Biological Trace Element Research

, Volume 173, Issue 2, pp 405–426 | Cite as

Toxic Effects of Titanium Dioxide Nanoparticles and Titanium Dioxide Bulk Salt in the Liver and Blood of Male Sprague-Dawley Rats Assessed by Different Assays

  • Muhammad Shakeel
  • Farhat JabeenEmail author
  • Naureen Aziz Qureshi
  • Muhammad Fakhr-e-Alam


This study evaluated the toxic effects of titanium dioxide (TiO2) bulk salt as well as its nanoparticles (NPs) in anatase phase with mean crystallite size of 36.15 nm in male Sprague-Dawley rats by subcutaneous injections at four different dose levels of either control (0), 50, 100 or 150 mg/kg of body weight (BW) of rat for 28 days on alternate days. Animal mortality, haematology, micronucleus assay, liver histology and activities of liver tissue damage markers like, alkaline phosphate (ALP), alanine transaminase (ALT), aspartate transaminase (AST), as well as oxidative stress indicators like superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), reduced glutathione (GSH) and lipid peroxidation (LPO) were investigated. The study revealed significant differences (P < 0.05) among control and experimental groups in all the haematological parameters at the end of experiment. Significantly elevated levels (P < 0.05) of ALT, AST and ALP were found for the group treated with TiO2 NPs at the dose of 150 mg/kg of body weight as compared to control. TiO2 and TiO2 NPs caused dose-dependent genotoxicity in the blood cells of the treated rat as revealed by micronuclei test. The highest frequency of micronuclei was observed in rats treated with NPs at the dose of 150 mg/kg BW which was significantly different (P < 0.001) from all other experimental groups after 28 days of exposure. Similarly, all the treatments showed dose-dependent oxidative stress in the treated rats. However, the significantly high decline in the activities of CAT, SOD, and GST as well as elevation in malondialdehyde and GSH was observed in the group receiving NPs at the rate of 150 mg/kg BW. TiO2 also caused histological alterations in the liver. The study revealed that higher dose of TiO2 NPs exerted significantly harmful effects on liver and blood as compared to its lower doses as well as from all other doses of their bulk counterparts.


TiO2 Nanoparticles Lipid peroxidation Micronucleus assay Liver function tests Oxidative stress Histological changes 


  1. 1.
    Ramsden CS (2012) The effects of manufactured nanoparticles on fish physiology, reproduction and behaviour. In: Faculty of Science. School of Biomedical and Biological Sciences, p 255Google Scholar
  2. 2.
    Pierzchala K, Oxidative stress on human cells in the presence of nano-sized titanium dioxide. 2010. École polytechnique fédérale de Lausanne EPFL: Lausanne.Google Scholar
  3. 3.
    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(1):231–241. doi: 10.1016/j.tiv.2010.11.008 PubMedCrossRefGoogle Scholar
  4. 4.
    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 nanoparticles. Toxicol Lett 195(2–3):161–168. doi: 10.1016/j.toxlet.2010.03.1116 PubMedCrossRefGoogle Scholar
  5. 5.
    Saman S, Moradhaseli S, Shokouhian A, Ghorbani M (2013) Histopathological effects of ZnO nanoparticles on liver and heart tissues in Wistar rats. Adv Biores 4(2):83–88Google Scholar
  6. 6.
    Philbrook NA, Investigating the effects of nanoparticles on reproduction and development in Drosophila melanogaster and CD-1 mice. 2010, Queen’s University, Kingston, Ontario, Canada p91.Google Scholar
  7. 7.
    Higarashi MM, Jardim WF (2002) Remediation of pesticide contaminated soil using TiO2 mediated by solar light. Catal Today 76(2–4):201–207. doi: 10.1016/S0920-5861(02)00219-5 CrossRefGoogle Scholar
  8. 8.
    Balasubramanian G, Dionysiou DD, Suidan MT, Baudin I, Laîné JM (2004) Evaluating the activities of immobilized TiO2 powder films for the photocatalytic degradation of organic contaminants in water. Appl Catal B Environ 47(2):73–84. doi: 10.1016/j.apcatb.2003.04.002 CrossRefGoogle Scholar
  9. 9.
    Konstantinou IK, Albanis TA (2004) TiO2-assisted photocatalytic degradation of azo dyes in aqueous solution: kinetic and mechanistic investigations: A review. Appl Catal B Environ 49(1):1–14. doi: 10.1016/j.apcatb.2003.11.010 CrossRefGoogle Scholar
  10. 10.
    Esterkin CR, Negro AC, Alfano OM, Cassano AE (2005) Air pollution remediation in a fixed bed photocatalytic reactor coated with TiO2. J Am Inst Chem Eng 51(8):2298–2310. doi: 10.1002/aic.10472 CrossRefGoogle Scholar
  11. 11.
    Kumari L, Li WZ (2010) Synthesis, structure and optical properties of zinc oxide hexagonal microprisms. Cryst Res Technol 45(3):311–315. doi: 10.1002/crat.200900600 CrossRefGoogle Scholar
  12. 12.
    Fujishima A, Rao TN, Tryk DA (2000) Titanium dioxide photocatalysis. J Photochem Photobiol C: Photochem Rev 1(1):1–21. doi: 10.1016/S1389-5567(00)00002-2 CrossRefGoogle Scholar
  13. 13.
    Ellsworth DK, Verhulst D, Spitler TM, Sabacky BJ (2000) Titanium nanoparticles move to the marketplace. Chem Innov 30(12):30–35Google Scholar
  14. 14.
    Wolf R, Matz H, Orion E, Lipozencić J (2003) Sunscreens—the ultimate cosmetic. Acta Dermatovenerol Croat 11(3):158–162PubMedGoogle Scholar
  15. 15.
    Gussman N (2005) We’re history—titanium dioxide: from black sand to white pigment. Chem Eng Prog 101(6):64–64Google Scholar
  16. 16.
    Lomer MCE, Thompson RPH, Commisso J, Keen CL, Powell JJ (2000) Determination of titanium dioxide in foods using inductively coupled plasma optical emission spectrometry. Analyst 125(12):2339–2343. doi: 10.1039/B006285P PubMedCrossRefGoogle Scholar
  17. 17.
    Holmberg JP (2012) Hydrolytic synthesis and physicochemical properties of TiO2 nanoparticles: fundamentals and applications. Department of Chemistry and Molecular Biology. University of Gothenburg, Sweden, p. 80Google Scholar
  18. 18.
    Zhang XD, Wu HY, Wu D, Wang YY, Chang JH, Zhai ZB, Meng AM, Liu PX, Zhang LA, Fan FY (2010) Toxicologic effects of gold nanoparticles in vivo by different administration routes. Int J Nanomedicine 5:771–781. doi: 10.2147/IJN.S8428 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Crosera M, Bovenzi M, Maina G, Adami G, Zanette C, Florio C, Filon Larese F (2009) Nanoparticle dermal absorption and toxicity: a review of the literature. Int Arch Occup Environ Health 82(9):1043–1055. doi: 10.1007/s00420-009-0458-x PubMedCrossRefGoogle Scholar
  20. 20.
    Bratosin D, Fagadar-Cosma E, Gheorghe A-M, Rugina A, Ardelean A, Montreuil J, Marinescu AG (2011) In vitro toxi-and ecotoxicological assessment of porphyrine nanomaterials by flow cytometry using nucleated erythrocytes. Carpathian J Earth Environ Sci 6(2):225–234Google Scholar
  21. 21.
    Handy RD, Shaw BJ (2007) Toxic effects of nanoparticles and nanomaterials: Implications for public health, risk assessment and the public perception of nanotechnology. Health Risk Soc 9(2):125–144. doi: 10.1080/13698570701306807 CrossRefGoogle Scholar
  22. 22.
    Handy R, Henry T, Scown T, Johnston B, Tyler C (2008) Manufactured nanoparticles: Their uptake and effects on fish—a mechanistic analysis. Ecotoxicology 17(5):396–409. doi: 10.1007/s10646-008-0205-1 PubMedCrossRefGoogle Scholar
  23. 23.
    Scown T (2009) Uptake and effects of nanoparticles in fish. In: Biological Sciences. University of Exeter, p 363Google Scholar
  24. 24.
    Fazilati M (2013) Investigation toxicity properties of zinc oxide nanoparticles on liver enzymes in male rat. European J Exp Biol 3(1):97–103Google Scholar
  25. 25.
    Medina C, Santos-Martinez M, Radomski A, Corrigan O, Radomski M (2007) Nanoparticles: pharmacological and toxicological significance. Br J Pharmacol 150(5):552–558PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Takhar P, Mahant S (2011) In vitro methods for nanotoxicity assessment: advantages and applications. Arch Appl Sci Res 3(2):389–403Google Scholar
  27. 27.
    Alarifi S, Ali D, Al-Doaiss AA, Ali BA, Ahmed M, Al-Khedhairy AA (2013) Histologic and apoptotic changes induced by titanium dioxide nanoparticles in the livers of rats. Int J Nanomedicine 8:3937–3943. doi: 10.2147/ijn.s47174 PubMedPubMedCentralGoogle Scholar
  28. 28.
    Abbas N (2014) Apoptotic effect of TiO2 in Rhabdomyosarcoma (Rd) cellular model. Department of Physics. Government College University, Faisalabad, InGoogle Scholar
  29. 29.
    Liang G, Pu Y, Yin L, Liu R, Ye B, Su Y, Li Y (2009) Influence of different sizes of titanium dioxide nanoparticles on hepatic and renal functions in rats with correlation to oxidative stress. J Toxic Environ Health A 72(11–12):740–745. doi: 10.1080/15287390902841516 CrossRefGoogle Scholar
  30. 30.
    Bergmeyer HU, Horder M, Rej R (1986) International Federation of Clinical Chemistry (IFCC): approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes part 3. IFCC method for alanine aminotransferase. J Clin Chem Clin Biochem 24(7):481–495PubMedGoogle Scholar
  31. 31.
    Sher Y, Hung M (2013) Blood AST, ALT and UREA/BUN level analysis. Bio-Protocol 3:e931Google Scholar
  32. 32.
    Bergmeyer HU, Horder M, Rej R (1986) International Federation of Clinical Chemistry (IFCC): approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes part 2. IFCC method for aspartate aminotransferase. J Clin Chem Clin Biochem 24(7):497–510PubMedGoogle Scholar
  33. 33.
    Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S (2004) Major depression following traumatic brain injury. Arch Gen Psychiatry 61(1):42–50. doi: 10.1001/archpsyc.61.1.42 PubMedCrossRefGoogle Scholar
  34. 34.
    Jabeen F, Chaudhry AS (2011) Effects of sodium selenite in cadmium chloride induced hepatoxicity in male Sprague-Dawley rats. Pakistan J Zool 43:957–965Google Scholar
  35. 35.
    Payá M, Halliwell B, Hoult JRS (1992) Interactions of a series of coumarins with reactive oxygen species: scavenging of superoxide, hypochlorous acid and hydroxyl radicals. Biochem Pharmacol 44(2):205–214. doi: 10.1016/0006-2952(92)90002-Z PubMedCrossRefGoogle Scholar
  36. 36.
    Peixoto AL, Pereira-Moura MVL (2008) A new genus of Monimiaceae from the Atlantic coastal forest in south-eastern Brazil. Kew Bull 63(1):137–141CrossRefGoogle Scholar
  37. 37.
    Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases the first enzymatic step in mercapturic acid formation. J Biol Chem 249(22):7130–7139PubMedGoogle Scholar
  38. 38.
    Uguz C, Iscan M, Ergüven A, Isgor B, Togan I (2003) The bioaccumulation of nonyphenol and its adverse effect on the liver of rainbow trout (Onchorynchus mykiss). Environ Res 92(3):262–270. doi: 10.1016/S0013-9351(03)00033-1 PubMedCrossRefGoogle Scholar
  39. 39.
    Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11(3):151–169PubMedCrossRefGoogle Scholar
  40. 40.
    Aebi H. Catalases, In: H.U. Bergmeyer (eds) Methods of enzymatic analysis. 1974, Chemic Academic Press Inc. Verlag Chemie International: New York. p. 673–684.Google Scholar
  41. 41.
    Genet S, Kale RK, Baquer NZ (2002) Alterations in antioxidant enzymes and oxidative damage in experimental diabetic rat tissues: effect of vanadate and fenugreek (Trigonella foenum graecum). Mol Cell Biochem 236(1–2):7–12. doi: 10.1023/A:1016103131408 PubMedCrossRefGoogle Scholar
  42. 42.
    Bamidele FP, Ajibade AJ, Oyewo EB, Hannah AO (2013) A study of some effects of aqueous extract of neem (Azadirachta indica) leaves on the lead acetate induced neurotoxicity in the superficial layers of superior colliculus of adult Wistar rats (Rattus norvegicus). British J Pharm Res 3(2):217–231CrossRefGoogle Scholar
  43. 43.
    Bancroft JD, Stevens A (1999) Theory and practice of histological techniques, 4th edn. Churchill-Livingstone, LondonGoogle Scholar
  44. 44.
    Schmid W (1975) The micronucleus test. Mutat Res Environ Mutagen Related Subjects 31(1):9–15. doi: 10.1016/0165-1161(75)90058-8 CrossRefGoogle Scholar
  45. 45.
    Vasantharaja D, Ramalingam V, Aadinaath Reddy G (2015) Oral toxic exposure of titanium dioxide nanoparticles on serum biochemical changes in adult male Wistar rats. Nanomedicine Journal 2(1):46–53Google Scholar
  46. 46.
    W.H.O (1969) In: FAO nutrition meetings report series no. 46 A: toxicological evaluation of some food colours, emulsifiers, stabilizers, anti-caking agents and certain other substances. WHO/FOOD ADD/70.36Google Scholar
  47. 47.
    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(2):347–357. doi: 10.1093/toxsci/kfh019 PubMedCrossRefGoogle Scholar
  48. 48.
    Grassian VH, O’Shaughnessy PT, Adamcakova-Dodd A, Pettibone JM, Thorne PS (2007) Inhalation exposure study of titanium dioxide nanoparticles with a primary particle size of 2 to 5 nm. Environ Health Perspect 115(3):397–402. doi: 10.1289/ehp.9469 PubMedCrossRefGoogle Scholar
  49. 49.
    Wang JX, Li YF, Zhou GQ, Li B, Jiao F, Chen CY, Gao YX, Zhao YL, Chai ZF (2007) Influence of intranasal instilled titanium dioxide nanoparticles on monoaminergic neurotransmitters of female mice at different exposure time. Chinese J Prev Med 41(2):91–95Google Scholar
  50. 50.
    Bermudez E, Mangum JB, Asgharian B, Wong BA, Reverdy EE, Janszen DB, Hext PM, Warheit DB, Everitt JI (2002) Long-term pulmonary responses of three laboratory rodent species to subchronic inhalation of pigmentary titanium dioxide particles. Toxicol Sci 70(1):86–97. doi: 10.1093/toxsci/70.1.86 PubMedCrossRefGoogle Scholar
  51. 51.
    Ferin J, Oberdörster G, Penney DP (1992) Pulmonary retention of ultrafine and fine particles in rats. Am J Respir Cell Mol Biol 6(5):535–542. doi: 10.1165/ajrcmb/6.5.535 PubMedCrossRefGoogle Scholar
  52. 52.
    Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, Kreyling W, Cox C (2002) Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxic Environ Health A 65(20):1531–1543. doi: 10.1080/00984100290071658 CrossRefGoogle Scholar
  53. 53.
    Fabian E, Landsiedel R, Ma-Hock L, Wiench K, Wohlleben W, van Ravenzwaay B (2008) Tissue distribution and toxicity of intravenously administered titanium dioxide nanoparticles in rats. Arch Toxicol 82(3):151–157. doi: 10.1007/s00204-007-0253-y PubMedCrossRefGoogle Scholar
  54. 54.
    Sugibayashi K, Todo H, Kimura E (2008) Safety evaluation of titanium dioxide nanoparticles by their absorption and elimination profiles. J Toxicol Sci 33(3):293–298. doi: 10.2131/jts.33.293 PubMedCrossRefGoogle Scholar
  55. 55.
    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(2):176–185. doi: 10.1016/j.toxlet.2006.12.001 PubMedCrossRefGoogle Scholar
  56. 56.
    Liu H, Ma L, Zhao J, Liu J, Yan J, Ruan J, Hong F (2009) Biochemical toxicity of nano-anatase TiO2 particles in mice. Biol Trace Elem Res 129(1–3):170–180. doi: 10.1007/s12011-008-8285-6 PubMedCrossRefGoogle Scholar
  57. 57.
    Huggins CB, Froehlich JP (1966) High concentration of injected titanium dioxide in abdominal lymph nodes. J Exp Med 124(6):1099–1106PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Wilson MR, Lightbody JH, Donaldson K, Sales J, Stone V (2002) Interactions between ultrafine particles and transition metals in vivo and in vitro. Toxicol Appl Pharmacol 184(3):172–179. doi: 10.1006/taap.2002.9501 PubMedCrossRefGoogle Scholar
  59. 59.
    Oberdorster G, Oberdorster E, Oberdorster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113(7):823–839. doi: 10.2307/3436201 PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Chen J, Dong X, Zhao J, Tang G (2009) In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection. J Appl Toxicol 29(4):330–337. doi: 10.1002/jat.1414 PubMedCrossRefGoogle Scholar
  61. 61.
    Elgrabli D, Beaudouin R, Jbilou N, Floriani M, Pery A, Rogerieux F, Lacroix G (2015) Biodistribution and clearance of TiO(2) nanoparticles in rats after intravenous injection. PLoS One 10(4):e0124490. doi: 10.1371/journal.pone.0124490 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    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(1):99–105. doi: 10.1016/j.biomaterials.2009.09.028 PubMedCrossRefGoogle Scholar
  63. 63.
    Cui Y, Liu H, Ze Y, Zengli Z, Hu Y, Cheng Z, Cheng J, Hu R, Gao G, Wang L, Tang M, Hong F (2012) Gene expression in liver injury caused by long-term exposure to titanium dioxide nanoparticles in mice. Toxicol Sci 128(1):171–185. doi: 10.1093/toxsci/kfs153 PubMedCrossRefGoogle Scholar
  64. 64.
    Fartkhooni FM, Noori A, Momayez M, Sadeghi L, Shirani K, Babadi VY (2013) The effects of nano titanium dioxide (TiO2) in spermatogenesis in wistar rat. Eur J Exp Biol 3(4):145–149Google Scholar
  65. 65.
    Younes NRB, Amara S, Mrad I, Ben-Slama I, Jeljeli M, Omri K, El Ghoul J, El Mir L, Rhouma K, Abdelmelek H, Sakly M (2015) Subacute toxicity of titanium dioxide (TiO2) nanoparticles in male rats: emotional behavior and pathophysiological examination. Environ Sci Pollut Res 22(11):8728–8737. doi: 10.1007/s11356-014-4002-5 CrossRefGoogle Scholar
  66. 66.
    Duan Y, Liu J, Ma L, Li N, Liu H, Wang J, Zheng L, Liu C, Wang X, Zhao X, Yan J, Wang S, Wang H, Zhang X, Hong F (2010) Toxicological characteristics of nanoparticulate anatase titanium dioxide in mice. Biomaterials 31(5):894–899. doi: 10.1016/j.biomaterials.2009.10.003 PubMedCrossRefGoogle Scholar
  67. 67.
    von Hundelshausen P, Weber C (2007) Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 100(1):27–40. doi: 10.1161/01.RES.0000252802.25497.b7 CrossRefGoogle Scholar
  68. 68.
    Xu J, Shi H, Ruth M, Yu H, Lazar L, Zou B, Yang C, Wu A, Zhao J (2013) Acute toxicity of intravenously administered titanium dioxide nanoparticles in mice. PLoS One 8(8):e70618. doi: 10.1371/journal.pone.0070618 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    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.can-09-2496 PubMedCrossRefGoogle Scholar
  70. 70.
    Shukla RK, Kumar A, Vallabani NVS, Pandey AK, Dhawan A (2014) Titanium dioxide nanoparticle-induced oxidative stress triggers DNA damage and hepatic injury in mice. Nanomedicine 9(9):1423–1434PubMedCrossRefGoogle Scholar
  71. 71.
    Farber E (1994) Programmed cell death: necrosis versus apoptosis. Mod Pathol 7(5):605–609PubMedGoogle Scholar
  72. 72.
    Ezz-Din D, Gabry MS, Farrag ARH, Moneim AEA (2011) Physiological and histological impact of Azadirachta indica (neem) leaves extract in a rat model of cisplatin-induced hepato and nephrotoxicity. J Med Plants Res 5(23):5499–5506Google Scholar
  73. 73.
    Zhao J, Li N, Wang S, Zhao X, Wang J, Yan J, Ruan J, Wang H, Hong F (2010) The mechanism of oxidative damage in the nephrotoxicity of mice caused by nano-anatase TiO2. J Exp Nanosci 5(5):447–462. doi: 10.1080/17458081003628931 CrossRefGoogle Scholar
  74. 74.
    Wang J-X, Fan Y-B, Gao Y, Hu Q-H, Wang T-C (2009) TiO2 nanoparticles translocation and potential toxicological effect in rats after intraarticular injection. Biomaterials 30(27):4590–4600. doi: 10.1016/j.biomaterials.2009.05.008 PubMedCrossRefGoogle Scholar
  75. 75.
    Gui S, Sang X, Zheng L, Ze Y, Zhao X, Sheng L, Sun Q, Cheng Z, Cheng J, Hu R, Wang L, Hong F, Tang M (2013) Intragastric exposure to titanium dioxide nanoparticles induced nephrotoxicity in mice, assessed by physiological and gene expression modifications. Part Fibre Toxicol 10(1):4PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Johar D, Roth JC, Bay GH, Walker JN, Kroczak TJ, Los M (2004) Inflammatory response, reactive oxygen species, programmed (necrotic-like and apoptotic) cell death and cancer. Annal Med Univ Bialystok 49:31–39Google Scholar
  77. 77.
    Gerlyng P, Åbyholm A, Grotmol T, Erikstein B, Huitfeldt H, Stokke T, Seglen P (1993) Binucleation and polyploidization patterns in developmental and regenerative rat liver growth. Cell Prolif 26(6):557–565PubMedCrossRefGoogle Scholar
  78. 78.
    Del Monte U (2005) Swelling of hepatocytes injured by oxidative stress suggests pathological changes related to macromolecular crowding. Med Hypotheses 64(4):818–825. doi: 10.1016/j.mehy.2004.08.028 PubMedCrossRefGoogle Scholar
  79. 79.
    Schrand AM, Rahman MF, Hussain SM, Schlager JJ, Smith DA, Syed AF (2010) Metal-based nanoparticles and their toxicity assessment. Wiley Interdisciplinary Reviews. Nanomed Nanobiotechnol 2(5):544–568CrossRefGoogle Scholar
  80. 80.
    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(3):222–229. doi: 10.1016/j.toxlet.2008.06.869 PubMedCrossRefGoogle Scholar
  81. 81.
    Johnston HJ, Hutchison GR, Christensen FM, Peters S, Hankin S, Stone V (2009) Identification of the mechanisms that drive the toxicity of TiO2 particulates: the contribution of physicochemical characteristics. Part Fibre Toxicol 6:33–59PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Thapa BR, Walia A (2007) Liver function tests and their interpretation. Indian J Pediatr 74(7):663–671PubMedCrossRefGoogle Scholar
  83. 83.
    Gontijo ÁMMC, Barreto RE, Speit G, Valenzuela Reyes VA, Volpato GL, Favero Salvadori DM (2003) Anesthesia of fish with benzocaine does not interfere with comet assay results. Mutat Res Genet Toxicol Environ Mutagen 534(1–2):165–172. doi: 10.1016/S1383-5718(02)00276-0 CrossRefGoogle Scholar
  84. 84.
    Dambach DM, Andrews BA, Moulin F (2005) New technologies and screening strategies for hepatotoxicity: use of in vitro models. Toxicol Pathol 33(1):17–26. doi: 10.1080/01926230590522284 PubMedCrossRefGoogle Scholar
  85. 85.
    Popper HANS (1968) Cholestasis. Annu Rev Med 19(1):39–56PubMedCrossRefGoogle Scholar
  86. 86.
    Nemmar A, Hoet PHM, Vanquickenborne B, Dinsdale D, Thomeer M, Hoylaerts MF, Vanbilloen H, Mortelmans L, Nemery B (2002) Passage of inhaled particles into the blood circulation in humans. Circulation 105(4):411–414. doi: 10.1161/hc0402.104118 PubMedCrossRefGoogle Scholar
  87. 87.
    De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJAM, Geertsma RE (2008) Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 29(12):1912–1919. doi: 10.1016/j.biomaterials.2007.12.037 PubMedCrossRefGoogle Scholar
  88. 88.
    Jain TK, Reddy MK, Morales MA, Leslie-Pelecky DL, Labhasetwar V (2008) Biodistribution, clearance, and biocompatibility of iron oxide magnetic nanoparticles in rats. Mol Pharm 5(2):316–327. doi: 10.1021/mp7001285 PubMedCrossRefGoogle Scholar
  89. 89.
    Burns AA, Vider J, Ow H, Herz E, Penate-Medina O, Baumgart M, Larson SM, Wiesner U, Bradbury M (2009) Fluorescent silica nanoparticles with efficient urinary excretion for nanomedicine. Nano Lett 9(1):442–448. doi: 10.1021/nl803405h PubMedCrossRefGoogle Scholar
  90. 90.
    Liu R, Yin L, Pu Y, Liang G, Zhang J, Su Y, Xiao Z, Ye B (2009) Pulmonary toxicity induced by three forms of titanium dioxide nanoparticles via intra-tracheal instillation in rats. Prog Nat Sci 19(5):573–579. doi: 10.1016/j.pnsc.2008.06.020 CrossRefGoogle Scholar
  91. 91.
    Nel A, Xia T, Mädler L, Li N (2006) Toxic potential of materials at the nanolevel. Science 311(5761):622–627. doi: 10.1126/science.1114397 PubMedCrossRefGoogle Scholar
  92. 92.
    Sies H (1997) Oxidative stress: oxidants and antioxidants. Exp Physiol 82(2):291–295. doi: 10.1113/expphysiol.1997.sp004024 PubMedCrossRefGoogle Scholar
  93. 93.
    Datta R, Alfonso-García A, Cinco R, Gratton E (2015) Fluorescence lifetime imaging of endogenous biomarker of oxidative stress. Sci Rep 5:1–10Google Scholar
  94. 94.
    Simonian NA, Coyle JT (1996) Oxidative stress in neurodegenerative diseases. Annu Rev Pharmacol Toxicol 36(1):83–106. doi: 10.1146/ PubMedCrossRefGoogle Scholar
  95. 95.
    Sharma P, Singh R, Jan M (2014) Dose-dependent effect of deltamethrin in testis, liver, and kidney of Wistar rats. Toxicol Int 21(2):131–139. doi: 10.4103/0971-6580.139789 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Ray DE (1991) Pesticides derived from plants and other organisms. Handb Pestic Toxicol 2(13):585–636Google Scholar
  97. 97.
    Kale M, Rathore N, John S, Bhatnagar D (1999) Lipid peroxidative damage on pyrethroid exposure and alterations in antioxidant status in rat erythrocytes: a possible involvement of reactive oxygen species. Toxicol Lett 105(3):197–205. doi: 10.1016/S0378-4274(98)00399-3 PubMedCrossRefGoogle Scholar
  98. 98.
    Latchoumycandane C, Mathur P (2002) Induction of oxidative stress in the rat testis after short-term exposure to the organochlorine pesticide methoxychlor. Arch Toxicol 76(12):692–698. doi: 10.1007/s00204-002-0388-9 PubMedCrossRefGoogle Scholar
  99. 99.
    Wu J, Liu W, Xue C, Zhou S, Lan F, Bi L, Xu H, Yang X, Zeng F-D (2009) Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure. Toxicol Lett 191(1):1–8. doi: 10.1016/j.toxlet.2009.05.020 PubMedCrossRefGoogle Scholar
  100. 100.
    Li Y, Li J, Yin J, Li W, Kang C, Huang Q, Li Q (2010) Systematic influence induced by 3 nm titanium dioxide following intratracheal instillation of mice. J Nanosci Nanotechnol 10(12):8544–8549PubMedCrossRefGoogle Scholar
  101. 101.
    Zhang Y, Tao J, He P, Tang Y, Wang Y (2009) Bio-effects of nano-TiO2 on lungs of mice. J Biomed Eng 26(4):803–806Google Scholar
  102. 102.
    El-Sharkawy NI, Hamza SM, Abou-Zeid EH (2010) Toxic impact of titanium dioxide (TiO2) in male albino rats with special reference to its effect on reproductive system. J Am Sci 6(11):865–872Google Scholar
  103. 103.
    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 PubMedCrossRefGoogle Scholar
  104. 104.
    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(2):445–454. doi: 10.1016/j.neuroscience.2009.10.057 PubMedCrossRefGoogle Scholar
  105. 105.
    Braydich-Stolle LK, Schaeublin NM, Murdock RC, Jiang J, Biswas P, Schlager J, Hussain SM (2009) Crystal structure mediates mode of cell death in TiO2 nanotoxicity. J Nanoparticle Res 11(6):1361–1374. doi: 10.1007/s11051-008-9523-8 CrossRefGoogle Scholar
  106. 106.
    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 (2008) Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO2 nanoparticles. Toxicology 254(1–2):82–90. doi: 10.1016/j.tox.2008.09.014 PubMedCrossRefGoogle Scholar
  107. 107.
    Jabeen F, Chaudhry AS (2011) Effects of cadmium chloride and sodium selenite alone or in combination on the liver of male Sprague–Dawley rats assessed by different assays. Biol Trace Elem Res 143(2):1077–1090PubMedCrossRefGoogle Scholar
  108. 108.
    Javed M, Usmani N, Ahmad I, Ahmad M (2015) Studies on the oxidative stress and gill histopathology in Channa punctatus of the canal receiving heavy metal-loaded effluent of Kasimpur thermal power plant. Environ Monit Assess 187(1):1–11CrossRefGoogle Scholar
  109. 109.
    Olmedo DG, Tasat DR, Evelson P, Rebagliatti R, Guglielmotti MB, Cabrini RL (2011) In vivo comparative biokinetics and biocompatibility of titanium and zirconium microparticles. J Biomed Mater Res Part A 98A(4):604–613. doi: 10.1002/jbm.a.33145 CrossRefGoogle Scholar
  110. 110.
    Grigoryeva V, Zayeva O, Krivova N (2015) Comparative study of the biological efficacy of titanium dioxide nano-and microparticles. Adv Mater Res Trans Tech Publ 1085:357–362Google Scholar
  111. 111.
    Xiong D, Fang T, Yu L, Sima X, Zhu W (2011) Effects of nano-scale TiO2, ZnO and their bulk counterparts on zebrafish: acute toxicity, oxidative stress and oxidative damage. Sci Total Environ 409(8):1444–1452. doi: 10.1016/j.scitotenv.2011.01.015 PubMedCrossRefGoogle Scholar
  112. 112.
    Shvedova A, Castranova V, Kisin E, Schwegler-Berry D, Murray A, Gandelsman V, Maynard A, Baron P (2003) Exposure to carbon nanotube material: assessment of nanotube cytotoxicity using human keratinocyte cells. J Toxic Environ Health A 66(20):1909–1926. doi: 10.1080/713853956 CrossRefGoogle Scholar
  113. 113.
    Kang JL, Moon C, Lee HS, Lee HW, Park EM, Kim HS, Castranova V (2008) Comparison of the biological activity between ultrafine and fine titanium dioxide particles in RAW 264.7 cells associated with oxidative stress. J Toxic Environ Health A 71(8):478–485CrossRefGoogle Scholar
  114. 114.
    Wang JJ, Sanderson BJS, Wang H (2007) Cyto- and genotoxicity of ultrafine TiO2 particles in cultured human lymphoblastoid cells. Mutat Res Genet Toxicol Environ Mutagen 628(2):99–106. doi: 10.1016/j.mrgentox.2006.12.003 CrossRefGoogle Scholar
  115. 115.
    Dick CAJ, Brown DM, Donaldson K, Stone V (2003) The role of free radicals in the toxic and inflammatory effects of four different ultrafine particle types. Inhal Toxicol 15(1):39–52. doi: 10.1080/08958370304454 PubMedCrossRefGoogle Scholar
  116. 116.
    Singh S, Shi T, Duffin R, Albrecht C, van Berlo D, Hohr 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 particles. Toxicol Appl Pharmacol 222(2):141–151. doi: 10.1016/j.taap.2007.05.001 PubMedCrossRefGoogle Scholar
  117. 117.
    SCCS (2013) Opinion on titanium dioxide (nano form). Sci Committee Consumer Safety, 22 July 2013Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Muhammad Shakeel
    • 1
  • Farhat Jabeen
    • 1
    Email author
  • Naureen Aziz Qureshi
    • 2
  • Muhammad Fakhr-e-Alam
    • 3
  1. 1.Department of ZoologyGovernment College UniversityFaisalabadPakistan
  2. 2.Government College Women UniversityFaisalabadPakistan
  3. 3.Department of PhysicsGovernment College UniversityFaisalabadPakistan

Personalised recommendations