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Chronic exposure to zinc oxide nanoparticles increases ischemic-reperfusion injuries in isolated rat hearts

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Abstract

The use of zinc oxide nanoparticles (ZnO NPs) in numerous products is increasing, although possible negative implications of their long-term consumption are not known yet. Our aim was to evaluate the chronic, 6-week oral exposure to two different concentrations of ZnO NPs on isolated rat hearts exposed to ischemic-reperfusion injury and on small intestine morphology. Wistar rats of both sexes (n = 18) were randomly divided into three groups: (1) 4 mg/kg ZnO NPs, (2) 40 mg/kg ZnO NPs, and (3) control. After 6 weeks of treatment, the hearts were isolated, the left ventricular pressure (LVP), the coronary flow (CF), the duration of arrhythmias and the lactate dehydrogenase release rate (LDH) were measured. A histological investigation of the small intestine was performed. Chronic exposure to ZnO NPs acted cardiotoxic dose-dependently. ZnO NPs in dosage 40 mg/kg maximally decreased LVP (3.3-fold) and CF (2.5-fold) and increased the duration of ventricular tachycardia (all P < 0.01) compared to control, whereas ZnO NPs in dosage 4 mg/kg acted less cardiotoxic. Goblet cells in the small intestine epithelium of rats, treated with 40 mg ZnO NPs/kg, were enlarged, swollen and numerous, the intestinal epithelium width was increased. Unexpectedly, ZnO NPs in both dosages significantly decreased LDH. A 6-week oral exposure to ZnO NPs dose-dependently increased heart injuries and caused irritation of the intestinal mucosa. A prolonged exposure to ZnO NPs might cause functional damage to the heart even with exposures to the recommended daily doses, which should be tested in future studies.

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References

  • Alarifi S, Ali D, Alkahtani S, Verma A, Ahamed M, Ahmed M, Alhadlaq HA (2013) Induction of oxidative stress DNA damage, and apoptosis in a malignant human skin melanoma cell line after exposure to zinc oxide nanoparticles. Int J Nanomedicine 8:983–993. doi:10.2147/IJN.S42028ijn-8-983

    Article  Google Scholar 

  • Alvarez-Collazo J, Diaz-Garcia CM, Lopez-Medina AI, Vassort G, Alvarez JL (2012) Zinc modulation of basal and beta-adrenergically stimulated L-type Ca2+ current in rat ventricular cardiomyocytes: consequences in cardiac diseases. Pflugers Arch 464:459–470. doi:10.1007/s00424-012-1162-3

    Article  Google Scholar 

  • Amara S et al (2014) Effects of zinc oxide nanoparticles and/or zinc chloride on biochemical parameters and mineral levels in rat liver and kidney. Hum Exp Toxicol 33:1150–1157. doi:10.1177/09603271135103270960327113510327

    Article  Google Scholar 

  • Bacchetta R et al (2014) Evidence and uptake routes for Zinc oxide nanoparticles through the gastrointestinal barrier in xenopus laevis. Nanotoxicology 8:728–744. doi:10.3109/17435390.2013.824128

    Google Scholar 

  • Baek M et al (2012) Pharmacokinetics, tissue distribution, and excretion of zinc oxide nanoparticles. Int J Nanomedicine 7:3081–3097. doi:10.2147/IJN.S32593ijn-7-3081

    Google Scholar 

  • Baky NA, Faddah LM, Al-Rasheed NM, Fatani AJ (2013) Induction of inflammation DNA damage and apoptosis in rat heart after oral exposure to zinc oxide nanoparticles and the cardioprotective role of alpha-lipoic acid and vitamin E. Drug Res (Stuttg) 63:228–236. doi:10.1055/s-0033-1334923

    Article  Google Scholar 

  • Bancroft JD, Gamble M (2008) Theory and practice of histological techniques. Elsevier Health Sciences, Churchill Livingstone, London

    Google Scholar 

  • Bondarenko O, Juganson K, Ivask A, Kasemets K, Mortimer M, Kahru A (2013) Toxicity of Ag, CuO and ZnO nanoparticles to selected environmentally relevant test organisms and mammalian cells in vitro: a critical review. Arch Toxicol 87:1181–1200. doi:10.1007/s00204-013-1079-4

    Article  Google Scholar 

  • Bumbudsanpharoke N, Choi J, Ko S (2015) Applications of nanomaterials in Food packaging. J Nanosci Nanotechnol 15:6357–6372

    Article  Google Scholar 

  • Chang Y-N, Zhang M, Xia L, Zhang J, Xing G (2012) The toxic effects and mechanisms of CuO and ZnO nanoparticles. Materials 5:2850. doi:10.3390/ma5122850

    Article  Google Scholar 

  • Cho WS, Kang BC, Lee JK, Jeong J, Che JH, Seok SH (2013) Comparative absorption, distribution, and excretion of titanium dioxide and zinc oxide nanoparticles after repeated oral administration. Part Fibre Toxicol 10:9. doi:10.1186/1743-8977-10-9-8977-10-9

    Article  Google Scholar 

  • Chung HE et al (2013) Toxicokinetics of zinc oxide nanoparticles in rats. J Phys Conf Ser 429:1–7. doi:10.1088/1742-6596/429/1/012037

    Article  Google Scholar 

  • Contado C (2015) Nanomaterials in consumer products: a challenging analytical problem. Front Chem 3:48. doi:10.3389/fchem.2015.00048

    Article  Google Scholar 

  • Croteau MN, Dybowska AD, Luoma SN, Valsami-Jones E (2011) A novel approach reveals that zinc oxide nanoparticles are bioavailable and toxic after dietary exposures. Nanotoxicology 5:79–90. doi:10.3109/17435390.2010.501914

    Article  Google Scholar 

  • Curtis MJ et al (2013) The Lambeth conventions (II): guidelines for the study of animal and human ventricular and supraventricular arrhythmias. Pharmacol Ther 139:213–248. doi:10.1016/j.pharmthera.2013.04.008S0163-7258(13)00087-9

    Article  Google Scholar 

  • De Berardis B, Civitelli G, Condello M, Lista P, Pozzi R, Arancia G, Meschini S (2010) Exposure to ZnO nanoparticles induces oxidative stress and cytotoxicity in human colon carcinoma cells. Toxicol Appl Pharmacol 246:116–127. doi:10.1016/j.taap.2010.04.012

    Article  Google Scholar 

  • Efeovbokhan N, Bhattacharya SK, Ahokas RA, Sun Y, Guntaka RV, Gerling IC, Weber KT (2014) Zinc and the prooxidant heart failure phenotype. J Cardiovasc Pharmacol 64:393–400. doi:10.1097/FJC.000000000000012500005344-201410000-00014

    Article  Google Scholar 

  • Esmaeillou M, Moharamnejad M, Hsankhani R, Tehrani AA, Maadi H (2013) Toxicity of ZnO nanoparticles in healthy adult mice. Environ Toxicol Pharmacol 35:67–71. doi:10.1016/j.etap.2012.11.003S1382-6689(12)00161-5

    Article  Google Scholar 

  • Espitia P, Ndt Soares, Jld Coimbra, de Andrade NL, Cruz R, Medeiros E (2012) Zinc oxide nanoparticles: synthesis antimicrobial activity and food packaging applications. Food Bioprocess Technol 5:1447–1464. doi:10.1007/s11947-012-0797-6

    Article  Google Scholar 

  • Estrada-Izquierdo I, Sánchez-Espindola E, Uribe-Hernández Rl, Ramón-Gallegos E (2012) Analysis of the impregnation of ZnO:Mn2+ nanoparticles on cigarette filters for trapping polycyclic aromatic hydrocarbons (PAHs). In: AIP conference proceedings, vol 1494, pp 140–142. doi:10.1063/1.4764624

  • Evangelou A, Kalfakakou V (1993) Electrocardiographic alterations induced by zinc ions on isolated guinea pig heart preparations. Biol Trace Elem Res 36:203–208. doi:10.1007/BF02783179

    Article  Google Scholar 

  • Fan W, Li Q, Yang X, Zhang L (2013) Zn subcellular distribution in liver of goldfish (carassius auratus) with exposure to zinc oxide nanoparticles and mechanism of hepatic detoxification. PLoS One 8:e78123. doi:10.1371/journal.pone.0078123

    Article  Google Scholar 

  • Formigari A, Irato P, Santon A (2007) Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: biochemical and cytochemical aspects. Comp Biochem Physiol C Toxicol Pharmacol 146:443–459. doi:10.1016/j.cbpc.2007.07.010

    Article  Google Scholar 

  • Golobic M, Jemec A, Drobne D, Romih T, Kasemets K, Kahru A (2012) Upon exposure to Cu nanoparticles, accumulation of copper in the isopod Porcellio scaber is due to the dissolved Cu ions inside the digestive tract. Environ Sci Technol 46:12112–12119. doi:10.1021/es3022182

    Article  Google Scholar 

  • Guo D, Bi H, Liu B, Wu Q, Wang D, Cui Y (2013) Reactive oxygen species-induced cytotoxic effects of zinc oxide nanoparticles in rat retinal ganglion cells. Toxicol In Vitro 27:731–738. doi:10.1016/j.tiv.2012.12.001

    Article  Google Scholar 

  • Hsiao IL, Huang YJ (2011) Titanium oxide shell coatings decrease the cytotoxicity of ZnO nanoparticles. Chem Res Toxicol 24:303–313. doi:10.1021/tx1001892

    Article  Google Scholar 

  • Hua J, Vijver MG, Richardson MK, Ahmad F, Peijnenburg WJ (2014) Particle-specific toxic effects of differently shaped zinc oxide nanoparticles to zebrafish embryos (Danio rerio). Environ Toxicol Chem 33:2859–2868. doi:10.1002/etc.2758

    Article  Google Scholar 

  • Kang T, Guan R, Chen X, Song Y, Jiang H, Zhao J (2013) In vitro toxicity of different-sized ZnO nanoparticles in Caco-2 cells. Nanoscale Res Lett 8:496. doi:10.1186/1556-276X-8-496

    Article  Google Scholar 

  • Kao YY, Chen YC, Cheng TJ, Chiung YM, Liu PS (2012) Zinc oxide nanoparticles interfere with zinc ion homeostasis to cause cytotoxicity. Toxicol Sci 125:462–472. doi:10.1093/toxsci/kfr319kfr319

    Article  Google Scholar 

  • Kim YH et al (2015) Retinopathy induced by zinc oxide nanoparticles in rats assessed by micro-computed tomography and histopathology. Toxicol Res 31:157–163. doi:10.5487/TR.2015.31.2.157

    Article  Google Scholar 

  • Konduru NV, Murdaugh KM, Sotiriou GA, Donaghey TC, Demokritou P, Brain JD, Molina RM (2014) Bioavailability, distribution and clearance of tracheally-instilled and gavaged uncoated or silica-coated zinc oxide nanoparticles. Part Fibre Toxicol 11:44. doi:10.1186/s12989-014-0044-6

    Article  Google Scholar 

  • Kuhar P, Lunder M, Drevensek G (2007) The role of gender and sex hormones in ischemic-reperfusion injury in isolated rat hearts. Eur J Pharmacol 561:151–159. doi:10.1016/j.ejphar.2007.01.043

    Article  Google Scholar 

  • Liu J, Feng X, Wei L, Chen L, Song B, Shao L (2016) The toxicology of ion-shedding zinc oxide nanoparticles. Crit Rev Toxicol 46:348–384. doi:10.3109/10408444.2015.1137864

    Article  Google Scholar 

  • Ma H, Williams PL, Diamond SA (2013) Ecotoxicity of manufactured ZnO nanoparticles—a review. Environ Pollut 172:76–85. doi:10.1016/j.envpol.2012.08.011

    Article  Google Scholar 

  • McIntosh R et al (2010) The critical role of intracellular zinc in adenosine A(2) receptor activation induced cardioprotection against reperfusion injury. J Mol Cell Cardiol 49:41–47. doi:10.1016/j.yjmcc.2010.02.001

    Article  Google Scholar 

  • Moos PJ, Chung K, Woessner D, Honeggar M, Cutler NS, Veranth JM (2010) ZnO particulate matter requires cell contact for toxicity in human colon cancer cells. Chem Res Toxicol 23:733–739. doi:10.1021/tx900203v

    Article  Google Scholar 

  • Nunes AD et al (2014) Manganese ferrite-based nanoparticles induce ex vivo, but not in vivo, cardiovascular effects. Int J Nanomedicine 9:3299–3312. doi:10.2147/IJN.S64254

    Google Scholar 

  • Paek HJ et al (2013) Modulation of the pharmacokinetics of zinc oxide nanoparticles and their fates in vivo. Nanoscale 5:11416–11427. doi:10.1039/c3nr02140h

    Article  Google Scholar 

  • Park HS et al (2014) A 90-day study of sub-chronic oral toxicity of 20 nm positively charged zinc oxide nanoparticles in sprague dawley rats. Int J Nanomedicine 9(Suppl 2):93–107. doi:10.2147/IJN.S57927

    Google Scholar 

  • Pasupuleti S, Alapati S, Ganapathy S, Anumolu G, Pully NR, Prakhya BM (2012) Toxicity of zinc oxide nanoparticles through oral route. Toxicol Ind Health 28:675–686. doi:10.1177/0748233711420473

    Article  Google Scholar 

  • Piccinno F, Gottschalk F, Seeger S, Nowack B (2012) Industrial production quantities and uses of ten engineered nanomaterials in Europe and the world. J Nanopart Res 14:1–11. doi:10.1007/s11051-012-1109-9

    Article  Google Scholar 

  • Pipan-Tkalec Z, Drobne D, Jemec A, Romih T, Zidar P, Bele M (2010) Zinc bioaccumulation in a terrestrial invertebrate fed a diet treated with particulate ZnO or ZnCl2 solution. Toxicology 269:198–203. doi:10.1016/j.tox.2009.08.004

    Article  Google Scholar 

  • Romih T et al (2016) FTIR microscopy reveals distinct biomolecular profile of crustacean digestive glands upon subtoxic exposure to ZnO nanoparticles. Nanotoxicology 10:462–470. doi:10.3109/17435390.2015.1078853

    Article  Google Scholar 

  • Savoly Z, Hracs K, Pemmer B, Streli C, Zaray G, Nagy PI (2016) Uptake and toxicity of nano-ZnO in the plant-feeding nematode, Xiphinema vuittenezi: the role of dissolved zinc and nanoparticle-specific effects. Environ Sci Pollut Res Int 23:9669–9678. doi:10.1007/s11356-015-5983-4

    Article  Google Scholar 

  • Schleh C et al (2012) Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration. Nanotoxicology 6:36–46. doi:10.3109/17435390.2011.552811

    Article  Google Scholar 

  • Song MK et al (2009) Body weight reduction in rats by oral treatment with zinc plus cyclo-(His-Pro). Br J Pharmacol 158:442–450. doi:10.1111/j.1476-5381.2009.00201.x

    Article  Google Scholar 

  • Stampfl A, Maier M, Radykewicz R, Reitmeir P, Gottlicher M, Niessner R (2011) Langendorff heart: a model system to study cardiovascular effects of engineered nanoparticles. ACS Nano 5:5345–5353. doi:10.1021/nn200801c

    Article  Google Scholar 

  • Tong H, McGee JK, Saxena RK, Kodavanti UP, Devlin RB, Gilmour MI (2009) Influence of acid functionalization on the cardiopulmonary toxicity of carbon nanotubes and carbon black particles in mice. Toxicol Appl Pharmacol 239:224–232. doi:10.1016/j.taap.2009.05.019

    Article  Google Scholar 

  • Vandebriel RJ, De Jong WH (2012) A review of mammalian toxicity of ZnO nanoparticles. Nanotechnol Sci Appl 5:61–71. doi:10.2147/NSA.S23932

    Article  Google Scholar 

  • Vasilache V, Popa C, Filote C, Cretu MA, Benta M (2011) Nanoparticles applications for improving the food safety and food processing. Recent 12:77–81

    Google Scholar 

  • Wang B et al (2006) Acute toxicity of nano- and micro-scale zinc powder in healthy adult mice. Toxicol Lett 161:115–123. doi:10.1016/j.toxlet.2005.08.007

    Article  Google Scholar 

  • Wang L, Ding W, Zhang F (2010) Acute toxicity of ferric oxide and zinc oxide nanoparticles in rats. J Nanosci Nanotechnol 10:8617–8624

    Article  Google Scholar 

  • Wroblewski F, Ladue JS (1955) Lactic dehydrogenase activity in blood. Proc Soc Exp Biol Med 90:210–213

    Article  Google Scholar 

  • Yu KN et al (2013) Zinc oxide nanoparticle induced autophagic cell death and mitochondrial damage via reactive oxygen species generation. Toxicol In Vitro 27:1187–1195. doi:10.1016/j.tiv.2013.02.010

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Biology, Biotechnical Faculty, University of Ljubljana, Večna Pot 111, 1000, Ljubljana, Slovenia

    Tamara Milivojević, Damjana Drobne, Tea Romih & Lilijana Bizjak Mali

  2. Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000, Ljubljana, Slovenia

    Irena Marin, Mojca Lunder & Gorazd Drevenšek

  3. Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, 6000, Koper, Slovenia

    Gorazd Drevenšek

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  1. Tamara Milivojević
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  2. Damjana Drobne
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  3. Tea Romih
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Milivojević, T., Drobne, D., Romih, T. et al. Chronic exposure to zinc oxide nanoparticles increases ischemic-reperfusion injuries in isolated rat hearts. J Nanopart Res 18, 309 (2016). https://doi.org/10.1007/s11051-016-3573-0

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