Advertisement

Titanium oxide (TiO2) nanoparticles in induction of apoptosis and inflammatory response in brain

  • Ramovatar Meena
  • Sumit Kumar
  • R. PaulrajEmail author
Research Paper

Abstract

The ever increasing applications of engineered nanoparticles in 21st century cause serious concern about its potential health risks on living being. Regulatory health risk assessment of such particles has become mandatory for the safe use of nanomaterials in consumer products and medicines. In order to study the mechanism underlying the effects of nano-TiO2 (TiO2 nanoparticles) on the brain, wistar rats were administrated intravenously with various doses of nano-TiO2 (21 nm) through the caudal vein, once a week for 4 weeks and different parameters such as bioaccumulation of nano-TiO2, oxidative stress-mediated response, level of inflammatory markers such as NF-κB (p65), HSP 60, p38, nitric oxide, IFN-γ and TNF-α, and level of neurochemicals in brain as well as DNA damage and expression of apoptosis markers (p53, Bax, Bcl-2, and cyto c) were evaluated. Results show that the concentration of nano-TiO2 in the brain increased with increasing the doses of nano-TiO2. Oxidative stress and injury of the brain occurred as nano-TiO2 appeared to trigger a cascade of reactions such as inflammation, lipid peroxidation, decreases the activities of antioxidative enzymes and melatonin level, the reduction of glutamic acid, downregulated levels of acetylcholinesterase activities, and the increase in caspase-3 activity (a biomarker of apoptosis), DNA fragmentation, and apoptosis. It may be concluded that nano-TiO2 induces oxidative stress that leads to activation of inflammatory cytokines and an alteration in the level of neurotransmitters resulted in the induction of mitochondrial-mediated apoptosis.

Keywords

TiO2 nanoparticles Oxidative stress Inflammation Apoptosis Nanomedicine Health effects 

References

  1. Aebi HE (1984) Catalase in vitro. Meth Enzymol 105:121–126CrossRefGoogle Scholar
  2. Amurao CV (2006) Nanotechnology it’s a small and scary world after all. Occup Health Tracker 9:3–6Google Scholar
  3. Bialik S, Geenen DL, Sasson IE, Cheng R, Horner JW, Evans SM, Lord EM, Koch CJ, Kitsis RN (1997) Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53. J Clin Invest 100:1363–1372CrossRefGoogle Scholar
  4. Cardaci S, Filomeni G, Rotilio G, Ciriolo MR (2008) Reactive oxygen species mediated p53 activation and apoptosis induced by sodium nitroprusside in SHSYSY cells. Mol Pharmacol 74:1234–1245CrossRefGoogle Scholar
  5. Chowdhury R, Chowdhury S, Roychoudhury P, Mandal C, Chaudhuri K (2009) Arsenic induced apoptosis in malignant melanoma cells is enhanced by menadione through ROS generation, p38 signaling and p53 activation. Apoptosis 14:108–123CrossRefGoogle Scholar
  6. De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJ, Geertsma RE (2008) Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 29:1912–1919CrossRefGoogle Scholar
  7. Donaldson K, Stone V, Tran CL, Kreyling W, Borm PJA (2004) Nanotoxicology. J Occup Environ Med 61:727–728CrossRefGoogle Scholar
  8. Dunford R, Salinaro A, Cai L, Serpone N, Horikoshi S, Hidaka H, Knowland J (1997) Chemical oxidation and DNA damage catalysed by inorganic sunscreen ingredients. FEBS Lett 418:87–90CrossRefGoogle Scholar
  9. Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdorster G (2006) Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect 114:1172–1178CrossRefGoogle Scholar
  10. Epperly MW, Sikora CA, DeFilippi SJ, Gretton JA, Zhan Q, Kufe DW, Greenberger JS (2002) Manganese superoxide dismutase (SOD2) inhibits radiation-induced apoptosis by stabilization of the mitochondrial membrane. Radiat Res 157:568–577CrossRefGoogle Scholar
  11. Galluzzi L, Blomgren K, Kroemer G (2009) Mitochondrial membrane permeabilization in neuronal injury. Nat Rev Neurosci 10:481–494CrossRefGoogle Scholar
  12. Hayashi I, Morishita Y, Imai K, Nakamura M, Nakachi K, Hayashi T (2007) High-throughput spectrophotometric assay of reactive oxygen species in serum. Mutat Res 631:55–61CrossRefGoogle Scholar
  13. Hoet PH, Bruske-Hohlfeld I, Salata OV (2004) Nanoparticles: known and unknown health risks. J Nanobiotechnology 2:12CrossRefGoogle Scholar
  14. Holly AK, St-Clair DK (2009) Watching the watcher: regulation of p53 by mitochondria. Future Oncol 5:117–130CrossRefGoogle Scholar
  15. 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 31:8043–8050CrossRefGoogle Scholar
  16. Hu RP, Zheng L, Zhang T, Cui YL, Gao GD et al (2011) Molecular mechanism of hippocampal apoptosis of mice following exposure to titanium dioxide nanoparticles. J Hazard Mater 191:32–40CrossRefGoogle Scholar
  17. Jeon Y-M, Park S-K, Lee M-Y (2011) Toxicoproteomic identification of TiO2 nanoparticle-induced protein expression changes in mouse brain. Anim Cells Syst 15:107–114CrossRefGoogle Scholar
  18. Jin CY, Zhu BS, Wang XF, Lu QH (2008) Cytotoxicity of titanium dioxide nanoparticles in mouse fibroblast cells. Chem Res Toxicol 21:1871–1877CrossRefGoogle Scholar
  19. Lankveld DP, Oomen AG, Krystek P, Neigh A, Troost-de Jong A, Noorlander CW, Van Eijkeren JC, Geertsma RE, De Jong WH (2010) The kinetics of the tissue distribution of silver nanoparticles of different sizes. Biomaterials 31:8350–8361CrossRefGoogle Scholar
  20. Larsen ST, Roursgaard M, Jensen KA, Nielsen GD (2010) Nano titanium dioxide particles promote allergic sensitization and lung inflammation in mice. Basic Clin Pharmacol Toxicol 106:114–117CrossRefGoogle Scholar
  21. Linak WP, Miller CA, Wendt JO (2000) Comparison of particle size distributions and elemental partitioning from the combustion of pulverized coal and residual fuel oil. J Air Waste Manag Assoc 50(8):1532–1544CrossRefGoogle Scholar
  22. Liu R, Yin LH, Pu YP, Li YH, Zhang XQ, Liang GY, Li XB, Zhang J, Li YF, Zhang XY (2010) The immune toxicity of titanium dioxide on primary pulmonary alveolar macrophages relies on their surface area and crystal structure. J Nanosci Nanotechnol 10:8491–8499CrossRefGoogle Scholar
  23. Long TC, Saleh N, Tilton RD, Lowry GV, Veronesi B (2006) Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity. Environ Sci Technol 40:4346–4352CrossRefGoogle Scholar
  24. 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 115:1631–1637CrossRefGoogle Scholar
  25. 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 31:99–105CrossRefGoogle Scholar
  26. Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47:469–474CrossRefGoogle Scholar
  27. Mazzola L (2003) Commercializing nanotechnology. Nat Biotechnol 21:1137–1143CrossRefGoogle Scholar
  28. Meena R, Paulraj R (2012) Oxidative stress mediated cytotoxicity of TiO2 nanoparticles in different organs of wistar rat. Toxicol Environ Chem 94:146–163CrossRefGoogle Scholar
  29. Meena R, Pal R, Pradhan SN, Rani M, Paulraj R (2012) Comparative study of TiO2 and TiSiO4 nanoparticles induced oxidative stress and apoptosis of HEK-293 cells. Adv Mater Lett 3(6):459–465Google Scholar
  30. Mills GC (1960) Glutathione peroxidase and the destruction of hydrogen peroxide in animal tissues. Arch Biochem Biophys 86:1–5CrossRefGoogle Scholar
  31. Nel A, Xia T, Madler L, Li N (2006) Toxic potential of materials at the nanolevel. Science 311:622–627CrossRefGoogle Scholar
  32. Oberdorster G, Oberdorster E, Oberdorster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113:823–839CrossRefGoogle Scholar
  33. Paull R, Wolfe J, Hebert P, Sinkula M (2003) Investing in nanotechnology. Nat Biotechnol 21:1144–1147CrossRefGoogle Scholar
  34. Paulraj R, Behari J (2006) Single strand DNA breaks in rat brain cells exposed to microwave radiation. Mutat Res 596:76–80CrossRefGoogle Scholar
  35. Pimentel C, Batista-Nascimento L, Rodrigues-Pousada C, Menezes RA (2012) Oxidative stress in Alzheimer’s and Parkinson’s diseases: insights from the yeast Saccharomyces cerevisiae. Oxid Med Cell Longev 2012:9Google Scholar
  36. Puccetti G, Leblanc RM (2000) A sunscreen-tanning compromise: 3D visualization of the actions of titanium dioxide particles and dihydroxyacetone on human epiderm. Photochem Photobiol 71:426–430Google Scholar
  37. Rabuffetti M, Sciorati C, Tarozzo G, Clementi E, Manfredi AA, Beltramo M (2000) Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines. J Neurosci 20:4398–4404Google Scholar
  38. Radnai M, Csonka C, Dux L, Fazekas A (2000) Adsorption of human serum proteins to titanium dioxide. Fogorv Sz 93:329–334Google Scholar
  39. Rogers F, Arnott WP, Zielinska B, Sagebiel J, Kelly KE, Wagner D, Lighty JS, Sarofim AF (2005) Real-time measurements of jet aircract engine exhaust. J Air Waste Manag Assoc 55:583–593CrossRefGoogle Scholar
  40. Sang X et al (2012) The chronic spleen injury of mice following long-term exposure to titanium dioxide nanoparticles. J Biomed Mater Res A 100:894–902CrossRefGoogle Scholar
  41. Saquib Q, Al-Khedhairy AA, Siddiqui MA, Abou-Tarboush FM, Azam A, Musarrat J (2012) Titanium dioxide nanoparticles induced cytotoxicity, oxidative stress and DNA damage in human amnion epithelial (WISH) cells. Toxicol In Vitro 26:351–361CrossRefGoogle Scholar
  42. Sawada M, Imamura K, Nagatsu T (2006) Role of cytokines in inflammatory process in Parkinson’s disease. J Neural Transm Suppl 70:373–381CrossRefGoogle Scholar
  43. Schaffazick SR, Siqueira IR, Badejo AS, Jornada DS, Pohlmann AR, Netto CA, Guterres SS (2008) Incorporation in polymeric nanocapsules improves the antioxidant effect of melatonin against lipid peroxidation in mice brain and liver. Eur J Pharm Biopharm 69:64–71CrossRefGoogle Scholar
  44. Schanen BC, Karakoti AS, Seal S, Drake DR 3rd, Warren WL, Self WT (2009) Exposure to titanium dioxide nanomaterials provokes inflammation of an in vitro human immune construct. ACS Nano 3:2523–2532CrossRefGoogle Scholar
  45. Seames WS, Fernandez A, Wendt JO (2002) A study of fine particulate emissions from combustion of treated pulverized municipal sewage sludge. Environ Sci Technol 36(12):2772–2776 CrossRefGoogle Scholar
  46. Selmeczy Z, Vizi ES, Csoka B, Pacher P, Hasko G (2008) Role of nonsynaptic communication in regulating the immune response. Neurochem Int 52(1):52–59Google Scholar
  47. Sheng L, Ze Y, Wang L, Yu X, Hong J, Zhao X, Ze et al (2014) Mechanisms of TiO2 nanoparticle-induced neuronal apoptosis in rat primary cultured hippocampal neurons. J Biomed Mater Res Part A. doi: 10.1002/jbm.a.35263 Google Scholar
  48. Shi H, Magaye R, Castranova V, Zhao J (2013) Titanium dioxide nanoparticles: a review of current toxicological data. Part Fibre Toxicol 10:15CrossRefGoogle Scholar
  49. 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 165:445–454CrossRefGoogle Scholar
  50. Simon HU, Yehia AH, Schaffer FL (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5:415–418CrossRefGoogle Scholar
  51. Vamanu CI, Cimpan MR, Hol PJ, Sornes S, Lie SA, Gjerdet NR (2008) Induction of cell death by TiO2 nanoparticles: studies on a human monoblastoid cell line. Toxicol In Vitro 22:1689–1696CrossRefGoogle Scholar
  52. Varshney R, Kale RK (1990) Effects of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes. Int J Radiat Biol 58:733–743CrossRefGoogle Scholar
  53. Wang J, Zhou G, Chen C, Yu H, Wang T, Ma Y, Chai Z (2007a) Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 168:176–185CrossRefGoogle Scholar
  54. Wang JJ, Sanderson BJ, Wang H (2007b) Cyto- and genotoxicity of ultrafine TiO2 particles in cultured human lymphoblastoid cells. Mutat Res 628:99–106CrossRefGoogle Scholar
  55. Win-Shwe TT, Yamamoto S, Ahmed S, Kakeyama M, Kobayashi T, Fujimaki H (2006) Brain cytokine and chemokine mRNA expression in mice induced by intranasal instillation with ultrafine carbon black. Toxicol Lett 163:153–160CrossRefGoogle Scholar
  56. Xu Y, Yan J, Zhou P, Li J, Gao H, Xia Y, Wang Q (2012) Neurotransmitter receptors and cognitive dysfunction in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 97:1–13CrossRefGoogle Scholar
  57. Yao JC, Jiang ZZ, Duan WG, Huang JF, Zhang LY, Hu L, He L, Fu LI, Xiao YI, Shu B, Liu CH (2008) Involvement of mitochondrial pathway in triptolide-induced cytotoxicity in human normal liver L-02 cells. Biol Pharm Bull 31:592–597CrossRefGoogle Scholar
  58. Ze YG, Zheng L, Zhao XY, Gui SX, Sang XZ et al (2013) Molecular mechanism of titanium dioxide nanoparticles-induced oxidative injury in the brain of mice. Chemosphere 92:1183–1189CrossRefGoogle Scholar
  59. Ze Y, Sheng L, Zhao X, Hong J, Ze X et al (2014) TiO2 nanoparticles induced hippocampal neuroinflammation in mice. PLoS ONE 9(3):e92230. doi: 10.1371/journal.pone.0092230 CrossRefGoogle Scholar
  60. Zhang R, Piao MJ, Kim KC, Kim AD, Choi JY, Choi JH, Hyun JW (2012) Endoplasmic reticulum stress signaling is involved in silver nanoparticles induced apoptosis. Int J Biochem Cell Biol 44:224–232CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  1. 1.School of Environmental SciencesJawaharlal Nehru UniversityNew DelhiIndia

Personalised recommendations