Research Article

DOI :10.26650/IstanbulJPharm.2021.837856   IUP :10.26650/IstanbulJPharm.2021.837856    Full Text (PDF)

Nickel oxide nanoparticles induced DNA damages in human liver cells

Mahmoud AbudayyakEmine Elif Güzel MeydanlıGül Özhan

Background and Aims: Nickel oxide nanoparticles (NiO-NPs) are one of the most used nanoparticles, especially as photosensitizers. Although some studies evaluate their toxicity in the liver, the information about their toxicity at the cellular and molecular levels is still controversial. In the present study, it was aimed to investigate the in vitro toxic potentials of NiO-NPs (average size 15.0 nm) in the liver (HepG2) cell line. Methods: NiO-NPs were characterized by Transmission Electron Microscopy (TEM), the cellular uptake of NPs and the morphologic changes were evaluated by TEM and Inductively Coupled Plasma-Mass Spectrometry (ICP-MS), the cytotoxicity was evaluated by MTT and neutral red uptake (NRU) tests, comet assay was used for genotoxicity, Annexin V-FITC/propidium iodide (PI) apoptosis detection kit was used for apoptosis/ necrosis evaluation and Enzyme-Linked Immune Sorbent Assays (ELISA) kits were used for the potential of oxidative damage. Results: Our results showed that cellular uptake of NiO-NPs led to morphological changes in the cells, and caused cell death (IC50 was 146.7 µg/mL by MTT) mainly by apoptosis. Genotoxicity and oxidative damage were observed to be in a dosedependent manner. Conclusion: Results confirm previous data and draw attention to the toxic effects of NiO-NPs; further in vivo and in vitro studies need to be done to clarify the safety or toxicity of NiO-NPs.

PDF View


  • Abudayyak, M., Guzel, E., & Özhan, G. (2017a). Nickel oxide nanoparticles induce oxidative DNA damage and apoptosis in kidney cell line (NRK-52E). Biological Trace Element Research, 178(1), 98-104. google scholar
  • Abudayyak, M., Guzel, E., & Özhan, G. (2017b). Nickel oxide nanoparticles are highly toxic to SH-SY5Y neuronal cells. Neu-rochemistry International, 108, 7-14. neuint.2017.01.017. google scholar
  • Ahamed, M. (2011). Toxic response of nickel nanoparticles in hu-man lung epithelial A549 cells. Toxicology in vitro, 25(4), 930-936. google scholar
  • Ahamed, M., Akhtar, M.J., Siddiqui, M.A., Ahmad, J., Musarrat, J., Al-Khedhairy, A.A. ... Alrokayan, S.A. (2011). Oxidative stress mediated apoptosis induced by nickel ferrite nanoparticles in cultured A549 cells. Toxicology, 283(2-3), 101-108. https://doi. org/10.1016/j.tox.2011.02.010. google scholar
  • Ahamed, M., Ali, D., Alhadlaq, H.A., & Akhtar, M.J. (2013). Nickel oxide nanoparticles exert cytotoxicity via oxidative stress and induce apoptotic response in human liver cells (HepG2). Che-mosphere, 93(10), 2514-2522. google scholar
  • Ahmad, J., Alhadlaq, H.A., Siddiqui, M.A., Saquib, Q., Al-Khedhairy, A.A., Musarrat, J., & Ahamed, M. (2013). Concentration-dependent induction of reactive oxygen species, cell cycle arrest and apop-tosis in human liver cells after nickel nanoparticles exposure. Environmental Toxicology, 30, 137-148. tox.21879. google scholar
  • Arora, S., Rajwade, J.M., & Paknikar, K.M. (2012). Nanotoxicology and in vitro studies: the need of the hour. Toxicology and Ap-plied Pharmacology, 258(2), 151-165. taap.2011.11.010. google scholar
  • Barillet, S., Simon-Deckers, A., Herlin-Boime, N., Mayne-L’Hermite, M., Reynaud, C., Cassio, D., & Carriere, M. (2010). Toxicological con-sequences of TiO2, SiC nanoparticles and multi-walled carbon nanotubes exposure in several mammalian cell types: an in vitro study. Journal of Nanoparticle Research, 12(1), 61-73. https://doi. org/10.1007/s11051-009-9694-y. google scholar
  • Boverhof, D.R., & Raymond M.D. (2010). Nanomaterial charac-terization: considerations and needs for hazard assessment and safety evaluation. Analytical and Bioanalytical Chemistry, 396(3), 953-961. google scholar
  • Bradford, M.M. (1976). A rapid and sensitive method for the quan-titation of microgram quantities of protein utilizing the prin-ciple of protein-dye binding. Analytical Biochemistry, 7, 248-254. google scholar
  • Brand, R.M., Hannah, T.L., Mueller, C., Cetin, Y., & Hamel, FG. (2000). A novel system to study the impact of epithelial barrierson cel-lular metabolism. Annals of Biomedical Engineering, 28, 1210-1217. google scholar
  • Brooking, J., Davis, S.S., & Illum, L. (2001). Transport of nanopar-ticles across the rat nasal mucosa. Journal of Drug Targeting, 9, 267-279. google scholar
  • Capasso, L., Marina, C., & Maurizio, G. (2014). Nickel oxide nanopar-ticles induce inflammation and genotoxic effect in lung epithelial cells. Toxicology Letters, 226(1), 28-34. toxlet.2014.01.040. google scholar
  • Chen, X, Wang, Z., Zhou, J., Fu, X., Liang, J., Qiu, Y., & Huang, Z. (2014). Renal interstitial fibrosis induced by high-dose mesopo-rous silica nanoparticles via the NF-KB signaling pathway. Interna-tional Journal of Nanomedicine, 10, 1-22. IJN.S73538. google scholar
  • Cho, W.S., Duffin, R., Poland, C.A., Howie, S.E., MacNee, W., Brad-ley, M. . Donaldson, K. (2010). Metal oxide nanoparticles induce unique inflammatory footprints in the lung: important implica-tions for nanoparticle testing. Environmental Health Perspectives, 118(12), 1699-1706. google scholar
  • Collins, A.R. (2004). The comet assay for DNA damage and repair: principles, applications, and limitations. Applied Biochemistry and Biotechnology - Part B Molecular Biotechnology, 26(3), 249-261. google scholar
  • Dhawan, A., & Sharma, V. (2010). Toxicity assessment of nano-materials: methods and challenges. Analytical and Bioanalytical Chemistry 398(2), 589-605. google scholar
  • Duan, W.X., He, M.D., Mao, L., Qian, F.H., Li, Y.M., Pi, H.F. . Zhou, Z. (2015). NiO nanoparticles induce apoptosis through repress-ing SIRT1 in human bronchial epithelial cells. Toxicology and Applied Pharmacology, 286(2), 80-91. taap.2015.03.024. google scholar
  • Dunnick, J.K., Benson, J.M., Hobbs, C.H., Hahn, F.F., Cheng, Y.S., & Eidson, A.F. (1988). Comparative toxicity of nickel oxide, nickel sulphate hexahydrate, and nickel subsulfide after 12 days of inha-lation exposure to F344/N rats and B6C3F1 mice. Toxicology, 50, 145-156. google scholar
  • Horev-Azaria, L., Kirkpatrick, C.J., Korenstein, R., Marche, P.N., Maimon, O., Ponti, J. . Villiers, C. (2011). Predictive toxicology of cobalt nanoparticles and ions: comparative in vitro study of different cellular models using methods of knowledge discovery from data. Journal of Toxicological Sciences, 122, 489-501. https:// google scholar
  • Horie, M., Fukui, H., Nishio, K., Endoh, S., Kato, H., Fujita, K., Miyau-chi, A. . Iwahashi, H. (2011). Evaluation of acute oxidative stress induced by NiO nanoparticles in vivo and in vitro. Journal of Oc-cupational Health, 53, 64-74. Horie, M., Fukui, H., Endoh, S., Maru, J., Miyauchi, A., Shichiri, M. . google scholar
  • Iwahashi, H. (2012). Comparison of acute oxidative stress on rat lung induced by nano and fine-scale, soluble and insoluble metal oxide particles: NiO and TiO2. Inhalation Toxicology, 24(7), 391-400. google scholar
  • Horie, M., Nishio, K., Fujita, K., Kato, H., Nakamura, A., Kinugasa, S. . Nakanishi, J. (2009). Ultrafine NiO particles induce cytotoxicity in vitro by cellular uptake and subsequent Ni(II) release. Chemical Research in Toxicology, 22(8), 1415-1426. tx900171n. google scholar
  • International Agency for Research on Cancer (IARC). (1990). Nickel compounds group 1, IARC monographs on the evaluation of carcinogenic risks to human’s chromium, nickel and welding. IARC 49, 257-411. google scholar
  • Jeong, J., Kim, J., Seok, S.H., & Cho, W.S. (2016). Indium oxide (In2O3) nanoparticles induce progressive lung injury distinct from lung injuries by copper oxide (CuO) and nickel oxide (NiO) nanoparticles. Archives of Toxicology, 90(4), 817-828. https://doi. org/10.1007/s00204-015-1493-x. google scholar
  • Kang, G.S., Gillespie, P.A., Gunnison, A., Rengifo, H., Koberstein, J., & Chen, L.C. (2011). Comparative pulmonary toxicity of inhaled nickel nanoparticles; role of deposited dose and solubility. Inha-lation Toxicology, 23(2), 95-103. 8.2010.543440. google scholar
  • Khatchadourian, A., & Maysinger, D. (2009). Lipid droplets: their role in nanoparticle-induced oxidative stress. Molecular Pharma-ceutics, 6(4), 1125-1137. google scholar
  • Kim, Y.J., Yu, M., Park, H.O., & Yang, S.I. (2010). Comparative study of cytotoxicity, oxidative stress and genotoxicity induced by silica nanomaterials in human neuronal cell line. Molecular and Cellular Toxicology, 6(4), 337-344. google scholar
  • Lanone, S., Rogerieux, F., Geys, J., Dupont, A., Maillot-Marechal, E., Boczkowski, J. ... Hoet, P(2009). Comparative toxicity of 24 man-ufactured nanoparticles in human alveolar epithelial and macro-phage cell lines. Particle and Fibre Toxicology, 6, 1-12. https://doi. org/10.1186/1743-8977-6-14. google scholar
  • Lee, J., Homma, T., Kurahashi, T., Kang, E.S., & Fujii, J. (2015). Oxida-tive stress triggers lipid droplet accumulation in primary cultured hepatocytes by activating fatty acid synthesis. Biochemical and Biophysical Research Communications, 464(1), 229-235. https://doi. org/10.1016/j.bbrc.2015.06.121. google scholar
  • Marmorato, P., Ceccone, G., Gianoncelli, A., Pascolo, L., Ponti, J., Rossi, F. . Kiskinova, M. (2011). Cellular distribution and degrada-tion of cobalt ferrite nanoparticles in balb/3T3 mouse fibroblasts. Toxicology Letters, 207(2), 128-136. google scholar
  • Martin, K.R., Failla, M.L., & Smith, J.C. (1997). Differential suscepti-bility of Caco-2 and HepG2 human cell lines to oxidative stress. Journal of the Elisha Mitchell Scientific Society, 113(4), 149-162. google scholar
  • Morimoto, Y., Ogami, A., Todoroki, M., Yamamoto, M., Murakami, M., Hirohashi, M. . Tanaka, I. (2010). Expression of inflammation-related cytokines following intratracheal instillation of nickel oxide nanoparticles. Nanotoxicology, 4(2), 161-176. https://doi. org/10.3109/17435390903518479. google scholar
  • Morimoto, Y., Hirohashi, M., Ogami, A., Oyabu, T., Myojo, T., Hashib, M. . Tanaka, I. (2011). Pulmonary toxicity following an intratracheal instillation of nickel oxide nanoparticle agglomer-ates. Journal of Occupational Health, 53(4), 293-295. https://doi. org/10.1539/joh.11-0034-BR. google scholar
  • Napierska, D., Thomassen, L.C., Lison, D., Marten,s J.A., & Hoet, P.H. 2010. The nanosilica hazard: another variable entity. Particle and Fibre Toxicology, 7(1), 39."> Nishi, K., Morimoto, Y., Ogami, A., Murakami, M., Myojo, T., Oyabu, T., Kadoya, C. . Tanaka, I. (2009). Expression of cytokine-induced neutrophil chemoattractant in rat lungs by intratracheal instilla-tion of nickel oxide nanoparticles. Inhalation Toxicology, 21, 10301039. 10.1080/08958370802716722. google scholar
  • O’Brien, P.J., Irwin, W., Diaz, D., Howard-Cofield, E., Krejsa, C.M., Slaughter, M.R., Gao, B. . Hougham, C. (2006). High concordance of drug-induced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-based model using high content screen-ing. Archives of Toxicology, 80, 580-604. s00204-006-0091-3. google scholar
  • Oberdorster, G. (2001). Pulmonary effects of inhaled ultrafine par-ticles. International Archives of Occupational and Environmental Health, 74, 1-8. google scholar
  • Oberdorster, G., Oberdorster, E., & Oberdorster, J. (2005). Nanotox-icology: An emerging discipline evolving from studies of ultrafine particles. Environmental Health Perspectives 113, 823-839. https:// google scholar
  • Ogami, A., Morimoto, Y., Myojo, T., Oyabu, T., Murakami, M., Todoroki, M. . Tanaka, I. (2009). Pathological features of dif-ferent sizes of nickel oxide following intratracheal instilla-tion in rats. Inhalation Toxicology, 21(10), 812-818. https://doi. org/10.1080/08958370802499022. google scholar
  • Oyabu, T., Ogami, A., Morimoto, Y., Shimada, M., Lenggoro, W., Okuyama, K., & Tanaka, I. (2007). Biopersistence of inhaled nickel oxide nanoparticles in rat lung. Inhalation Toxicology, 19(1), 55-58. google scholar
  • Repetto, G., del Peso, A., & Zurita, J.L. (2008). Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nature Proto-cols, 3(7), 1125-1131. google scholar
  • Sadeghi, L., Tanwir, F., & Babadi, V.Y. (2015). In vitro toxicity of iron oxide nanoparticle: oxidative damages on HepG2 cells. Ex-perimental and Toxicologic Pathology, 67, 197-203. https://doi. org/10.1016/j.etp.2014.11.010. google scholar
  • Sahu, S., Njoroge, J, Bryce, S.M., Yourick, J.J., & Sprando, R.L. (2014). Comperative genotoxicity of nanosilver in human liver HepG2 and colon Caco2 cells evaluated by a flow cytometric in vitro micronucleus assay. Journal of Applied Toxicology, 34, 1226-1234. google scholar
  • Schrand, A.M., Rahman, M.F., Hussain, S.M., Schlager, J.J., Smith, D.A., & Syed, A.F. (2010). Metal-based nanoparticles and their tox-icity assessment. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 2(5), 544-568. wnan.103. google scholar
  • Siddiqui, M.A., Ahamed, M., Ahmad, J., Majeed Khan M.A., Musar-rat, J. Al-Khedhairy, A.A., & Alrokayan, S.A. (2012). Nickel oxide nanoparticles induce cytotoxicity, oxidative stress and apoptosis in cultured human cells that is abrogated by the dietary antioxi-dant curcumin. Food and Chemical Toxicology, 50(3-4), 641-647. google scholar
  • Speit, G., & Hartmann, A. (1999). The comet assay (single-cell gel test). A sensitive genotoxicity test for the detection of DNA dam-age and repair. Methods in Molecular Biology 113, 203-212. https:// google scholar
  • Van Meerloo, J., Kaspers, G.J., & Cloos, J. (2011). Cell sensitivity as-says: the MTT assay. Methods in Molecular Biology 731, 237-245. google scholar
  • Walczyk, D., Bombelli, F.B., Monopoli, M.P., Lynch, I., & Dawson, K.A. (2010). What the cell “Sees” in bionanoscience. Journal of the Ameri-can Chemical Society 132(16), 5761-5768. https://doi: 10.1021/ ja910675v. google scholar
  • Zhang, H., Ji, Z., Xia, T., Low-Kam, C., Liu, R., Pokhrel, S. . Nel, A.E. (2012). Use of metal oxide nanoparticle band gap to develop a predictive paradigm for oxidative stress and acute pulmonary inflammation. ACS Nano 6, 4349-4368. 10.1021/ nn3010087. google scholar


Copy and paste a formatted citation or use one of the options to export in your chosen format



Abudayyak, M., Güzel Meydanlı, E.E., & Özhan, G. (2021). Nickel oxide nanoparticles induced DNA damages in human liver cells. İstanbul Journal of Pharmacy, 51(2), 175-182.


Abudayyak M, Güzel Meydanlı E E, Özhan G. Nickel oxide nanoparticles induced DNA damages in human liver cells. İstanbul Journal of Pharmacy. 2021;51(2):175-182.


Abudayyak, M.; Güzel Meydanlı, E.E.; Özhan, G. Nickel oxide nanoparticles induced DNA damages in human liver cells. İstanbul Journal of Pharmacy, [Publisher Location], v. 51, n. 2, p. 175-182, 2021.

Chicago: Author-Date Style

Abudayyak, Mahmoud, and Emine Elif Güzel Meydanlı and Gül Özhan. 2021. “Nickel oxide nanoparticles induced DNA damages in human liver cells.” İstanbul Journal of Pharmacy 51, no. 2: 175-182.

Chicago: Humanities Style

Abudayyak, Mahmoud, and Emine Elif Güzel Meydanlı and Gül Özhan. Nickel oxide nanoparticles induced DNA damages in human liver cells.” İstanbul Journal of Pharmacy 51, no. 2 (Sep. 2021): 175-182.

Harvard: Australian Style

Abudayyak, M & Güzel Meydanlı, EE & Özhan, G 2021, 'Nickel oxide nanoparticles induced DNA damages in human liver cells', İstanbul Journal of Pharmacy, vol. 51, no. 2, pp. 175-182, viewed 24 Sep. 2021,

Harvard: Author-Date Style

Abudayyak, M. and Güzel Meydanlı, E.E. and Özhan, G. (2021) ‘Nickel oxide nanoparticles induced DNA damages in human liver cells’, İstanbul Journal of Pharmacy, 51(2), pp. 175-182. (24 Sep. 2021).


Abudayyak, Mahmoud, and Emine Elif Güzel Meydanlı and Gül Özhan. Nickel oxide nanoparticles induced DNA damages in human liver cells.” İstanbul Journal of Pharmacy, vol. 51, no. 2, 2021, pp. 175-182. [Database Container],


Abudayyak M, Güzel Meydanlı EE, Özhan G. Nickel oxide nanoparticles induced DNA damages in human liver cells. İstanbul Journal of Pharmacy [Internet]. 24 Sep. 2021 [cited 24 Sep. 2021];51(2):175-182. Available from: doi: 10.26650/IstanbulJPharm.2021.837856


Abudayyak, Mahmoud - Güzel Meydanlı, EmineElif - Özhan, Gül. Nickel oxide nanoparticles induced DNA damages in human liver cells”. İstanbul Journal of Pharmacy 51/2 (Sep. 2021): 175-182.


Published Online31.08.2021


Attribution-NonCommercial (CC BY-NC)

This license lets others remix, tweak, and build upon your work non-commercially, and although their new works must also acknowledge you and be non-commercial, they don’t have to license their derivative works on the same terms.


Istanbul University Press aims to contribute to the dissemination of ever growing scientific knowledge through publication of high quality scientific journals and books in accordance with the international publishing standards and ethics. Istanbul University Press follows an open access, non-commercial, scholarly publishing.