Zinc oxide nanoparticles (ZnO-NPs) are used in many industries and medications, increasing the exposure to ZnO-NPs that may have harmful side effects. So, we studied the hepatotoxic effect of ZnO-NPs and explored the role of vitamin E in the reduction of their toxic effects. Forty male albino rats, divided into four groups (10 rats per group) were included in the study; control group, ZnO-NPs intoxicated group, vitamin E control group and vitamin E protected ZnO-NPs intoxicated group. ZnO-NPs were given in a dose of 400 mg / kg body weight for seven days. Vitamin E was given in a dose of 100 mg / kg body weight for four weeks. Our results showed that ZnO-NPs induced liver damage indicated by significant increase of serum ALT and AST and significant decrease of serum albumin and total protein levels. Moreover, ZnO-NPs induced oxidative stress in the liver suggested by significant elevation of malondialdehyde level and significant reduction of reduced glutathione level, glutathione peroxidase activity and glutathione peroxidase-1 expression in liver homogenate. Furthermore, ZnO-NPs caused significant increase in the serum pro-inflammatory biomarker, tumor necrosis factor alpha (TNF- α). On the other hand, vitamin E alleviated the liver damage, oxidative stress and the elevated serum TNF- α induced by ZnO-NPs.
Mona A. El Shemy,
Naglaa Ibrahim Azab,
Rabab Fawzy Salim,
Zinc Oxide Nanoparticles: The Hidden Danger, International Journal of Biochemistry, Biophysics & Molecular Biology.
Vol. 2, No. 1,
2017, pp. 1-9.
Afifi M, Almaghrabi OA and Kadasa NM (2015). Ameliorative Effect of Zinc Oxide Nanoparticles on Antioxidants and Sperm Characteristics in Streptozotocin-Induced Diabetic Rat Testes. BioMed Research International, Volume 2015, Article ID 153573, 6 pages.
Al-Rasheed N, Abdel Baky NA, Al-Rasheed N, Shebly W, Ahmed AM and Faddah LM (2012). Effect of vitamin E and alpha lipoic acid on nano zinc oxide induced renal cytotoxicity in rats. African Journal of pharmacy and pharmacololgy, 629 (29): 2211-2223.
Al-Rasheed NM, Al-Rasheed NM, Abdel Baky NA, Faddah LM, Fatani AJ, Hasan IH and Mohamad RA (2014). Prophylactic role of α-lipoic acid and vitamin E against zinc oxide nanoparticles induced metabolic and immune disorders in rat's liver. Eur Rev Med Pharmacol Sci, 18 (12): 1813-1828.
Al-Rasheed NM, Faddah LM, Ali HM and Abdel Baky NA (2016). Modulation of glutathione, phospholipids and lipid peroxides liver contents induced by zinc oxide Nanoparticles using natural antioxidants. Digest Journal of Nanomaterials and Biostructures, 11 (1): 303-312.
Ansar S, Abudawood M, Hamed SS and Aleem MM (2016). Exposure to Zinc Oxide Nanoparticles Induces Neurotoxicity and Proinflammatory Response: Amelioration by Hesperidin. Biological Trace Element Research, First Online: 14 June 2016. In press.
Arthur J R (2000). The glutathione peroxidases. Cellular and Molecular Life Sciences : CMLS, 57(13–14): 1825-1835.
Bai W, Zhang Z, Tian W, He X, Ma Y, Zhao Y and Chai Z (2010). Toxicity of zinc oxide nanoparticles to zebrafish embryo: a physicochemical study of toxicity mechanism. Journal of Nanoparticle Research, 12 (5): 1645-1654.
Beutler E, Duron O and Kelly BM (1963). Improved method for the determination of blood glutathione. J. Lab. Clin. Med, 61: 882-888.
Chang Y-N, Zhang M, Xia L, Zhang J, and Xing G (2012). Toxic Effects and Mechanisms of CuO and ZnO Nanoparticles. Materials, 5(12): 2850-2871.
Chen RH, Qin R, Wang FD, Wang JP and Lu TX (1992). The effects of oral excess zinc on the zinc level and morphology of tissues. Zhonghua Yixue Zazhi, 72: 391-393.
Ciacci C, Canonico B, Bilanicov D, Fabbri R, Cortese K, Gallo G, Marcomini A, Pojana G and Canesi L (2012). Immunomodulation by different types of N-oxides in the hemocytes of the marine bivalve Mytilus galloprovincialis. PLoS One, 7(5): e36937.
D’Alessandris C, Lauro R, Presta I and Sesti G (2007). C reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser307 and Ser 612 in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport. Diabetologia, 50: 840-849.
Faddah LM, Abdel Baky NA, Al-Rasheed NM, Al-rasheed NM, Fatani AJ and Atteya M (2012). Role of quercetin and arginine in ameliorating nano zinc oxide-induced nephrotoxicity in rats. BMC Complem Altern Med, 12: 60.
Faddah LM, Abdel Baky NA, Mohamed AM, Al-Rasheed NM and Al-Rasheed NM (2013). Protective effect of quercetin and/or L-arginine against nano-zinc oxide-induced cardiotoxicity in rats. J Nanopart Res, 15: 1520.
Fox ES, Brower JS, Bellezzo JM and Leingang KA (1997). N-acetylcysteine and alpha-tocopherol reverse the inflammatory response in activated rat Kupffer cells. J Immunol, 158: 5418-5423.
Garcia-Ruiz C, Colell A, Mari M, Morales A, and Fernández-Checa JC (1997). Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species: role of mitochondrial glutathione. J Biol Chem, 272:11369-11377.
Goossens V, Grooten J, De Vos K and Fiers W (1995). Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci U S A, 92: 8115-8119.
Hao L and Chen L (2012). Oxidative stress responses in different organs of carp (Cyprinus carpio) with exposure to ZnO nanoparticles. Ecotoxicol. Environ. Saf, 80: 103-110.
Idriss NK, Sayyed HG, Zakhary MM and Sayed S (2014). Implication of tumor necrosis factor alpha receptor 1 and hexosaminidase: relationship to pathogenesis of liver diseases. Comparative Clinical Pathology, 23 (4): 1095-1102.
Iskusnykh IY, Popova TN, Agarkov AA, Pinheiro de Carvalho MÂA, and Rjevskiy SG (2013). Expression of Glutathione Peroxidase and Glutathione Reductase and Level of Free Radical Processes under Toxic Hepatitis in Rats. Journal of Toxicology. Volume 2013, Article ID 870628, 9 pages.
Jamaluddin M, Wang S, Boldogh I, Tian B and Brasier AR (2007). TNF-alpha induced NF-kappaB/RelA Ser (276) phosphorylation and enhanceosome formation is mediated by an ROS-dependent PKAc pathway. Cell Signal, 19: 1419-1433.
Kallinowski B, Haseroth K, Marinos G,Hanck C, Stremmel W, Theilmann L, Singer MV and Rossol S (1998). Induction of tumour necrosis factor (TNF) receptor type p55 and p75 in patients with chronic hepatitis C virus (HCV) infection. Clin Exp Immunol, 111:269-277.
Kerksick C and Willoughby D (2005). The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress. Journal of the International Society of Sports Nutrition, 2(2): 38-44.
Kerner A, Avizohar O, Sella R, Bartha P, Zinder O, Markiewicz W, Levy Y, Brook G J and Aronson D (2005). Association Between Elevated Liver Enzymes and C-Reactive Protein Possible Hepatic Contribution to Systemic Inflammation in the Metabolic Syndrome. Arterioscler Thromb Vasc Biol, 25: 93-197.
Khanna P, Ong C, Bay BH and Baeg GH (2015). An interplay of oxidative stress, inflammation and cell death. Nanomaterials, 20(5): 1163-1180.
Li CH, Shen CC, Cheng YW, Huang SH, Wu CC, Kao CC, Liao JW and Kang JJ (2011). Organ bio distribution, clearance, and genotoxicity of orally administered zinc oxide nanoparticles in mice. Nanotoxicology, 6(7): 746-756.
Li CJ, Li RW, Kahl S and lsasser TH (2012). Alpha-tocopherol alters transcription activities that modulates Tumor necrosis factor alpha (TNF-α) induced inflammatory response in bovine cells. Gene Regulation and Systems Biology, (6): 1-14.
Liu ZG and Han J (2001). Cellular responses to tumor necrosis factor. Curr Issues Mol Biol, 3: 79-90.
Livak KJ and 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.
Lovern SB and Klaper R (2006). Daphnia magna mortality when exposed to titanium dioxide and fullerene (C60) nanoparticles. Environ Toxicol Chem, 25 (4): 1132-1137.
Ma H, Williams PL and Diamond SA (2013). Diamond Ecotoxicity of manufactured ZnO nanoparticles. Environ. Pollut. 172:76-85.
Macdonald J, Galley HF and Webster NR (2003). Oxidative stress and gene expression in sepsis. British Journal of Anaesthesia, 90 (2): 221-232.
Manke A, Wang L, and Rojanasakul Y (2013). Mechanisms of Nanoparticle- Induced oxidative stress and toxicity. Bio Med Research International, 2103(15): 650-665.
Mansouri E, Khorsadi L, Orazizadeh M and Jozi Z (2015). Dose- dependent hepatotoxicity effect of zinc oxide nanoparticles. Nanomed J, 2(4): 273-282.
Marí M, Morales A, Colell A, García-Ruiz C and Fernández-Checa JC (2009). Mitochondrial glutathione, a key survival antioxidant. Antioxidants & Redox Signaling, 11(11): 2685-2700.
Mariappan N, Soorappan RN, Haque M, Sriramula S and Francis J (2007). TNF-induced mitochondrial oxidative stress and cardiac dysfunction: restoration by superoxide dismutase mimetic Tempol. Am J Physiol Heart Circ Physiol, 293: H2726-H2737.
Mironava T, Hadjrargyrou M, Simon M, Jurukovski V and Rafailovich MH (2010). Gold nanoparticles cellular toxicity and recovery effect of size concentration and exposure time. Toxicological & Experimental chemistry, 92 (2): 391-407.
Moura AS, Carmo RA, Teixeira AL, Teixeira MM and Rocha MO (2011). Soluble inflammatory markers as predictors of virological response in patients with chronic hepatitis C virus infection treated with interferon-α plus ribavirin. Memórias Do Instituto Oswaldo Cruz, 106(1): 38-43.
Muller FL, Lustgarten MS, Jang Y, Richardson A, and Van Remmen H (2007). Trends in oxidative aging theories. Free Radical Biology and Medicine, 43(4): 477-503.
Neuschwander-Tetri BA and Roll FJ (1990). Chemotactic activity for human PMN generated during ethanol metabolism by rat hepatocytes: role of glutathione and glutathione peroxidase. Biochem Biophys Res Commun, 167: 1170-1176.
Ohkawa H, Ohishi W and Yagi K (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem, 95(2): 351-8.
Paglia DE and Valentine WN (1967). Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J. Lab. Clin. Med, 70: 158-169.
Peinnequin A, Mouret C, Birot O, Alonso A, Mathieu J, Clarençon D, Agay D, Chancerelle Y and Multon E (2004). Rat pro-inflammatory cytokine and cytokine related mRNA quantification by real-time polymerase chain reaction using SYBR green. BMC Immunology, 5: 3-13.
Saddick S, Afifi M and Abu Zinadaa OA (2015). Effect of Zinc nanoparticles on oxidative stress-related genes and antioxidant enzymes activity in the brain of Oreochromis niloticus and Tilapia zillii. Saudi Journal of Biological Sciences. Available online 18 November 2015 In Press.
Sahu D, Kannan GM and Vijayaraghavan R (2014). Size dependant effect of zinc oxide on toxicity and inflammatory potential of human monocyte. J Toxicol Environ Health A, 77(4): 177-191.
Saptarshi SR, Duschl A and Lopata AL (2015). Biological reactivity of zinc oxide nanoparticles with mammalian test systems. Nanomedicine, 10(13): 2075 - 2092.
Sayes CM, Reed KL and Warheit DB (2007). Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles, Toxicol. Sci 97: 163-180.
Sharma V, Anderson D and Dhawan A (2012). Zinc oxide nanoparticles induce oxidative DNA damage and ROS-triggered mitochondria mediated apoptosis in human liver cells (HepG2). Apoptosis. 17(8): 852-870.
Snedecor GW and Cochran WG (1982). Statistical method.7th ed, Iowa state university press, Ame Iowa, USA.
Somayeh B and Mohammad F (2014). Vitamin C can reduce toxic effect of nano zinc oxide. Int. J. Biological Sci, 3(3): 65-70.
Suematsu N, Tsutsui H, Wen J, Kang D, Ikeuchi M, Ide T, Hayashidani S, Shiomi T, Kubota T, Hamasaki N and Takeshita A (2003). Damage and Dysfunction in Cardiac Myocytes Oxidative Stress Mediates Tumor Necrosis Factor-a-Induced Mitochondrial DNA Circulation, 107: 1418-1423.
Trevisan R, Flesch S, Mattos J, Milani MR, Bainy AC and Dafre AL (2014). Zinc causes acute impairment of glutathione metabolism followed by coordinated antioxidant defenses amplification in gills of brown mussels Perna perna. Comp. Biochem. Physiol. C, 159: 22-30.
Vandebriel RJ and De Jong WH (2012). A review of mammalian toxicity of ZnO nanoparticles. Nanotechnology, Science and Applications, 5: 61-71.
Wang B, Feng WY, Wang M, Wang TC, Gu YQ, Zhu MT, Ouyang H, Shi JW, Zhang F, Zhao YL, Chai ZF, Wang HF and Wang J (2008). Acute toxicological impact of nano and submicro-scaled zinc oxide powder on healthy adult mice. J Nanopart Res, 10: 263-276.
Wang B, Feng WY, Wang TC, Jia G, Wang M, Shi JW, Zhang F, Zhao YL and Chai ZF (2006). Acute toxicity of nano- and micro-scale zinc powder in healthy adult mice. Toxicol Lett, 161 (2): 115-23.
Wang B, Zhang Y, Mao Z, Yu D and Gao C (2014). Toxicity of ZnO nanoparticles to macrophages due to cell uptake and intracellular release of zinc ions. J Nanosci Nanotechnol, 14 (8): 5688-5696.
Wang L, Wang L, Ding W and Zhang F (2010). Acute Toxicity of ferric oxide and zinc oxide Nanoparticles in Rats. Journal of Nanoscience and Nanotechnology, 10 (12): 8617-8624.
Yang X, Shao H, Liu W, Gu W, Shu X, Mo Y, Chen X, Zhang Q and Jiang M (2015). Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity. Toxicol Lett, 2; 234 (1): 40-9.
Yoshida N, Yoshikawa T, Manabe H, Terasawa Y, Kondo M, Noguchi N and Niki E (1999). Vitamin E protects against polymorphonuclear leukocyte-dependent adhesion to endothelial cells. J Leukoc Biol, 65: 757-63.
Yousef JM and Mohamed AM (2015). Prophylactic role of B vitamins against bulk and zinc oxide nanoparticles toxicity induced oxidative DNA damage apoptosis in rat livers. Pak. J. Pharm. Sci, 28 (1): 175-184.
Yousef JM (2014). Potential prophylactic impact of B vitamins against zinc oxide bulk and its nanoparticles induced kidney damage. Life Science Journal, 11 (8):729-738.
Abdel Baky NA, Faddah LM, Al-Rasheed NM, Al-Rasheed NM, Shebali W (2013). Role of quercetin and L-arginine in alleviating zinc oxide nanoparticle hepatotoxicity in rats, Chiang Mai J. Sci, 40: 577–592.