Skip to main content
SpringerLink
Log in

Titanium dioxide nanoparticle-induced cytotoxicity and the underlying mechanism in mouse myocardial cells

  • Research Paper
  • Published:
Journal of Nanoparticle Research Aims and scope Submit manuscript

Abstract

Exposure to fine particulate matter (PM) is known to cause cardiovascular disease. While extensive research has focused on the risk of atmospheric PM to public health, particularly heart disease, limited studies to date have attempted to clarify the molecular mechanisms underlying myocardial cell damage caused by exposure to titanium dioxide nanoparticles (TiO2 NPs). Data from the current investigation showed that TiO2 NPs are deposited in myocardial mitochondria via the blood circulation accompanied by obvious ultrastructural changes and impairment of mitochondrial structure and function in mouse myocardial cells, including reduction in mitochondrial membrane potential and ATP production, aggravation of oxidative stress along with increased levels of reactive oxygen species, malondialdehyde and protein carbonyl, and decreased glutathione content and enzymatic activities, including superoxide dismutase and glutathione peroxidase. Furthermore, TiO2 NPs induced a significant decrease in the activities of complex I, complex II, complex III, complex IV, succinate dehydrogenase, NADH oxidase, Ca2+-ATPase, Na+/K+-ATPase, and Ca2+/Mg2+-ATPase, and upregulation of cytokine expression (including cytochrome c, caspase-3, and p-JNK) in mitochondria-mediated apoptosis while downregulating Bcl-2 expression in mouse myocardial cells. Our results collectively indicate that chronic exposure to TiO2 NPs induces damage in mitochondrial structure and function as well as mitochondria-mediated apoptosis in mouse myocardial cells, which may be closely associated with heart disease in animals and humans.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Allen RW, Criqui MH, Diez Roux AV, Allison M, Shea S, Detrano R, Sheppard L, Wong ND, Stukovsky KH, Kaufman JD (2009) Fine particulate matter air pollution, proximity to traffic, and aortic atherosclerosis. Epidemiology 20:254–264

    Article  Google Scholar 

  • Araujo JA, Nel AE (2009) Particulate matter and atherosclerosis: role of particle size, composition and oxidative stress. Part Fibre Toxicol 6:24

    Article  Google Scholar 

  • Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Cogliano V (2006) Carcinogenicity of carbon black, titanium dioxide, and talc. Lancet Oncol 7:295–296

    Article  Google Scholar 

  • Bennett B, Geyh AS, Breysse PN, Tankersley CG (2011) Effect of particulate matter (PM) and ozone (O3) exposure on heart rate regulation in DBA/2J mice. FASEB 25(1 Supplement):1045.6

    Google Scholar 

  • Brook RD, Rajagopalan S, Pope CA, Brook JR, Bhatnagar A, Diez-Roux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, Peters A, Siscovick D, Smith SC Jr, Whitsel L, Kaufman JD (2010) Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circ 121:2331–2378

    Article  Google Scholar 

  • Capaldi RA (1982) Arrangement of proteins in the mitochondrial inner membrane. Biochim Biophys Acta 694:291–306

    Article  Google Scholar 

  • Chen C, Pinkerton K, Bonham A (2007) Time-dependent decrease in heart rate variability to particulate matter exposure in mice. FASEB J 21(5):A473–A474

    Google Scholar 

  • Chen T, Hu JQ, Chen CY, Pu J, Cui XX, Jia G (2013) Cardiovascular effects of pulmonary exposure to titanium dioxide nanoparticles in ApoE knockout mice. J Nanosci Nanotechnol 13:3214–3222

    Article  Google Scholar 

  • Chen YF, Cao J, Zhong JN, Chen X, Cheng M, Yang J, Gao YD, Chen YF, Cao J, Zhong JN (2014) Plasma membrane Ca2+-ATPase regulates Ca2+ signaling and the proliferation of airway smooth muscle cells. Eur J Pharmacol 740:733–741

    Article  Google Scholar 

  • Cossarizza A, Franceschi C, Monti D, Salvioli S, Bellesia E, Rivabene R, Biondo L, Rainaldi G, Tinari A, Malorni W (1995) Protective effect of N-acetylcysteine in tumor necrosis factor-alpha-induced apoptosis in U937 cells: the role of mitochondria. ExpCell Res 220:232–240

    Google Scholar 

  • Crestanello JA, Doliba NM, Babsky AM, Doliba NM, Niibori K, Osbakken MD, Whitman GJ (2002) Mitochondrial function during ischemic preconditioning. Surgery 131:172–178

    Article  Google Scholar 

  • Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95

    Article  Google Scholar 

  • Hall JE, Guyton AC (2011) Guyton and Hall textbook of medical physiology. Saunders/Elsevier, Amsterdam, pp 773–788

    Google Scholar 

  • Hejzlarová K, Kaplanová V, Nůsková H, Kovářová JP, Drahota Z, Mráček T, Seneca S (2015) Alteration of structure and function of ATP synthase and cytochrome c oxidase by lack of Fo-a and Cox3 subunits caused by mitochondrial DNA 9205delTA mutation. Biochem J 466(3):601–611

    Article  Google Scholar 

  • Helfenstein M, Miragoli M, Rohr S, Muller L, Wick P, Mohr M, Gehr P, Rothen-Rutishauser B (2008) Effects of combustion-derived ultrafine particles and manufactured nanoparticles on heart cells in vitro. Toxicology 253:70–78

    Article  Google Scholar 

  • Hong FS, Wang L, Yu XH, Zhou YJ, Hong J, Sheng L (2015) Toxicological effect of TiO2 nanoparticle-induced myocarditis in mice. Nanoscale Res Lett 10:326

    Article  Google Scholar 

  • Hong FS, Wu N, Zhao XY, Tian YS, Zhou YJ, Chen T, Zhai YY, Ji L (2016) Titanium dioxide nanoparticle-induced dysfunction of cardiac hemodynamics is involved in cardiac inflammation in mice. J Biomed Mater Res A 104:2917–2927

    Article  Google Scholar 

  • Hong FS, Yu XH, Wu N, Zhang YQ (2017) Progress of in vivo studies on the systemic toxicities induced by titanium dioxide nanoparticles. Toxicol Res 6:115–133

    Article  Google Scholar 

  • Houštěk J, Pícková A, Vojtísková A, Jesina P (2006) Mitochondrial diseases and genetic defects of ATP synthase. Biochim Biophys Acta 1757:1400–1405

    Article  Google Scholar 

  • Houštěk J, Kmoch S, Mayr JA, Sperl W, Zeman J (2010) 4L.3 genetic disorders of mitochondrial ATP synthase. Biochim Biophys Acta 1797:47

    Google Scholar 

  • Hu RP, Zheng L, Zhang T, Gao GD, Cui YL, Cheng Z, Cheng J, Hong MM, Tang M, Hong FS (2011) Molecular mechanism of hippocampal apoptosis of mice following exposure to titanium dioxide nanoparticles. J Hazard Mater 191:32–40

    Article  Google Scholar 

  • Jezek P, Hlavata L (2005) Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int J Biochem Cell Biol 37:2478–2503

    Article  Google Scholar 

  • Jia G, Cheng G, Gangahar DM, Agrawal DK (2006) Insulin-like growth factor-1 and TNF-alpha regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells. Immunol Cell Biol 84:448–454

    Article  Google Scholar 

  • Lenaz G, Genova ML (2010) Structure and organization of mitochondrial respiratory complexes: a new understanding of an old subject. Antioxid Redox Signal 12:961–1008

    Article  Google Scholar 

  • Lewalle A, Niederer SA, Smith NP (2014) Species-dependent adaptation of the cardiac Na+/K+ pump kinetics to the intracellular Na+ concentration. J Physiol 592:5355–5371

    Article  Google Scholar 

  • Liu HT, Ma LL, Zhao JF, Liu J, Yan JY, Ruan J (2009) Biochemical toxicity of mice caused by nano-anatase TiO2 particles. Biol Trace Elem Res 129:170–180

    Article  Google Scholar 

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

    Article  Google Scholar 

  • Marsden VS, O'Connor L, O'Reilly LA, Silke J, Metcalf D, Ekert PG, Huang DC, Cecconi F, Kuida K, Tomaselli KJ, Roy S, Nicholson DW, Vaux DL, Bouillet P, Adams JM, Strasser A (2002) Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Nature 419:634–637

    Article  Google Scholar 

  • Mikkelsen L, Sheykhzade M, Jensen KA, Saber AT, Jacobsen NR, Vogel U, Wallin H, Loft S, Moller P (2011) Modest effect on plaque progression and vasodilatory function in atherosclerosis-prone mice exposed to nanosized TiO2. Part Fibre Toxicol 8:32

    Article  Google Scholar 

  • National Institute for Occupational Safety and Health (NIOSH) (2011) Outlines Guidance on Handling Titanium Dioxide (TiO2). Atlanta

  • Nurkiewicz TR, Porter DW, Hubbs AF, Stone S, Moseley AM, Cumpston JL, Goodwill AG, Frisbee SJ, Perrotta PL, Brock RW, Frisbee JC, Boegehold MA, Frazer DG, Chen BT, Castranova V (2011) Pulmonary particulate matter and systemic microvascular dysfunction. Res Rep Health Eff Inst 364:3–48

    Google Scholar 

  • Park EJ, Choi J, Park YK, Park K (2008) Oxidative stress induced by cerium oxide nanoparticles in cultured BEAS-2B cells. Toxicology 245:90–100

    Article  Google Scholar 

  • Pei Y, Jiang R, Zou Y, Wang Y, Zhang S, Wang G, Zhao J, Song W (2016) Effects of fine particulate matter (PM2.5) on systemic oxidative stress and cardiac function in ApoE−/− mice. Int J Environ Res Public Health 13(5):484

    Article  Google Scholar 

  • Pepe S, Sheeran F (2010) 4L.5 mitochondrial energy, redox dysregulation in human heart failure: role of post-oxidative enzyme modification. Biochim Biophys Acta 1797:48

    Article  Google Scholar 

  • Peters A, Dockery DW, Muller JE, Mittleman MA (2001) Increased particulate air pollution and the triggering of myocardial infarction. Circulation 103:2810–2815

    Article  Google Scholar 

  • Puett RC, Hart JE, Yanosky JD, Paciorek C, Schwartz J, Suh H, Speizer FE, Laden F (2009) Chronic fine and coarse particulate exposure, mortality, and coronary heart disease in the Nurses’ health study. Environ Health Perspect 117:1697–1701

    Article  Google Scholar 

  • Sha BY, Gao W, Wang SQ, Li W, Liang X, Xu F, Lu TJ (2013) Nano-titanium dioxide induced cardiac injury in rat under oxidative stress. Food Chem Toxicol 58:280–288

    Article  Google Scholar 

  • Shattock MJ, Ottolia M, Bers DM, Blaustein MP, Boguslavskyi A, Bossuyt J, Bridge JH, Ye CI, Clancy CE, Edwards A, Goldhaber J, Kaplan J, Lingrel JB, Pavlovic D, Philipson K, Sipido KR, Xie ZJ (2015) Na+/Ca2+ exchange and Na+/K+-ATPase in the heart. J Physiol 593:1361–1382

    Article  Google Scholar 

  • Sheng L, Wang XC, Sang XZ, Ze YG, Zhao XY, Liu D, Gui SX, Sun QQ, Cheng J, Cheng Z, Hu RP, Wang L, Hong FS (2013) Cardiac oxidative damage in mice following exposure to nanoparticulate titanium dioxide. J Biomed Mater Res A 101:3238–3246

    Google Scholar 

  • Simkhovich BZ, Kleinman MT, Kloner RA (2009) Particulate air pollution and coronary heart disease. Curr Opin Cardiol 24:604–609

    Article  Google Scholar 

  • Sullivan J, Sheppard L, Schreuder A, Ishikawa N, Siscovick D, Kaufman J (2005) Relation between short-term fine-particulate matter exposure and onset of myocardial infarction. Epidemiology 16:41–48

    Article  Google Scholar 

  • Sun Q, Hong X, Wold LE (2010) Cardiovascular effects of ambient particulate air pollution exposure. Circulation 121:2755–2765

    Article  Google Scholar 

  • Valko M, Morris H, Cronin MT (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12:1161–1208

    Article  Google Scholar 

  • Wei N, He HB, Zhang CC, Yuan D (2013) Research development between JNK pathway and apoptosis. Chin J Clin Pharmacol Ther 18:807–812

    Google Scholar 

  • Yang P, Lu C, Hua NP, Du YK (2002) Titanium dioxide nanoparticles co-doped with Fe3+ and Eu3+ ions for photocatalysis. Mater Lett 57:794–801

    Article  Google Scholar 

  • Yu XH, Zhao XY, Ze YG, Wang L, Liu D, Hong J, Xu BQ, Lin AA, Zhang C, Zhao Y, Li BY, Hong FS (2014) Changes of serum parameters of TiO2 nanoparticle-induced atherosclerosis in mice. J Hazard Mater 280:364–371

    Article  Google Scholar 

  • Yu XH, Hong FS, Zhang YQ (2016a) Bio-effect of nanoparticles in the cardiovascular system. J Biomed Mater Res A 104:2881–2897

    Article  Google Scholar 

  • Yu XH, Hong FS, Zhang YQ (2016b) Cardiac inflammation involving in PKCε or ERK1/2-activated NF-κB signalling pathway in mice following exposure to titanium dioxide nanoparticles. J Hazard Mater 313:68–77

    Article  Google Scholar 

  • Zhao D, Dhalla NS (1988) Characterization of rat heart plasma membrane Ca2+/Mg2+ ATPase. Arch Biochem Biophys 263:281–292

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant Nos. 31671033, 81473007, 81273036, and 30901218); the National Natural Science Foundation of Jiangsu Province (grant No. BK20161306); and the top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015A018).

Author information

Author notes

  1. Yingjun Zhou, and Fashui Hong contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huai’an, 223300, China

    Yingjun Zhou & Fashui Hong

  2. Laboratory for Food Safety and Nutritional Function, Huaiyin Normal University, Huai’an, 223300, China

    Yingjun Zhou & Fashui Hong

  3. Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huai’an, 223300, China

    Yingjun Zhou & Fashui Hong

  4. School of Life Sciences, Huaiyin Normal University, Huai’an, China

    Yingjun Zhou & Fashui Hong

  5. Library of Soochow University, Suzhou, 215123, China

    Ling Wang

Authors
  1. Yingjun Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fashui Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ling Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fashui Hong.

Ethics declarations

All animal experiments were conducted during the light phase and approved by the Animal Experimental Committee of Soochow University (Grant 2111270). Procedures were performed in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, Y., Hong, F. & Wang, L. Titanium dioxide nanoparticle-induced cytotoxicity and the underlying mechanism in mouse myocardial cells. J Nanopart Res 19, 356 (2017). https://doi.org/10.1007/s11051-017-4052-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11051-017-4052-y

Keywords

Search

Navigation