Environmental Science and Pollution Research

, Volume 22, Issue 7, pp 5519–5530 | Cite as

Cytotoxicity, DNA damage, and apoptosis induced by titanium dioxide nanoparticles in human non-small cell lung cancer A549 cells

  • Yurong WangEmail author
  • Haiyan Cui
  • Jiaping Zhou
  • Fengjuan Li
  • Jinju Wang
  • Mianhua Chen
  • Qingdai LiuEmail author
Research Article


Concerns about the risk of titanium dioxide nanoparticles (TiO2 NPs) to human health and environment are gradually increasing due to their wide range of applications. In this study, cytotoxicity, DNA damage, and apoptosis induced by TiO2 NPs (5 nm) in A549 cells were investigated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays revealed the time- and concentration-dependent cytotoxic effects of TiO2 NPs in a concentration range of 50 to 200 μg/mL. A statistically significant (p < 0.05) induction in DNA damage was observed by the comet assay in cells exposed to 50 to 200 μg/mL TiO2 NPs for 48 h. A significant (p < 0.05) induction in micronucleus formation determined by 4,6-diamino-2-phenylindole (DAPI) staining was also observed at the above concentrations. Typical apoptotic morphological feature and apoptotic bodies in A549 cells induced by TiO2 NPs at the above concentrations were observed by scanning electron micrographs. Flow cytometric analysis demonstrated that the cells treated with TiO2 NPs at concentrations of 100 and 200 μg/mL showed a significant G2/M phase arrest and a significant increased proportion of apoptotic cells. TiO2 NPs also disrupted the mitochondrial membrane potential evaluated by rhodamine 123 staining. Further analysis by quantitative real-time PCR (qRT-PCR) indicated that the expression of caspase-3 and caspase-9 messenger RNA (mRNA) was increased significantly at the concentrations of 100 and 200 μg/mL TiO2 NPs for 48 h. Taken together, these findings suggest that TiO2 NPs can inhibit A549 cell proliferation, cause DNA damage, and induce apoptosis via a mechanism primarily involving the activation of the intrinsic mitochondrial pathway. The assay data provide strong evidence that TiO2 NPs can induce cytotoxicity, significant DNA damage, and apoptosis of A549 cells, suggesting that exposure to TiO2 NPs could cause cell injury and be hazardous to health.


Nanosized titanium dioxide A549 cells DNA damage Apoptosis Cytotoxicity 



This study was supported by the National Natural Science Foundation of China (Grant No. 31101357).


  1. Adrie C, Bachelet M, Vayssier-Taussat M, Russo-Marie F, Bouchaert I, Adib-Conquy M, Cavaillon JM, Pinsky MR, Dhainaut JF, Polla BS (2001) Mitochondrial membrane potential and apoptosis peripheral blood monocytes in severe human sepsis. Am J Respir Crit Care Med 164(3):389–395CrossRefGoogle Scholar
  2. Albanese A, Tang PS, Chan WC (2012) The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng 14:1–16CrossRefGoogle Scholar
  3. Andersson PO, Lejon C, Ekstrand-Hammarstrom B, Akfur C, Ahlinder L, Bucht A, Osterlund L (2011) Polymorph- and size-dependent uptake and toxicity of TiO2 nanoparticles in living lung epithelial cells. Small 7(4):514–523CrossRefGoogle Scholar
  4. Aueviriyavit S, Phummiratch D, Kulthong K, Maniratanachote R (2012) Titanium dioxide nanoparticles-mediated in vitro cytotoxicity does not induce hsp70 and grp78 expression in human bronchial epithelial A549 cells. Biol Trace Elem Res 149:123–132. doi: 10.1007/s12011-012-9403-z CrossRefGoogle Scholar
  5. Autrup H, Foldberg R, Deng F, Dang DA, Olesen P (2009) Ag and TiO2 nanoparticles induce oxidative stress in A549 cells. Toxicol Let 189(SI):S181–S181. doi: 10.1016/j. toxlet. 2009.06.633 CrossRefGoogle Scholar
  6. Bauer S, Park J, Faltenbacher J, Berger S, von der Mark K, Schmuki P (2009) Size selective behavior of mesenchymal stem cells on ZrO2 and TiO2 nanotube arrays. Integr Biol 1:525–532CrossRefGoogle Scholar
  7. Bermudez E, Mangum JB, Wong BA, Asgharian B, Hext PM, Warheit DB, Everitt JI (2004) Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol Sci 77:347–357CrossRefGoogle Scholar
  8. Bernardeschi M, Guidi P, Scarcelli V, Frenzilli G, Nigro M (2010) Genotoxic potential of TiO2 on bottle nose dolphin leukocytes. Anal Bioanal Chem 396(2):619–623CrossRefGoogle Scholar
  9. Bhattacharya K, Davoren M, Boertz J, Schins RP, Hoffmann E, Dopp E (2009) Titanium dioxide nanoparticles induce oxidative stress and DNA-adduct formation but not DNA-breakage in human lung cells. Part Fibre Toxicol 6:17CrossRefGoogle Scholar
  10. Chen X, Mao SS (2007) Titanium dioxide nanomaterials: synthesis, properties, modifications, and applications. Chem Rev 107(7):2891–2959CrossRefGoogle Scholar
  11. Chen HW, Su SF, Chien CT, Lin WH, Yu SL, Chou CC, Chen JJ, Yang PC (2006) Titanium dioxide nanoparticles induce emphysema-like lung injury in mice. FASEB J 20(13):2393–2395CrossRefGoogle Scholar
  12. Choi HS, Ashitate Y, Lee JH, Kim SH, Matsui A, Insin N, Bawendi MG, Semmler-Behnke M, Frangioni JV, Tsuda A (2010) Rapid translocation of nanoparticles from the lung airspaces to the body. Nat Biotechnol 28:1300–1303CrossRefGoogle Scholar
  13. Cui Y, Gong X, Duan Y, Li N, Hu R, Liu H, Hong M, Zhou M, Wang L, Wang H, Hong F (2010) Hepatocyte apoptosis and its molecular mechanisms in mice caused by titanium dioxide nanoparticles. J Hazard Mater 183(1–3):874–880. doi: 10.1016/j.jhazmat. 2010.07.109 CrossRefGoogle Scholar
  14. Cui HY, Wang CL, Wang YR, Li ZJ, Zhang YN, Chen MH, Li FJ (2014) Pleurotus nebrodensis polysaccharide induces apoptosis in human non-small cell lung cancer A549 cells. Carbohyd Polym. doi: 10.1016/j.carbpol.2014.01.001 Google Scholar
  15. Falck GC, Lindberg HK, Suhonen S, Vippola M, Vanhala E, Catalan J, Savolainen K, Norppa H (2009) Genotoxic effects of nanosized and fine TiO2. Hum Exp Toxicol 28(6–7):339–352. doi: 10.1177/0960327109105163 CrossRefGoogle Scholar
  16. Ferin J, Oberdörster G, Penney DP (1992) Pulmonary retention of ultrafine and fine particles in rats. Am J Respir Cell Mol Biol 6:535–542CrossRefGoogle Scholar
  17. Freyre-Fonsecaa V, Delgado-Buenrostroa NL, Gutiérrez-Cirlosb EB, Calderón-Torresa CM, Cabellos-Avelarb T, Sánchez-Pérezc Y, Pinzónd E, Torresd I, Molina-Jijóne E, Zazuetaf C, Pedraza-Chaverrie J, García-Cuéllarc CM, Yolanda I, Chirino YI (2011) Titanium dioxide nanoparticles impair lung mitochondrial function. Toxicol Lett 202(2):111–119. doi: 10.1016/j.toxlet.2011.01.025 CrossRefGoogle Scholar
  18. Gao G, Ze Y, Li B, Zhao X, Zhang T, Sheng L, Hu R, Gui S, Sang X, Sun Q, Cheng J, Cheng Z, Wang L, Tang M, Hong F (2012) Ovarian dysfunction and gene-expressed characteristics of female mice caused by long-term exposure to titanium dioxide nanoparticles. J HAZARD MATER 243:19–27CrossRefGoogle Scholar
  19. Gao A, Hang R, Huang X, Zhao L, Zhang X, Wang L, Tang B, Ma S, Chu PK (2014) The effects of titania nanotubes with embedded silver oxide nanoparticles on bacteria and osteoblasts. Biomaterials. Pii, S0142-9612 (14) 00088-X. DOI:  10.1016/j.biomaterials.2014. 01.058
  20. Gheshlaghi ZN, Riazi GH, Ahmadian S, Ghafari M, Mahinpour R (2008) Toxicity and interaction of titanium dioxide nanoparticles with microtubule protein. Acta Biochim Biophys Sin (Shanghai) 40(9):777–782CrossRefGoogle Scholar
  21. Ghosh M, Bandyopadhyay M, Mukherjee A (2010) Genotoxicity of titanium dioxide (TiO2) nanoparticles at two trophic levels: plant and human lymphocytes. Chemosphere 81(10):1253–1262. doi: 10.1016/j.chemosphere.2010.09.022 CrossRefGoogle Scholar
  22. Gui SX, Zhang ZL, Zheng L, Cui YL, Liu XR, Li N, Hong FS (2011) Molecular mechanism of kidney injury of mice caused by exposure to titanium dioxide nanoparticles. J Hazard Mater 195:365–370CrossRefGoogle Scholar
  23. Gurr JR, Wang ASS, Chen CH, Jan KY (2005) Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells. Toxicology 213(1–2):66–73CrossRefGoogle Scholar
  24. Heemels MO (2000) The biochemistry of apoptosis. Nature 407(6805):770–776. doi: 10.1038/ 35037710 CrossRefGoogle Scholar
  25. Heinrich U, Fuhst R, Rittinghausen S, Creutzenberg O, Bellman B, Koch W, Levsen K (1995) Chronic inhalation exposure of Wistar rats and two different strains of mice to diesel engine exhaust, carbon black, and titanium dioxide. Inhal Toxicol 7:533–556CrossRefGoogle Scholar
  26. Hoet PH, Brüske-Hohlfeld I, Salata OV (2004) Nanoparticles—known and unknown health risks. J Nanobiotechnol 2:12. doi: 10.1186/1477-3155-2-12 CrossRefGoogle Scholar
  27. Hsiao IL, Huang YJ (2011) Improving the interferences of methyl thiazolyl tetrazolium and IL-8 assays in assessing the cytotoxicity of nanoparticles. J Nanosci Nanotechnol 11(6):5228–5233. doi: 10.1166/jnn.2011.4132 CrossRefGoogle Scholar
  28. Husain M, Saber AT, Guo C, Jacobsen NR, Jensen KA, Yauk CL, Williams A, Vogel U, Wallin H, Halappanavar S (2013) Pulmonary instillation of low doses of titanium dioxide nanoparticles in mice leads to particle retention and gene expression changes in the absence of inflammation. Toxicol Appl Pharmacol 269(3):250–62. doi: 10.1016/j.taap.2013.03.018 CrossRefGoogle Scholar
  29. Hussain S, Thomassen LC, Ferecatu I, Borot MC, Andreau K, Martens JA, Fleury J, Baeza-Squiban A, Marano F, Boland S (2010) Carbon black and titanium dioxide nanoparticles elicit distinct apoptotic pathways in bronchial epithelial cells. Part Fibre Toxicol 7:10CrossRefGoogle Scholar
  30. IRAC (2006) IARC: cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and vanadium pentoxide. IARC. Monogr. Eval. Carcinog. Risks Hum. 86Google Scholar
  31. Jeon YM, Park SK, Kim WJ, Ham JH, Lee MY (2011) The effects of TiO2 nanoparticles on the protein expression in mouse lung. Mol Cell Toxicol 7:283–289. doi: 10.1007/s13273-011-0034-9 CrossRefGoogle Scholar
  32. Jin CY, Zhu BS, Wang XF, Lu QH (2008) Cytotoxicity of titanium dioxide nanoparticles in mouse fibroblast cells. Chem Res Toxicol 21:1871–1877. doi: 10.1021/tx800179f CrossRefGoogle Scholar
  33. Kang SJ, Kim BM, Lee YJ, Chung HW (2008) Titanium dioxide nanoparticles trigger P53-mediated damage response in peripheral blood lymphocytes. Environ Mol Mutagen 49(5):399–405. doi: 10.1002/em.20399 CrossRefGoogle Scholar
  34. Landsiedel R, Ma-Hock L, Van Ravenzwaay B, Schulz M, Wiench K, Champ S, Schulte S, Wohlleben W, Oesch F (2010) Gene toxicity studies on titanium dioxide and zinc oxide nanomaterials used for UV-protection in cosmetic formulations. Nanotoxicology 4:364–381CrossRefGoogle Scholar
  35. Lee YS, Yoon S, Yoon HJ, Lee K, Yoon HK, Lee JH, Song CW (2009) Inhibitor of differentiation 1 (Id1) expression attenuates the degree of TiO2-induced cytotoxicity in H1299 non-small cell lung cancer cells. Toxicol Lett 189:191–199CrossRefGoogle Scholar
  36. Li N, Duan Y, Hong M, Zheng L, Fei M, Zhao X, Wang J, Cui Y, Liu H, Cai J, Gong S, Wang H, Hong F (2010) Spleen injury and apoptotic pathway in mice caused by titanium dioxide nanoparticules. Toxicol Lett 195(2–3):161–168CrossRefGoogle Scholar
  37. Limbach LK, Li YC, Grass RN, Brunner TJ, Hintermann MA, Muller M, Gunther D, Stark WJ (2005) Oxide nanoparticle uptake in human lung fibroblasts: effects of particle size, agglomeration, and diffusion at low concentrations. Environ Sci Tech 39:9370–376CrossRefGoogle Scholar
  38. Lindberg HK, Falck GC, Catalán J, Koivisto AJ, Suhonen S, Järventaus H, Rossi EM, Nykäsenoja H, Peltonen Y, Moreno C, Alenius H, Tuomi T, Savolainen KM, Norppa H (2012) Genotoxicity of inhaled nanosized TiO2 in mice. Mutat Res 745(1–2):58–64CrossRefGoogle Scholar
  39. Liu HT, Ma LL, Zhao JF, Liu J, Yan JY, Ruan J, Hong FS (2009) Biochemical toxicity of nano-anatase TiO2 particles in mice. Biol Trace Elem Res 129:170–180CrossRefGoogle Scholar
  40. Liu SC, Xu LJ, Zhang T, Ren GG, Yang Z (2010) Oxidative stress and apoptosis induced by nanosized titanium dioxide in PC12 cells. Toxicol 267(1–3):172–177. doi: 10.1016/j.tox 2009.11.012 CrossRefGoogle Scholar
  41. Lowe SW, Lin AW (2000) Apoptosis in cancer. Carcinogenesis 21:485–95CrossRefGoogle Scholar
  42. McLeish IA, Bell S, McKay T, Tenev T, Marani M, Lemoine NR (2003) Expression of Smac/DIABLO in ovarian carcinoma cells induces apoptosis via a caspase-9-mediated pathway. Exp Cell Res 286(2):186–198CrossRefGoogle Scholar
  43. Meena R, Paulraj R (2012) Oxidative stress mediated cytotoxicity of TiO2 nano anatase in liver and kidney of Wistar rat. Toxico Enviro Chem 94(1):146–163. doi: 10.1080/02772248. 2011. 638441 CrossRefGoogle Scholar
  44. Meng H, Xia T, George S, Nel AE (2009) A predictive toxicological paradigm for the safety assessment of nanomaterials. ACS Nano 3(7):1620–1677. doi: 10.1021/nn9005973 CrossRefGoogle Scholar
  45. Mondal D, Nguyen L, Oh IH, Lee BT (2013) Microstructure and biocompatibility of composite biomaterials fabricated from titanium and tricalcium phosphate by spark plasma sintering. J, Biomed, Mater, Res, A 101(5):1489–1501. doi: 10.1002/jbm.a.34455 CrossRefGoogle Scholar
  46. Monteiller C, Tran L, MacNee W, Faux S, Jones A, Miller B, Donaldson K (2007) The pro-inflammatory effects of low-toxicity low-solubility particles, nanoparticles and fine particles, on epithelial cells in vitro: the role of surface area. Occup Environ Med 64(9):609–615. doi: 10.1136/oem.2005.024802 CrossRefGoogle Scholar
  47. Naya M, Kobayashi N, Ema M, Kasamoto S, Fukumuro M, Takami S, Nakajima M, Hayashi M, Nakanishi J (2012) In vivo genotoxicity study of titanium dioxide nanoparticles using comet assay following intratracheal instillation in rats. Regul Toxicol Pharmacol 62:1–6CrossRefGoogle Scholar
  48. Noël A, Charbonneau M, Cloutier Y, Tardif R, Truchon G (2013) Rat pulmonary responses to inhaled nano-TiO2: effect of primary particle size and agglomeration state. Part Fibre Toxicol 10:48. doi: 10.1186/1743-8977-10-48 CrossRefGoogle Scholar
  49. Oberdörster G, Ferin J, Lehnert BE (1994) Correlation between particle size, in vivo particle persistence, and lung injury. Environ Health Perspect 102:173–179CrossRefGoogle Scholar
  50. Oberdörster G, Finkelstein JN, Johnston C, Gelein R, Cox C, Baggs R, Elder AC (2000) Acute pulmonary effects of ultrafine particles in rats and mice. Res Rep Health Eff Inst 96:5–74, disc. 75–86Google Scholar
  51. 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 6:437–445CrossRefGoogle Scholar
  52. Park J, Bauer S, von der Mark K, Schmuki P (2007a) Nanosize and vitality: TiO2 nanotube diameter directs cell fate. Nano Lett 7:1686–1691CrossRefGoogle Scholar
  53. Park S, Lee YK, Jung M, Kim KH, Chung N, Ahn EK, Lim Y, Lee KH (2007b) Cellular toxicity of various inhalable metal nanoparticles on human alveolar epithelial cells. Inhal Toxicol 19(1):59–65. doi: 10.1080/08958370701493282 CrossRefGoogle Scholar
  54. Park EJ, Yi J, Chung KH, Ryu DY, Choi J, Park K (2008) Oxidative stress and apoptosis induced by titanium dioxide nanoparticles in cultured BEAS-2B cells. Toxicol Lett 180:222–229CrossRefGoogle Scholar
  55. Park J, Bauer S, Schlegel KA, Neukam FW, von der Mark K, Schmuki P (2009) TiO2 nanotube surfaces: 15 nm—an optimal length scale of surface topography for cell adhesion and differentiation. Small 5:666–671CrossRefGoogle Scholar
  56. Park EJ, Shim HW, Lee GH, Kim JH, Kim DW (2013) Comparison of toxicity between the different-type TiO2 nanowires in vivo and in vitro. Arch Toxicol 87:1219–1230. doi: 10.1007/s00204-013-1019-3 CrossRefGoogle Scholar
  57. Petkovic J, Zegura B, Stevanovic M, Drnovsek N, Uskokovic D, Novak S, Filipic M (2011) DNA damage and alterations in expression of DNA damage responsive genes induced by TiO2 nanoparticles in human hepatoma HepG2 cells. Nanotoxicology 5(3):341–353. doi: 10.3109/17435390.2010.507316 CrossRefGoogle Scholar
  58. Porter AG, Janicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6(2):99–104CrossRefGoogle Scholar
  59. Porter DW, Wu N, Hubbs A, Mercer R, Funk K, Meng F, Li J, Wolfarth M, Battelli L, Friend S, Andrew M, Hamilton R, Sriram K, Yang F, Castranova V, Holian A (2013) Differential mouse pulmonary dose- and time course-responses to titanium dioxide nanospheres and nanobelts. Toxicol Sci 131:179–193CrossRefGoogle Scholar
  60. Ramkumar KM, Manjula C, GnanaKumar G, Kanjwal MA, Sekar TV, Paulmurugan R, Rajaguru P (2012) Oxidative stress-mediated cytotoxicity and apoptosis induction by TiO2 nanofibers in HeLa cells. Eur J Pharm Biopharm 81(2):324–333. doi: 10.1016/j.ejpb. 2012.02.013 CrossRefGoogle Scholar
  61. Reeves JF, Davies SJ, Dodd NJF, Jha AN (2008) Hydroxyl radicals (OH) are associated with titanium dioxide (TiO2) nanoparticle-induced cytotoxicity and oxidative DNA damage in fish cells. Mutat Res 640(1–2):113–122. doi: 10.1016/j.mrfmmm.2007.12.010 CrossRefGoogle Scholar
  62. Renwick LC, Brown D, Clouter A, Donaldson K (2004) Increased inflammation and altered macrophage chemotactic responses caused by two ultrafine particle types. Occup Environ Med 61(5):442–447CrossRefGoogle Scholar
  63. Rivera-Chacon DM, Alvarado-Velez M, Acevedo-Morantes CY, Singh SP, Gultepe E, Nagesha D, Sridhar S, Ramirez-Vick JE (2013) Fibronectin and vitronectin promote human fetal osteoblast cell attachment and proliferation on nanoporous titanium surfaces. J Biomed Nanotechnol 9(6):1092–1097CrossRefGoogle Scholar
  64. Rotoli BM, Bussolati O, Costa AL, Blosi M, Cristo DL, Zanello PP, Bianchi MG, Visigalli R, Bergamaschi E (2012) Comparative effects of metal oxide nanoparticles on human airway epithelial cells and macrophages. J Nanopart Res 14(9):1069. doi: 10.1007/s 1051- 12-1069-0 CrossRefGoogle Scholar
  65. Sang XZ, Zheng L, Sun QQ, Li N, Cui YL, Hu RP, Gao GD, Cheng Z, Cheng J, Gui SX, Liu HT, Zhang ZL, Hong FS (2012) The chronic spleen injury of mice following long-term exposure to titanium dioxide nanoparticles. J Biomed Mater Res A 100(4):894–902CrossRefGoogle Scholar
  66. Sayes CM, Wahi R, Kurian PA, Liu Y, West JL, Ausman KD, Warheit DB, Colvin VL (2006) Correlating nanoscale titania structure with toxicity: a cytotoxicity and inflammatory response study with human dermal fibroblasts and human lung epithelial cells. Toxicol Sci 92:174–185CrossRefGoogle Scholar
  67. Shi Y, Wang F, He J, Yadav S, Wang H (2010) Titanium dioxide nanoparticles cause apoptosis in BEAS-2B cells through the caspase 8/t-Bid-independent mitochondrial pathway. Toxicol Lett 2010(196):21–27CrossRefGoogle Scholar
  68. Shukla RK, Sharma V, Pandey AK, Singh S, Sultana S, Dhawan A (2011) ROS mediated genotoxicity induced by titanium dioxide nanoparticles in human epidermal cells. Toxicol In Vitro 25:231–241CrossRefGoogle Scholar
  69. Shukla RK, Kumar A, Gurbani D, Pandey AK, Singh S, Dhawan A (2013) TiO2 nanoparticles induce oxidative DNA damage and apoptosis in human liver cells. Nanotoxicology 7(1):48–60. doi: 10.3109/17435390.2011.629747 CrossRefGoogle Scholar
  70. Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantification of low levels of DNA damage in individual cells. Exp Cell Res 175(1):184–191CrossRefGoogle Scholar
  71. Singh S, Shi TM, Duffin R, Albrecht C, Van Berlo D, Hoehr D, Fubini B, Martra G, Fenoglio I, Borm PJA, Schins RPF (2007) 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 particle. Toxicol Appl Pharmacol 222(2):141–151. doi: 10.1016/j.taap.2007.05.001 CrossRefGoogle Scholar
  72. Stringer B, Kobzik L (1998) Environmental particulate-mediated cytokine production in lung epithelial cells (A549): role of preexisting inflammation and oxidant stress. J Toxicol Environ Health a 55(1):31–44CrossRefGoogle Scholar
  73. Tang Y, Wang FD, Jin C, Liang H, Zhong X, Yang YJ (2013) Mitochondrial injury induced by nanosized titanium dioxide in A549 cells and rats. Environ Toxicol Pharmacol 36(1):66–72. doi: 10.1016/j.etap.2013.03.006 CrossRefGoogle Scholar
  74. Tedja R, Marquis C, Lim M, Amal R (2011) Biological impacts of TiO2 on human lung cell lines A549 and H1299: particle size distribution effects. J Nanopart Res 13(9):3801–3813. doi: 10.1007/s11051-011-0302-6 CrossRefGoogle Scholar
  75. Trouiller B, Reliene R, Westbrook A, Solaimani P, Schiestl RH (2009) Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice. Cancer Res 69(22):8784–8789. doi: 10.1158/0008-5472 CrossRefGoogle Scholar
  76. Turkez H (2011) The role of ascorbic acid on titanium dioxide-induced genetic damage assessed by the comet assay and cytogenetic tests. Exp Toxicol Pathol 63(5):453–457CrossRefGoogle Scholar
  77. Unfried K, Albrecht C, Klotz L-O, Von Mikecz A, Grether-Beck S, Schins R (2007) Cellular responses to nanoparticles: target structures and mechanisms. Nanotoxicology 1:52–71CrossRefGoogle Scholar
  78. 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 22:1689–1696. doi: 10.1016/j.tiv.2008.07.002 CrossRefGoogle Scholar
  79. Wang JJ, Sanderson BJS, Wang H (2007a) Cyto- and genotoxicity of ultrafine TiO2 particles in cultured human lymphoblastoid cells. Mutat Res 628(2):99–106CrossRefGoogle Scholar
  80. Wang JX, Zhou GQ, Chen CY, Yu HW, Wang TC, Ma YM, Jia G, Gao YX, Li B, Sun J, Li YF, Jia F, Zhao YL, Chai ZF (2007b) Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 168(2):176–185CrossRefGoogle Scholar
  81. Warheit DB, Webb TR, Sayes CM, Colvin VL, Reed KL (2006) Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: toxicity is not dependent upon particle size and surface area. Toxicol Sci 91:227–236CrossRefGoogle Scholar
  82. Watanabe M, Okada M, Kudo Y, Tonori Y, Niitsuya M, Sato T, Aizawa Y, Kotani M (2002) Differences in the effects of fibrous and particulate titanium dioxide on alveolar macrophages of Fischer 344 rats. J Toxicol Environ Health A 65:1047–1060CrossRefGoogle Scholar
  83. Xia T, Kovochich M, Brant J, Hotze M, Semp J, Oberley T, Sioutas C, Yeh JI, Wiesner MR, Nel AE (2006) Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano ett 6:1794–807Google Scholar
  84. Yakovlev AG, Knoblach SM, Fan L, Fox GB, Goodnight R, Faden AI (1997) Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci 17(19):74l5–7424Google Scholar
  85. Yeo MK, Kang M (2012) The biological toxicities of two crystalline phases and differential sizes of TiO2 nanoparticles during zebrafish embryogenesis development. Mol Cell Toxicol 8:317–326. doi: 10.1007/s13273-012-0039-z CrossRefGoogle Scholar
  86. Zhao F, Zhao Y, Liu Y, Chang XL, Chen CY, Zhao YL (2011) Cellular uptake, intracellular trafficking, and cytotoxicity of nanomaterials. Small 7:1322–1337CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Key Laboratory of Food Nutrition and Safety, Ministry of Education, School of Food Engineering and BiotechnologyTianjin University of Science and TechnologyTianjinChina

Personalised recommendations