Dose-dependent hepatotoxicity effects of Zinc oxide nanoparticles

Document Type : Research Paper

Authors

1 Cell & Molecular Research Center, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

Abstract

Objective(s):  
Zinc oxide nanoparticles (ZNP) are increasingly used in sunscreens, biosensors, food additives and pigments. In this study the effects of ZNP on liver of rats was investigated.  
 
Materials and Methods:
Experimental groups received 5, 50 and 300 mg/kg ZNP respectively for 14 days. Control group received only distilled water. ALT, AST and ALP were considered as biomarkers to indicate hepatotoxicity. Lipid peroxidation (MDA), SOD and GPx were detected for assessment of oxidative stress in liver tissue. Histological studies and TUNEL assay were also done. 
Results:  
Plasma concentration of zinc (Zn) was significantly increased in 5 mg/kg ZNP-treated rats. Liver concentration of Zn was significantly increased in the 300 mg/kg ZNP-treated animals. Weight of liver was markedly increased in both 5 and 300 mg/kg doses of ZNP. ZNP at the doses of 5 mg/kg induced a significant increase in oxidative stress through the increase in MDA content and a significant decrease in SOD and GPx enzymes activity in the liver tissue. Administration of ZNP at 5 mg/kg induced a significant elevation in plasma AST, ALT and ALP. Histological studies showed that treatment with 5 mg/kg of ZNP caused hepatocytes swelling, which was accompanied by congestion of RBC and accumulation of inflammatory cells. Apoptotic index was also significantly increased in this group. ZNP at the dose of 300 mg/kg had poor hepatotoxicity effect. 
Conclusion:  
It is concluded that lower doses of ZNP has more hepatotoxic effects on rats, and recommended to use it with caution if there is a hepatological problem.

Keywords


1. Adams LK, Lyon DY, Alvarez PJJ. Comparative eco-toxicity of nanoscale TiO2, SiO2, and ZnO water suspensions. Water Res. 2006; 40 (19): 3527-3532.
2. Mody VV, Siwale R, Singh A, Mody HR. Introduction to metallic nanoparticles. J Pharm Bioallied Sci. 2010; 2(4): 282-289.
3. Warheit DB. Nanoparticles: Health impacts? Materials Today 2004; 7(2): 32-35.
4. Fubini B, Ghiazza M, Fenoglio I. Physico-chemical features of engineered nanoparticles relevant to their toxicity.  Nanotoxicol. 2010; 4: 347-363.
5. Borm PJ, Kreyling W. Toxicological hazards of inhaled nanoparticles potential implications for drug delivery. J Nanosci Nanotechnol. 2004; 4(5): 521-531.
6. Chen Y, Xue Z, Zheng D, Xia K, Zhao Y, Liu T, et al. Sodium chloride modified silica nanoparticles as a non-viral vector with a high efficiency of DNA transfer into cells. Curr Gene Ther. 2003; 3(3): 273-279.
7. Burnett ME, Wang SQ. Current sunscreen controversies: a critical review. Photodermatol Photoimmunol Photomed. 2011; 27(2): 58-67.
8. Nohynek GJ, Lademann J, Ribaud C, Roberts MS. Grey goo on the skin? Nanotechnology, cosmetic and sunscreen safety. Crit Rev Toxicol. 2007; 37(3): 251-277.
9. Oberdörster G, Maynard A, Donaldson K, Castranova V, Fitzpatrick J, Ausman K, et al. Principles for characterizing the potential human health effects from exposure to nanomaterials: elements of a screening strategy. Part Fibre Toxicol. 2005; 2(8): 1-35.
10. Zvyagin AV, Zhao X, Gierden A, Sanchez W, Ross JA, Roberts MS. Imaging of zinc oxide nanoparticle penetration in human skin in vitro and in vivo. J Biomed Opt. 2008; 13(6): 064031.
11. Filipe P, Silva JN, Silva R, Cirne de Castro JL, Marques Gomes M, Alves LC, et al. Stratum corneum is an effective barrier to TiO2 and ZnO nanoparticle percutaneous absorption. Skin Pharmacol Physiol. 2010; 22(5): 266-275.
12. John S, Marpu S, Li J, Omary M, Hu Z, Fujita Y, et al. Hybrid zinc oxide nanoparticles for biophotonics.  J Nanosci Nanotechnol. 2010; 10(3):1707-12.
13. Tankhiwale R, Bajpai SK. Preparation, characterization and antibacterial applications of ZnO-nanoparticles coated polyethylene films for food packaging. Colloids Surf. B Biointerfaces. 2012; 90: 16-20.
14. Emamifar A, Kadivar M, Shahedi M, Soleimanian-Zad S. Effect of nanocomposite packaging containing Ag and ZnO on inactivation of Lactobacillus plantarum in orange juice. Food Control. 2011; 22(3-4): 408-413.
15. Ates M, Arslan Z, Demir V, Daniels J, Farah IO. Accumulation and toxicity of CuO and ZnO nanoparticles through waterborne and dietary exposure of goldfish (Carassius auratus). Environ Toxicol. 2015;30(1):119-28
16. Hernandez-Viezcas JA, Castillo-Michel H,  Andrews JC, Cotte M, Rico C, Peralta-Videa JR, et al. In Situ synchrotron X-ray fluorescence mapping and speciation of CeO2 and ZnO nanoparticles in soil cultivated Soybean (Glycine max). ACS Nano. 2013; 7(2): 1415-23.
17. Oberdorster G, Oberdorster E,  OberdorsterJ.  Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect. 2005; 113(7): 823-39.
18. Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, et al. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. J Toxicol Environ Health A. 2002; 65(20): 1531-43.
19. Cho WS, Kang BC, Lee JK, Jeong J, Che JH, Seok SH. Comparative absorption, distribution, and excretion of titanium dioxide and zinc oxide nanoparticles after repeated oral administration. Part Fibre Toxicol. 2013; 10:9
20. De Louise LA. Applications of nanotechnology in dermatology. J Invest Dermatol. 2012; 132 (3): 964-975.
21. Meyer K, Rajanahalli P, Ahamed M, Rowe JJ, Hong Y. ZnO nanoparticles induce apoptosis in human dermal fibroblasts via p53 and p38 pathways. Toxicol in Vitro. 2011; 25(8): 1721-6.
22. Jeng HA, Swanson J. Toxicity of metal oxide nanoparticles in mammalian cells. J Environ Sci Health A Tox Hazard Subst Environ Eng. 2006; 41(12): 2699-2711.
23. Gojova A, Guo B, Kota RS, Rutledge JC, Kennedy IM, Barakat AI. Induction of inflammation in vascular endothelial cells by metal oxide nanoparticles: Effect of particle composition. Environ Health Perspect. 2007; 115(3): 403-409.
24. Sharma V, Anderson D, Dhawan A. Zinc oxide nanoparticles induce oxidative stress and genotoxicity in human liver cells (HepG2). J Biomed Nanotechnol. 2011; 7(1): 98-99.
25. Talebi AR, Khorsandi L, Moridian M. The effect of zinc oxide nanoparticles on mouse spermatogenesis. J Assist Reprod Genet. 2013; 30(9):1203-9.
26. Sharma V, Singh P, Pandey AK, Dhawan A. Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles. Mutat Res. 2012; 45(1-2): 84-91.
27. Mansouri E, Panahi M, Ghaffari MA, Ghorbani A. Effects of grape seed proanthocyanidin extract on oxidative stress induced by diabetes in rat kidney. Iran Biomed J. 2010; 15(3):100-6.
28. Suttle NF. Copper deficiency in ruminants recent developments. Vet Rec. 1998; 119(21): 519-522.
29. Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med. 1967; 70(1): 158-69.
30. Orazizadeh M, Hashemitabar M, Khorsandi L. Protective effect of minocycline on dexamethasone induced testicular germ cell apoptosis in mice. Eur Rev Med Pharmacol Sci. 2009; 13(1):1-5.
31. Pasupuleti S, Alapati S, Ganapathy S, Anumolu G, Pully NR, Prakhya BM. Toxicity of zinc oxide nanoparticles through oral route. Toxicol Ind Health. 2012; 28(8): 675-86.
32. Akhtar MJ, Ahamed M, Kumar S, Khan MM, Ahmad J, Alrokayan SA. Zinc oxide nanoparticles selectively induce apoptosis in human cancer cells through reactive oxygen species. Int J Nanomedicine. 2012; 7: 845-857.
33. Guan R, Kang T, Lu F, Zhang Z, Shen H, Liu M. Cytotoxicity, oxidative stress, and genotoxicity in human hepatocyte and embryonic kidneycells exposed to ZnO nanoparticles.  Nanoscale Res Lett. 2012; 7(1): 602.
34. Wang J, Deng X, Zhang F, Chen D, Ding W. ZnO nanoparticle-induced oxidative stress triggers apoptosis by activating JNK signaling pathway in cultured primary astrocytes.  Nanoscale Res Lett. 2014; 9(1): 117.
35. Buzea C, Pacheco II, Robbie K. Nanomaterials and nanoparticles: Sources and toxicity. Biointerphases. 2007; 2(4): 17-71.
36. Song L, Connolly M, Fernández-Cruz ML, Vijver MG, Fernández M, Conde E, et al. Species-specific toxicity of copper nanoparticles among mammalian and piscine cell lines. Nanotoxicology. 2014; 8(4): 383-93.
37. Shvedova AA, Kisin ER, Mercer R, Murray AR, Johnson VJ, Potapovich AI, et al. Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am J Physiol Lung Cell Mol Physiol. 2005; 289(5): 698-708.
38. Warheit DB, Laurence BR, Reed KL, Roach DH, Reynolds GA, Webb TR. Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats.  Toxicol Sci. 2004; 77(1): 117-125.
39. Aragon G, Younossi ZM. When and how to evaluate mildly elevated liver enzymes in apparently healthy patients. Cleve Clin J Med. 2010; 77(3): 195-204.
40. Sha B, Gao W, Wang S, Gou X, Li W, Liang X, et al. Oxidative stress increased hepatotoxicity induced by nano-titanium dioxide in BRL-3A cells and Sprague-Dawley rats. J Appl Toxicol. 2014; 34(4): 345-356.
41. Singh S, Shi T, Duffin R, Albrecht C, van Berlo D, Höhr D, et al. Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: role of the specific surface area and of surface methylation of the particles. Toxicol Appl Pharmacol. 2007; 222(2): 141-151.
42. Johar D, Roth JC, Bay GH, Walker JN, Kroczak TJ, Los M. Inflammatory response, reactive oxygen species, programmed (necrotic-like and apoptotic) cell death and cancer. Rocz Akad