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Drug Res (Stuttg) 2013; 63(05): 228-236
DOI: 10.1055/s-0033-1334923
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Induction of Inflammation, DNA Damage and Apoptosis in Rat Heart after Oral Exposure to Zinc Oxide Nanoparticles and the Cardioprotective Role of α-lipoic Acid and Vitamin E

N.A. A. Baky
1   Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, KSA
2   Department of Pharmacology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
,
L. M. Faddah
1   Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, KSA
,
N. M. Al-Rasheed
1   Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, KSA
,
N. M. Al-Rasheed
1   Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, KSA
,
A. J. Fatani
1   Pharmacology Department, Faculty of Pharmacy, King Saud University, Riyadh, KSA
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 11. September 2012

accepted 31. Januar 2013

Publikationsdatum:
26. März 2013 (online)

Auch verfügbar auf
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Abstract

Although zinc oxide nanoparticles (ZnO-NP) are being used on a wide scale in the world consumer market, their potential hazards on humans remain largely unknown. The present study was aimed at investigating the oral toxicity of ZnO-NP in 2 dose regimen (600 mg/kg and 1 g/kg body weight for 5 consecutive days) in rats. In addition, the protective role of either α-lipoic acid (Lipo) or vitamin E (Vit E) against this cardiotoxic effect of ZnO-NPs was assessed. Results revealed that, co-administration of Lipo (200 mg/Kg body weight) or Vit E (100 mg/Kg body weight) daily for 3 weeks to rats intoxicated with ZnO-NPs (in either of the 2 dose regimen) significantly ameliorated the cardiotoxic effect of these nanoparticles. As, both agents significantly reduced the increase in serum cardiac injury markers including troponin-T, creatine kinase-MB (CK-MB), and myoglobin. Additionally, Lipo and Vit E significantly decreased the increase in serum pro-inflammatory biomarkers level including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP). Moreover, either of the 2 used agents successfully alleviated the alteration in nitric oxide (NO) and vascular endothelial growth factor (VEGF) in ZnO-NPs in sera of intoxicated group. They also significantly reduced the increase in cardiac calcium concentration and the consequent oxidative deoxyribonucleic acid (DNA) damage, as well as the increase in cardiac caspase-3 activity of intoxicated rats. Conclusively, these results indicate that early treatment with either α-lipoic acid or vitamin E may offer protection against cardiac tissue injury induced by the deleterious toxic impacts of ZnO–NPs.

Key words

α-lipoic acid - deoxyribonucleic acid - vitamin E - zinc oxide nanoparticles
 

  • References

  • 1 Nel A, Xia T, Madler L et al. Toxic potential of materials at the nano-level. Sci 2006; 311: 622-627
    CrossrefPubMedGoogle Scholar
  • 2 Service RF. U.S. nanotechnology. Health and safety research slated for sizable gains. Sci 2007; 315: 926
    PubMedGoogle Scholar
  • 3 Lu S, Duffin R, Poland C et al. Efficacy of simple short-term in vitro assays for predicting the potential of metal oxide nanoparticles to cause pulmonary inflammation. Environ. Health Perspect 2009; 117: 241-247
    PubMedGoogle Scholar
  • 4 Nel AE, Madler L, Velegol D et al. Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 2009; 8: 543-557
    CrossrefPubMedGoogle Scholar
  • 5 Johnston HJ, Hutchison G, Christensen FM et al. Areview of the in vivo and in vitro toxicity of silver and gold particulates: particle attributes and biological mechanisms responsible for the observed toxicity. Crit Rev Toxicol 2010; 40: 328-346
    CrossrefPubMedGoogle Scholar
  • 6 Colvin VL. The potential environmental impact of engineered nanomaterials. Nat Biotechnol 2003; 21: 1166-1170
    CrossrefPubMedGoogle Scholar
  • 7 Donaldson K, Tran L, Jimenez LA et al. Combustion-derived nanoparticles: A review of their toxicology following inhalation exposure. Part Fibre Toxicol 2005; 2: 10
    CrossrefPubMedGoogle Scholar
  • 8 Li N, Sioutas C, Cho A et al. Ultrafine particulate pollutants induce oxidative stress and mitochrondrial damage. Env Health Perspect 2003; 111: 455-460
    PubMedGoogle Scholar
  • 9 Heinlaan M, Ivask A, Blinova I et al. Toxicity of nanosized and bulk ZnO, CuO and TiO2 to bacteria Vibrio fischeri and crustaceans Daphnia magna and Thamnocephalus platyurus. Chemosphere 2008; 71: 1308-1316
    CrossrefPubMedGoogle Scholar
  • 10 Gojova A, Guo B, Kota RS et al. Induction of inflammation in vascular endothelial cells by metal oxide nanoparticles: effect of particle composition. Environ Health Perspect 2007; 115: 403-409
    CrossrefPubMedGoogle Scholar
  • 11 Lin WS, Xu Y, Huang CC et al. Toxicity of nano- and micro-sized ZnO particles in human lung epithelial cells. J Nanopart Res 2009; 11: 25-29
    CrossrefPubMedGoogle Scholar
  • 12 Pasupuleti S, Alapati S, Ganapathy S et al. Toxicity of zinc oxide nanoparticles through oral route. Toxicol Ind Health 2012; 28: 675-686
    CrossrefPubMedGoogle Scholar
  • 13 Wu GH, Zhang YW, Wu ZH. Modulation of postoperative immune and inflammatory response by immune-enhancing enteral diet in gastrointestinal cancer patients. World J Gastroentero 2001; 7: 357-362
    PubMedGoogle Scholar
  • 14 Dias AS, Porawski M, Alonso M et al. Quercetin Decreases Oxidative Stress, NF-κB Activation, and iNOS Overexpression in Liver of Streptozotocin-Induced Diabetic Rats. J Nutr 2005; 135: 2299-2304
    PubMedGoogle Scholar
  • 15 Chana ST, Chuangb CH, Yehb CL et al. Quercetin supplementation suppresses the secretion of pro-inflammatory cytokines in the lungs of Mongolian gerbils and in A549 cells exposed to benzo[a]pyrene alone or in combination with β-carotene: in vivo and ex vivo studies. J Nutr Biochem 2011; (in press)
    PubMedGoogle Scholar
  • 16 Bilska A, Wlodek L. Α-lipoic acid — the drug of the future?. Pharmacol Rep 2005; 57: 570-577
    PubMedGoogle Scholar
  • 17 Budhwar R, Kumar S. Substantial inhibition of chromate induced DNA-protein crosslink formation in vivo by alpha-α-lipoic acid. Environ. Toxicol Pharmacol 2005; 20: 246-249
    PubMedGoogle Scholar
  • 18 Lee WJ, Lee IK, Kim HS et al. Α-lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase. Arterioscler Thromb Vasc Biol 2005; 25: 2488-2494
    CrossrefPubMedGoogle Scholar
  • 19 Schonheit K, Gille L, Nohl H. Effect of alpha-α-lipoic acid and ihydroα-lipoic acid on ischemia/reperfusion injury of the heart and heart mitochondria. Biochem Biophys Acta 1995; 1271: 335-342
    PubMedGoogle Scholar
  • 20 Cao Z, Tsang M, Zhao H et al. Induction of endogenous anti-oxidants and phase 2 enzymes by alpha-α-lipoic acid in rat cardiac H9C2 cells: protection against oxidative injury. Biochem Biophys Res Commun 2003; 310: 979-985
    CrossrefPubMedGoogle Scholar
  • 21 Oh SK, Yun KH, Yoo NJ et al. Cardioprotective Effects of Alpha-Α-lipoic Acid on Myocardial Reperfusion Injury: Suppression of Reactive Oxygen Species Generation and Activation of Mitogen-Activated Protein Kinase. Korean Circ J 2009; 39: 359-366
    CrossrefPubMedGoogle Scholar
  • 22 Schaffer S, Müller WE, Eckert GP. Tocotrienols: constitutional effects in aging and disease. J Nutr 2005; 135: 151-154
    PubMedGoogle Scholar
  • 23 Zingg JM. Modulation of signal transduction by vitamin E. Molecular Aspects of Medicine 2007; 28: 481-506
    CrossrefPubMedGoogle Scholar
  • 24 Yang CS, Lu G, Ju J et al. Inhibition of Inflammation and Carcinogenesis in the Lung and Colon by Tocopherols. Ann N Y Acad Sci 2010; 1203: 29-34
    CrossrefPubMedGoogle Scholar
  • 25 Qureshi AA, Reis JC, Qureshi N et al. δ-Tocotrienol and quercetin reduce serum levels of nitric oxide and lipid parameters in female chickens. Lipids in Health and Disease 2011; 10: 39-58
    CrossrefPubMedGoogle Scholar
  • 26 Tahan G, Aytac E, Aytekin H et al. Vitamin E has a dual effect of anti-inflammatory and antioxidant activities in acetic acid – induced ulcerative colitis in rats. Can J Surg 2011; 54: 333-338
    CrossrefPubMedGoogle Scholar
  • 27 Makpol S, Durani LW, Chua KH et al. Tocotrienol-Rich Fraction Prevents Cell Cycle Arrest and Elongates Telomere Length in Senescent Human Diploid Fibroblasts. J Biomed Biotechnol 2011; 2011: 506171
    PubMedGoogle Scholar
  • 28 Wang B, Feng W, Wang W et al. Acute toxicological impact of nano-and submicro-scaled zinc oxide powder on healthy adult mice. J nano part Res 2008; 10: 263-276
    PubMedGoogle Scholar
  • 29 Sharma M, Gupta YK. Effect of alpha α-lipoic acid on intracerebroventricular streptozotocin model of cognitive impairment in rats. Eur Neuropsychopharmacol 2003; 13: 241-247
    CrossrefPubMedGoogle Scholar
  • 30 Ishrat T, Parveen K, Hoda MN et al. Effects of Pycnogenol and vitamin E on cognitive deficits and oxidative damage induced by intracerebroventricular streptozotocin in rats. Behav Pharmacol 2009; 20: 567-575
    CrossrefPubMedGoogle Scholar
  • 31 Kaden J. IL-6 determination in serum of kidney graft recipients by a new bedside test: its diagnostic relevance. Transplant Proc 2007; 39: 511-513
    CrossrefPubMedGoogle Scholar
  • 32 Kim N, Kim YJ, Cho DK. Gold nanoparticle-based signal augmentation of quartz crystal microbalance immunosensor measuring C-reactive protein. Curr Appl Phys 2010; 10: 1227-1230
    CrossrefPubMedGoogle Scholar
  • 33 Yao DF, Wu XH, Zhu Y et al. Quantitative analysis of vascular endothelial growth factor, microvascular density and their clinicopathologic features in human hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2005; 4: 220-226
    PubMedGoogle Scholar
  • 34 Moshage H, Kok B, Uuizenga JR et al. Nitrite and Nitrate Determination in Plasma: A Critical Evaluation. Clin Chim 1995; 41: 892-896
    PubMedGoogle Scholar
  • 35 Nath R, Raser KJ, Stafford D et al. Nonerythroid alpha-spectrin breakdown by calpain and ICE-like protease(s) in apoptotic cells: contribu-tory roles of both protease families in neuronal apoptosis. Biochem J 1996; 319: 683-690
    PubMedGoogle Scholar
  • 36 Singh NP, McCoy MT, Tice RR et al. A simple technique foe quantitation of low levels of DNA damage in individaul cells Exp Cell Res 1988; 175: 184-191
    CrossrefPubMed
  • 37 Beckett WS, Chalupa DF, Pauly-Brown A et al. Comparing inhaled ultrafine versus fine zinc oxide particles in healthy adults: a human inhalation study. Am J Respir Crit Care Med 2005; 171: 1129-1135
    CrossrefPubMedGoogle Scholar
  • 38 Sharma V, Singh P, Pandey AK et al. Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles. Mutat Res 2012; 745: 84-91 Epub 2011 Dec 17
    PubMedGoogle Scholar
  • 39 Yan G, Huang Y, Bu Q et al. Zinc oxide nanoparticles cause nephrotoxicity and kidney metabolism alterations in rats. J Environ Sci Health A Tox Hazard Subst Environ Eng 2012; 47: 577-588
    CrossrefPubMedGoogle Scholar
  • 40 Tsung SH. Several conditions causing elevation of serum CK-MB and CK-BB. Am J Clin Pathol 1981; 75: 711-715
    PubMedGoogle Scholar
  • 41 Braunwald E. Unstable angina – a classification. Circulation 1989; 80: 410-414
    CrossrefPubMedGoogle Scholar
  • 42 Hamm CW, Ravkilde J, Gerhardt W et al. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992; 327: 146-150
    CrossrefPubMedGoogle Scholar
  • 43 Santos ES, Baltar VT, Pereira MP et al. Comparison between Cardiac Troponin I and CK-MB Mass in Acute Coronary Syndrome without ST Elevation. Arq Bras Cardiol 2011; 96: 179-187
    CrossrefPubMedGoogle Scholar
  • 44 Adamcova M, Kokstein Z, Vavrova J. Clinical utility of cardiac troponin I and cardiac troponin T measurements. Acta Medica 1997; 40: 83-87
    PubMedGoogle Scholar
  • 45 Soukaloun D, Lee SJ, Chamberlain K et al. Erythrocyte Transketolase Activity, Markers of Cardiac Dysfunction and the Diagnosis of Infantile Beriberi. PLoS Negl Trop Dis 2011; 5: e971-e981
    CrossrefPubMedGoogle Scholar
  • 46 Robinson DJ, Christenson RH. Creatine kinase and its CK-MB isoenzyme: the conventional marker for the diagnosis of acute myocardial infarction. J Emerg Med 1999; 17: 95-104
    CrossrefPubMedGoogle Scholar
  • 47 Fromm RE. Cardiac troponins in the intensive care unit: common causes of increased levels and interpretation. Crit Care Med 2007; 35: 584-588
    CrossrefPubMedGoogle Scholar
  • 48 Sethi R, Takeda N, Nagano M et al. Beneficial Effects of Vitamin E Treatment in Acute Myocardial Infarction. Cardiovasc Pharmaco Ther 2000; 5: 51-58
    PubMedGoogle Scholar
  • 49 Irwin MW, Mak S, Mann DL et al. Tissue expression and immunolocalization of tumor necrosis factor-alpha in postinfarction dysfunctional myocardium. Circulation 1999; 99: 1492-1498
    CrossrefPubMedGoogle Scholar
  • 50 Suematsu N, Tsutsui H, Wen JMD et al. Oxidative Stress Mediates Tumor Necrosis Factor – Induced Mitochondrial DNA Damage and Dysfunction in Cardiac Myocytes. Circulation 2003; 108: 1418-1423
    PubMedGoogle Scholar
  • 51 De Ferranti SD, Rifai N. C-reactive protein: a nontraditional serum marker of cardiovascular risk. Cardiovasc Pathol 2007; 16: 14-21
    CrossrefPubMedGoogle Scholar
  • 52 Patel DN, King CA, Bailey SR. Interleukin-17 stimulates C-reactive protein expression in hepatocytes and smooth muscle cells via p38 MAPK and ERK1/2-dependent NF-kappaB and C/EBPbeta activation. J Biol Chem 2007; 282: 27229-27238
    CrossrefPubMedGoogle Scholar
  • 53 Venugopal SK, Devaraj S, Jialal I. Effect of C-reactive protein on vascular cells: evidence for a proinfl ammatory, proatherogenic role. Curr Opin Nephrol Hypertens 2005; 14: 33-37
    CrossrefPubMedGoogle Scholar
  • 54 Zhang WJ, Wei H, Hagen T et al. Α-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. PNAS 2007; 104: 4077-4082
    CrossrefPubMedGoogle Scholar
  • 55 Lee Y, Kim M, Choi K et al. Relationship between inflammation biomarkers, antioxidant vitamins, and bone mineral density in patients with metabolic syndrome. Nutr Res Pract 2011; 5: 150-156
    CrossrefPubMedGoogle Scholar
  • 56 Das UN. Free radicals, cytokines and nitric oxide in cardiac failure and myocardial infarction. Mol Cell Biochem 2000; 215: 145-152
    CrossrefPubMedGoogle Scholar
  • 57 Mechtcheriakova D, Schabbauer G, Lucerna M et al. Specificity, diversity, and convergence in VEGF and TNF-alpha signaling events leading to tissue factor up-regulation via EGR-1 in endothelial cells. FASEB J 2001; 15: 230-242
    CrossrefPubMedGoogle Scholar
  • 58 Obrosova IG, Minchenko AG, Marinescu V et al. Antioxidants attenuate early up regulation of retinal vascular endothelial growth factor in streptozotocin diabetic rats. Diabetologia 2001; 44: 1102-1110
    CrossrefPubMedGoogle Scholar
  • 59 Hasenfuss G. Alterations of calcium-regulatory proteins in heart failure. Cardiovasc Res 1998; 37: 279-289
    CrossrefPubMedGoogle Scholar
  • 60 Kain V, Kumar S, Sitasawad S. Azelnidipine prevents cardiac dysfunction in streptozotocin-diabetic rats by reducing intracellular calcium accumulation, oxidative stress and apoptosis. Cardiovasc Diabetol 2011; 10: 97-137
    CrossrefPubMedGoogle Scholar
  • 61 Agarwal S, Tafel AA, Kanaar R. DNA double-strand break repair and chromosome translocations. DNA Repair (Amst) 2006; 5: 1075-1081
    CrossrefPubMedGoogle Scholar
  • 62 Tice RR, Strauss GHS. The single cell gel electrophoresis comet assay – a potential tool for detecting radiation-induced DNA damage in humans. Stem CelLs 1995; 13 (Suppl. 01) 207-214
    PubMedGoogle Scholar
  • 63 ColLins AR, Dusinska M, Gedik CM et al. Oxidative damage to DNA: Do we have a reLiabLe biomarker?. Environ HeaLth Perspect 1996; 104: 465-469
    PubMedGoogle Scholar
  • 64 Huang TH, Lee H, Kao CT. Evaluation of the Genotoxicity of Zinc Oxide Eugenol-Based, Calcium Hydroxide-Based, and Epoxy Resin-Based Root Canal Sealers by Comet Assay. J Endownllcs 2001; 27: 744-748
    PubMedGoogle Scholar
  • 65 Sharma V, Shukla RK, Saxena N et al. DNA damaging potential of zinc oxide nanoparticles in human epidermal cells. Toxicol Lett 2009; 185: 211-218
    CrossrefPubMedGoogle Scholar
  • 66 Xiong D, Fang T, Yu L et al. Effects of nano-scale TiO2, ZnO and their bulk counterparts on zebrafish: acute toxicity, oxidative stress and oxidative damage. Sci Total Environ 2011; 409: 1444-1452
    CrossrefPubMedGoogle Scholar
  • 67 Martinez GR, Loureiro AP, Marques SA et al. Oxidative and alkylating damage in DNA. Mutat Res 2003; 544: 115-127
    PubMedGoogle Scholar
  • 68 Marnett LJ. Oxy radicals, lipid peroxidation and DNA damage. Toxicol 2002; 182: 219-222
    CrossrefPubMedGoogle Scholar
  • 69 Niedernhofer LJ, Daniels JS, Rouzer CA et al. Malondialdehyde, a product of lipid peroxidation, is mutagenic in human cells. J Biol Chem 2003; 278: 31426-31433
    CrossrefPubMedGoogle Scholar
  • 70 Takagi A, Sai K, Umemura T et al. Inhibitory effects of vitamin E and ellagic acid on 8-hydroxy- deoxyguanosine formation in liver nuclear DNA of rats treated with 2- nitropropane. Cancer Lett 1995; 91: 139-144
    CrossrefPubMedGoogle Scholar
  • 71 Cadenas S, Barjal G, Poulsen HE et al. Oxidative DNA damage estimated by oxo8dG in the liver of guinea-pigs supplemented with graded dietary doses of ascorbic acid and a-tocopherol. Carcinogenesis 1997; 18: 2373-2377
    CrossrefPubMedGoogle Scholar
  • 72 Burillo SL, Tan DX, Mayo JC et al. Melatonin, xanthurenic acid, resveratrol, EGCG, vitamin C and α-lipoic acid differentially reduce oxidative DNA damage induced by Fenton reagents: a study of their individual and synergistic actions. J Pineal Res 2003; 34: 269-277
    CrossrefPubMedGoogle Scholar
  • 73 Rybak LP, Hussain K, Whiteworth C et al. Dose dependent protection by α-lipoic acid against cisplatin-induced ototoxicity in rats. Antioxidant defense system. Toxicol Sci 1999; 47: 195-202
    CrossrefPubMedGoogle Scholar
  • 74 Aboul-Soud MAM, Othman AM, El-Desoky GE et al. Hepatoprotective effect of vitamin E/selenium against malathion induced injuries on the antioxidant status and apoptosis realted gene expression in rats. J Toxicol Sci 2011; 36: 285-296
    CrossrefPubMedGoogle Scholar