Skip to main content
Log in

P38-Nrf-2 Signaling Pathway of Oxidative Stress in Mice Caused by Nanoparticulate TiO2

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Some recent studies have been previously suggested that nanoparticulate titanium dioxide (TiO2) damaged liver function and decreased immunity of mice, but the spleen injury and its oxidative stress mechanism are still unclear. To understand the spleen injury induced by intragastric administration of nanoparticulate anatase TiO2 for consecutive 30 days, the spleen pathological changes, the oxidative stress, and p38 and c-Jun N-terminal kinase signaling pathways, along with nuclear factor-κB and nuclear factor-E2-related factor-2 (Nrf-2), were investigated as the upstream events of oxidative stress in the mouse spleen from exposure to nanoparticulate TiO2. The results suggested that nanoparticulate TiO2 caused congestion and lymph nodule proliferation of spleen tissue, which might exert its toxicity through oxidative stress, as it caused significant increases in the mouse spleen reactive oxygen species accumulations, subsequently leading to the strong lipid peroxidation and the significant expression of heme oxygenase-1 via the p38-Nrf-2 signaling pathway. The studies on the mechanism by which nanoparticulate TiO2 induced the p38-Nrf-2 signaling pathway are helpful to a better understanding of the nanoparticulate TiO2-induced oxidative stress and reduction of immune capacity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Dagani R (2003) Nanomaterials: safe or unsafe? Chem Eng News 81:30–33

    Article  Google Scholar 

  2. Service RF (2003) American Chemical Society meeting. Nanomaterials show signs of toxicity. Science 300:243

    Article  PubMed  Google Scholar 

  3. Warheit DB (2004) Nanoparticles: health impacts? Mater Today 7:32–35

    Article  CAS  Google Scholar 

  4. Gurr J, Wang ASS, Chen C, Jan K (2005) Ultrafine titanium dioxide particle in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells. Toxicol 213:66–73

    Article  CAS  Google Scholar 

  5. J Fisher, T Egerton (2001) Kirk-Othmer encyclopedia of chemical technology. New York: John Wiley & Sons, Titanium Compounds, Inorganic

  6. Choi H, Stathatos E, Dionysiou DD (2006) Solgel preparation of mesoporous photocatalytic TiO2 films and TiO2/Al2O3 composite membranes for environmental applications. Appl Catal B-Environ 63:60–67

    Article  CAS  Google Scholar 

  7. Esterkin CR, Negro AC, Alfano OM, Cassano AE (2005) Air pollution remediation in a fixed bed photocatalytic reactor coated with TiO2. AIChE J 51:2298–2310

    Article  CAS  Google Scholar 

  8. Jin CY, Zhu BS, Wang XF, Lu QH (2008) Cytotoxicity of titanium dioxide nanoparticles in mouse fibroblast cells. Chem Res Toxicol 21(9):1871–1877

    Article  PubMed  CAS  Google Scholar 

  9. Oberdörster G, Oberdörster E, Oberdörster J (2005) Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113(7):823–839

    Article  PubMed  Google Scholar 

  10. Afaq F, Abidi P, Matin R, Rahman Q (1998) Cytotoxicity, pro-oxidant effects and antioxidant depletion in rat lung alveolar macrophages exposed to ultrafine titanium dioxide. J Appl Toxicol 18:307–312

    Article  PubMed  CAS  Google Scholar 

  11. Federici G, Shaw BJ, Handy RD (2007) Toxicity of titanium dioxide nanoparticles to rainbow trout (Oncorhynchus mykiss): gill injury, oxidative stress, and other physiological effects. Aquat Toxicol 84:415–430

    Article  PubMed  CAS  Google Scholar 

  12. Ma LL, Liu J, Li N, Wang J, Duan YM, Yan JY, Liu HT, Wang H, Hong FS (2010) Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. Biomaterials 31:99–105

    Article  PubMed  CAS  Google Scholar 

  13. Liu HT, Ma LL, Liu J, Zhao JF, Yan JY, Hong FS (2010) Toxicity of nano-anatase TiO2 to mice: liver injury, oxidative stress. Toxicol Environ Chem 92(1):175–186

    Article  CAS  Google Scholar 

  14. Zhao JF, Wang J, Wang SS, Zhao XY, Yan JY, Ruan J, Li N, Duan YM, Wang H, Hong FS (2010) The mechanism of oxidative damage in nephrotoxicity of mice caused by nano-anatase TiO2. J Exp Nanoscience doi:10.1080/17458081003628931, 2010 in press

  15. Duan YM, Liu J, Ma LL, Li N, Liu HT, Wang J, Zheng L, Liu C, Wang XF, Zhang XG, Yan JY, Wang H, Hong FS (2010) Toxicological characteristics of nanoparticulate anatase titanium dioxide in mice. Biomaterials 31:894–899

    Article  PubMed  CAS  Google Scholar 

  16. Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869

    PubMed  CAS  Google Scholar 

  17. Takeda K, Matsuzawa A, Nishitoh H, Ichijo H (2003) Roles of MAPKKK ASK1 in stress-induced cell death. Cell Struct Funct 28:23–29

    Article  PubMed  CAS  Google Scholar 

  18. Hagemann C, Blank JL (2001) The ups and downs of MEK kinase interactions. Cell Signall 13(12):863–875

    Article  CAS  Google Scholar 

  19. Qadri I, Iwahashi M, Capasso JM, Hopken MW, Flores S, Schaack J, Simon FR (2004) Induced oxidative stress and activated expression of manganese superoxide dismutase during hepatitis C virus replication: role of JNK, p38 MAPK and AP-1. Biochem J 378:919–928

    Article  PubMed  CAS  Google Scholar 

  20. Camacho-Barquero L, Villegas I, Sánchez-Calvo JM, Talero E, Sánchez-Fidalgo S, Motilva V, Alarcón de la Lastra C (2007) Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. Int Immunopharmacol 7:333–342

    Article  PubMed  CAS  Google Scholar 

  21. Janssen YM, Barchowsky A, Treadwell M, Driscoll KE, Mossman BT (1995) Asbestos induces nuclear factor kappa B (NF-kappa B) DNA-binding activity and NF-kappa B-dependent gene expression in tracheal epithelial cells. Proc Natl Acad Sci USA 92:8458–8462

    Article  PubMed  CAS  Google Scholar 

  22. Pinkus R, Weiner LM, Daniel V (1996) Role of oxidants and antioxidants in the induction of AP-1, NF-kappaB, and glutathione S-transferase gene expression. J Biol Chem 271:13422–13429

    Article  PubMed  CAS  Google Scholar 

  23. Sen CK, Packer L (1996) Antioxidant and redox regulation of gene transcription. FASEB J 10:709–720

    PubMed  CAS  Google Scholar 

  24. Itoh K, Wakabayashi N, Katoh Y, Ishii T, O’connor T, Yamamoto M (2003) Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 8:379–391

    Article  PubMed  CAS  Google Scholar 

  25. Maines MD (1988) Heme oxygenase: function, multiplicity, regulatory mechanism, and clinical applications. FASEB J 2:2557–2568

    PubMed  CAS  Google Scholar 

  26. Choi AM, Alam J (1996) Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 15(1):9–19

    PubMed  CAS  Google Scholar 

  27. Maines MD (1997) The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol 37:517–554

    Article  PubMed  CAS  Google Scholar 

  28. Okinaga S, Takahashi K, Takeda K, Yoshizawa M, Fujita H, Sasaki H, Shibahara S (1996) Regulation of human heme oxygenase-1 gene expression under thermal stress. Blood 87:5074–5084

    PubMed  CAS  Google Scholar 

  29. Cantoni L, Rossi C, Rizzardini M, Gardina M, Ghezzi P (1991) Interleukin-1 and tumor necrosis factor induce hepatic haeme oxygenase. Biochem J 279:891–894

    PubMed  CAS  Google Scholar 

  30. Chen K, Gunter K, Maines MD (2002) Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death. J Neurochem 75(1):304–313

    Article  Google Scholar 

  31. Willis D, Moore AR, Frederick R, Willoughby DA (1996) Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat Med 2:87–90

    Article  PubMed  CAS  Google Scholar 

  32. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S (1999) Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. Clin Invest 103(1):129–135

    Article  CAS  Google Scholar 

  33. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophy Res Commun 236:313–322

    Article  CAS  Google Scholar 

  34. Chan K, Kan YW (1999) Nrf2 is essential for protection against acute pulmonary injury in mice. Proc Natl Acad Sci USA 96:12731–12736

    Article  PubMed  CAS  Google Scholar 

  35. Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, Wolf CR, Yamamoto M (2000) The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin. Biochem Soc Trans 28:33–41

    PubMed  CAS  Google Scholar 

  36. Chan K, Han XD, Kan YW (2001) An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci USA 98:4611–4616

    Article  PubMed  CAS  Google Scholar 

  37. Kim YC, Masutani H, Yamaguchi Y, Itoh K, Yamamoto M, Yodoi J (2110) Hemin induced activation of the thioredoxin gene by Nrf2. A differential regulation of the antioxidant responsive element by a switch of its binding factors. J Biol Chem 276:18399–18406

    Article  Google Scholar 

  38. Kwak MK, Itoh K, Yamamoto M, Kensler TW (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 22:2883–2892

    Article  PubMed  CAS  Google Scholar 

  39. Oliveira CP, Lopasso FP, Laurindo FR, Leitao RM, Laudanna A (2001) Protection against liver ischemia-reperfusion injury in rats by silymarin or verapamil. Transplant Proc 33:3010–3014

    Article  PubMed  CAS  Google Scholar 

  40. Nourooz-Zadeh J, Tajaddini-Sarmadi J, Wolff SP (1994) Measurement of plasma hydroperoxide concentrations by the ferrous oxidation-xylenol orange assay in conjunction with triphenylphosphine. Anal Biochem 220:403–409

    Article  PubMed  CAS  Google Scholar 

  41. Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Meth Enzymol 52:302–310

    Article  PubMed  CAS  Google Scholar 

  42. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  43. Ke LD, Chen Z (2000) A reliability test of standard-based quantitative PCR: exogenous vs endogenous standards. Mol Cell Probes 14(2):127–135

    Article  PubMed  CAS  Google Scholar 

  44. Liu WH, David Saint A (2002) Validation of a quantitative method for real time PCR kinetics. Biochem Biophys Res Commun 294:347–353

    Article  PubMed  CAS  Google Scholar 

  45. 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 (2007) Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 168:176–185

    Article  PubMed  CAS  Google Scholar 

  46. Chen JY, Dong X, Zhao J, Tang GP (2009) In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection. J Appl Toxicol 29:330–337

    Article  PubMed  CAS  Google Scholar 

  47. 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(1):170–180

    Article  PubMed  CAS  Google Scholar 

  48. Long TC, Saleh N, Tilton RD, Lowry G, Veronesi B (2006) Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity. Environ Sci Technol 40:4346–4352

    Article  PubMed  CAS  Google Scholar 

  49. Long TC, Tajuba J, Sama P, Sale N, Swartz C, Parker J, Hester S, Lowry GV, Veronesi B (2007) Nano-TiO2 stimulates ROS in brain microglia and damages neurons in vitro. Environ Health Perspect 115:1631–1637

    Article  PubMed  CAS  Google Scholar 

  50. Gao HW, Xu Q, Chen L, Wang SL, Wang Y, Wu LL, Yuan Y (2008) Potential protein toxicity of synthetic pigments, binding of poncean S to human serum albumin. Biophys J 94:906–917

    Article  PubMed  CAS  Google Scholar 

  51. Xu Z, Liu XW, Ma YS, Gao HW (2010) Interactions of nano-TiO2 with lysozyme: insights into the enzyme toxicity of nanosized particles. Environ Sci Pollut Res 17:798–806

    Article  CAS  Google Scholar 

  52. Maines MD (1988) Hemeoxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J 2:2557–2568

    PubMed  CAS  Google Scholar 

  53. Morse D, Choi AM (2002) Heme oxygenase-1: the “emerging molecule” has arrived. Am J Respir Cell Mol Biol 27:8–16

    PubMed  CAS  Google Scholar 

  54. Otterbein LE, Soares MP, Yamashita K, Bach FH (2003) Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol 24:449–455

    Article  PubMed  CAS  Google Scholar 

  55. Chen CY, Jang JH, Li MH, Surh YJ (2005) Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells. Biochem Biophys Res Commun 331:993–1000

    Article  PubMed  CAS  Google Scholar 

  56. Lee JS, Surh YJ (2005) Nrf2 as a novel molecular target for chemoprevention. Cancer Lett 224:171–184

    Article  PubMed  CAS  Google Scholar 

  57. Lim HJ, Lee KS, Lee S, Park JH, Choi HE, Go SH, Kwak HJ, Park HY (2007) 15d-PGJ2 stimulates HO-1 expression through p38 MAP kinase and Nrf-2 pathway in rat vascular smooth muscle cells. Toxicol Appl Pharmacol 223:20–27

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant no. 30901218), the Medical Development Foundation of Soochow University (grant no. EE120701, China), the National Bringing New Ideas Foundation of Student of China (grant nos. 57315427, 57315927), and the Bringing New Ideas Foundation of Postgraduate of Medical College of Soochow University (China) and the Soochow University Start-up Fund (grant no. Q4134918, China).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fashui Hong.

Additional information

Jue Wang, Na Li, Lei Zheng and Ying Wang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, J., Li, N., Zheng, L. et al. P38-Nrf-2 Signaling Pathway of Oxidative Stress in Mice Caused by Nanoparticulate TiO2 . Biol Trace Elem Res 140, 186–197 (2011). https://doi.org/10.1007/s12011-010-8687-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-010-8687-0

Keywords

Navigation