lett 214:91–98
Yarlagadda A, Alfson E, Clayton AH (2009) The blood brain barrier and the role of cytokines in neuropsychiatry. Psychiatry (Edgmont) 6:18–22
Ze Y, Sheng L, Zhao X, Hong J, Ze X, Yu X, Pan X, Lin A, Zhao Y, Zhang C, Zhou Q, Wang L, Hong F (2014) TiO2 nanoparticles induced hippocampal neuroinflammation in mice. PLoS One 9(3):e92230
Acknowledgments
This work was supported by funds allocated to the Research Unit of Histology and Genetic UR12ES10 by the “Ministère Tunisien de l’Enseingement Supérieur et de la Recherché Scientifique”. The authors thank Pr Fadwa Neffati from the Laboratory of Biochemistry of the University Hospital “Fattouma Bourguiba” of Monastir, for her help in the determination of protein total.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
“All procedures performed in studies involving animals were in accordance with the guidelines for animals care of the “Faculty of Medicine of Monastir”, Tunisia at which the studies were conducted.”
The manuscript does not contain clinical studies or patient data.
Additional information
Responsible editor: Philippe Garrigues
Highlights
• TiO2 NPs could induce a downregulated level of AChE activities.
• TiO2 NPs provoke an increase in plasmatic IL-6 level as compared to the control group accompanied by a dose-dependent decrease inter-doses, associated to an increase in the cerebral IL-6 level as a response to a local inflammation in the brain.
• TiO2 NPs increase GFAP expression and reflect astrocytic stimulation as an inflammatory response.
Rights and permissions
About this article
Cite this article
Grissa, I., Guezguez, S., Ezzi, L. et al. The effect of titanium dioxide nanoparticles on neuroinflammation response in rat brain. Environ Sci Pollut Res 23, 20205–20213 (2016). https://doi.org/10.1007/s11356-016-7234-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-016-7234-8