Assessing risks caused by nickel-based nanomaterials: hazardous factor identification

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I.V. Gmoshinski1, S.A. Khotimchenko1,2


1Federal Research Centre of Nutrition, Biotechnology and Food Safety, 2/14 Ustinsky lane, Moscow, 109240, Russian Federation
2I.M. Sechenov First Moscow State Medical University, 4 Bldg., 2 Bol'shaya Pirogovskaya Str., Moscow, 119435, Russian Federation


Nanoparticles of nickel (Ni) and its compounds attract a lot of attention bearing in mind their promising innovative properties allowing their use as catalysts, components in electrical appliances, electronic devices and photonic appliances, and materials used in producing medications, diagnostic preparations, and pesticides. Production volumes of these materials in their nano-form are likely to grow rapidly in the nearest future and it involves greater loads created by these nanomaterials on a human body. And we should remember that Ni and its compounds are highly toxic for humans even in their traditional disperse forms. Their toxicity induces oxidative stress, cellular membranes and mitochondria dysfunction, expression of nuclear transcription factors that are responsible for apoptosis, caspases, as well as proto-oncogenes. Leading role in toxicity of Ni-containing nanomaterials obviously belongs to ions of heavy Ni++ being emitted from them since this heavy metal has pro-oxidant properties and influences enzyme activity and gene expression. Cytotoxic effects produced by Ni-containing nanomaterials were revealed in Model experiments in vitro performed with suing cellular cultures that were morphologically and functionally similar to epithelial cells of respiratory and gastrointestinal tract, liver, kidneys, and nervous system; these materials were able to stimulate oxidant stress, influence expression of apoptosis proteins and nuclear transcription factors, induce apoptosis and necrosis. There are data indicating that Ni-containing nanomaterials can produce malignant transforming effects in vitro. All the above mentioned proves that nickel compounds in their nanoform are a new hazardous factor that requires assessing related risks for workers, consumer, and population in general.
Our review focuses on analyzing literature sources on cytotoxicity of Ni-containing nanomaterials and their effects produced on molecular-genetic and cellular levels taken over a period starting from 2011.

nickel, nickel oxide, nanoparticles, cytotoxicity, genotoxicity, transforming ability, apoptosis, gene expression, risk assessment
Gmoshinski I.V., Khotimchenko S.A. Assessing risks caused by nickel-based nanomaterials: hazardous factor identification. Health Risk Analysis, 2021, no. 2, pp. 177–191. DOI: 10.21668/health.risk/2021.2.17.eng
  1. O'Braien R. Zhiry i masla. Proizvodstvo, sostav i svoistva, primenenie [Fats and oils. Manufacturing, structure and properties, use]. Sankt-Peterburg, Professiya Publ., 2007, 383 p. (in Russian).
  2. Chang X., Zhu A., Liu F., Zou L., Su L., Li S., Sun Y. Role of NF-B activation and Th1/Th2 imbalance in pulmonary toxicity induced by nano NiO. Environ. Toxicol, 2017, vol. 32, no. 4, pp. 1354–1362. DOI: 10.1002/tox.22329
  3. Zhang P., Wang L., Yang S., Schott J.A., Liu X., Mahurin S.M., Huang C., Zhang Y. [et al.]. Solid-state synthesis of ordered mesoporous carbon catalysts via a mechanochemical assembly through coordination cross-linking. Nat. Commun, 2017, vol. 28, no. 8, pp. 15020. DOI: 10.1038/ncomms15020
  4. Bhattacharjee D., Sheet S.K., Khatua S., Biswas K., Joshi S., Myrboh B. A reusable magnetic nickel nanoparticle based catalyst for the aqueous synthesis of diverse heterocycles and their evaluation as potential antibacterial agent. Bioorganic Medicinal Chemistry, 2018, vol. 26, no. 18, pp. 5018–5028. DOI: 10.1016/j.bmc.2018.08.033
  5. Zhu F.Q., Chern G.W., Tchernyshyov O., Zhu X.C., Zhu J.G., Chien C.L. Magnetic bistability and controllable reversal of asymmetric ferromagnetic nanorings. Phys. Rev. Lett, 2006, vol. 96, no. 2, pp. 027205. DOI: 10.1103/PhysRevLett.96.027205
  6. Lei D., Lee D.C., Magasinski A., Zhao E., Steingart D., Yushin G. Performance enhancement and side reactions in rechargeable nickel-iron batteries with nanostructured electrodes. ACS Appl. Materials. Interfaces, 2016, vol. 8, no. 3, pp. 2088–2096. DOI: 10.1021/acsami.5b10547
  7. Chou K.S., Chang S.C., Huang K.C. Study on the characteristics of nanosized nickel particles using sodium borohydride to promote conversion. Azo J. Mater. Online, 2007, vol. 3, pp. 172–179. DOI: 10.2240/azojomo0232
  8. Bajpai R., Roy S., Kulshrestha N., Rafiee J., Koratkar N., Misra D.S. Graphene supported nickel nanoparticle as a viable replacement for platinum in dye sensitized solar cells. Nanoscale, 2012, vol. 4, no. 3, pp. 926–930. DOI: 10.1039/c2nr11127f
  9. Wu X., Xiao T., Luo Z., He R., Cao Y., Guo Z. [et al.]. A micro-/nano-chip and quantum dots-based 3D cytosensor for quantitative analysis of circulating tumor cells. J. Nanobiotechnol, 2018, vol. 16, no. 1, pp. 65. DOI: 10.1186/s12951-018-0390-x
  10. Borowska S., Brzóska M.M. Metals in cosmetics: implications for human health. J. Appl. Toxicol, 2015, vol. 35, no. 6, pp. 551–752. DOI: 10.1002/jat.3129
  11. Ban I., Stergar J., Drofenik M., Ferk G., Makovec D. Synthesis of copper-nickel nanoparticles prepared by mechanical milling for use in magnetic hyperthermia. J. Magn. Magn. Mater, 2011, vol. 323, no. 17, pp. 2254–2258. DOI: 10.1016/j.jmmm.2011.04.004
  12. Angajala G., Ramya R., Subashini R. In-vitro anti-inflammatory and mosquito larvicidal efficacy of nickel nanoparticles phytofabricated from aqueous leaf extracts of Aegle marmelos Correa. Acta Tropica, 2014, no. 135, pp. 19–26. DOI: 10.1016/j.actatropica.2014.03.012
  13. Elango G., Roopan S.M., Dhamodaran K.I., Elumalai K., Al-Dhabi N.A., Arasu M.V. Spectroscopic investigation of biosynthesized nickel nanoparticles and its larvicidal, pesticidal activities. J. Photochem. Photobiol. B: Biology, 2016, vol. 162, pp. 162–167. DOI: 10.1016/j.jphotobiol.2016.06.045
  14. Gomes S.I.L., Roca C.P., Scott-Fordsmand J.J., Amorim M.J.B. High-throughput transcriptomics: insights into the pathways involved in (nano) nickel toxicity in a key invertebrate test species. Environ. Pollut, 2019, no. 245, pp. 131–140. DOI: 10.1016/j.envpol.2018.10.123
  15. Katsnelson B., Privalova L., Sutunkova M.P., Gurvich V.B., Loginova N.V., Minigalieva I.A., Kireyeva E.P., Shur V.Y. [et al.]. Some inferences from in vivo experiments with metal and metal oxide nanoparticles: the pulmonary phagocytosis response, subchronic systemic toxicity and genotoxicity, regulatory proposals, searching for bioprotectors, a self-overview. Int. J. Nanomed, 2015, vol. 16, no. 10, pp. 3013–3029. DOI: 10.2147/IJN.S80843
  16. Magaye R., Zhao J. Recent progress in studies of metallic nickel and nickel-based nanoparticles' genotoxicity and carcinogenicity. Environ. Toxicol. Pharmacol, 2012, vol. 34, no. 3, pp. 644–650. DOI: 10.1016/j.etap.2012.08.012
  17. Ali A., Suhail M., Mathew S., Shah M.A., Harakeh S.M., Ahmad S., Kazmi Z., Alhamdan M.A.R. [et al.]. Nanomaterial induced immune responses and cytotoxicity. J. Nanosci. Nanotechnol, 2016, vol. 16, no. 1, pp. 40–57. DOI: 10.1166/jnn.2016.10885
  18. Kornick R., Zug K.A. Nickel. Dermatitis, 2008, vol. 19, no. 1, pp. 3–8. DOI: 10.2310/6620.2008.07082
  19. Garcia A., Eastlake A., Topmiller J.L., Sparks C., Martinez K., Geraci C.L. Nano-metal oxides: exposure and engineering control assessment. J. Occup. Environ. Hyg, 2017, vol. 14, no. 9, pp. 727–737. DOI: 10.1080/15459624.2017.1326699
  20. Wu Y., Kong L. Advance on toxicity of metal nickel nanoparticles. Environ. Geochem. Health, 2020, vol. 42, no. 7, pp. 2277–2286. DOI: 10.1007/s10653-019-00491-4
  21. Pietruska J.R., Liu X., Smith A., McNeil K., Weston P., Zhitkovich A., Hurt R., Kane A.B. Bioavailability, intracellular mobilization of nickel, and HIF-1α activation in human lung epithelial cells exposed to metallic nickel and nickel oxide nanoparticles. Toxicol. Sci, 2011, vol. 124, no. 1, pp. 138–148. DOI: 10.1093/toxsci/kfr206
  22. Siddiqui M.A., Ahamed M., Ahmad J., Khan M.A.M., Musarrat J., Al-Khedhairy A.A., Alrokayan S.A. Nickel oxide nanoparticles induce cytotoxicity, oxidative stress and apoptosis in cultured human cells that is abrogated by the dietary antioxidant curcumin. Food Chem. Toxicol, 2012, vol. 50, no. 3–4, pp. 641–647. DOI: 10.1016/j.fct.2012.01.017
  23. De Carli R.F., Chaves D.D.S., Cardozo T.R., de Souza A.P., Seeber A., Flores W.H., Honatel K.F., Lehmann M., Dihl R.R. Evaluation of the genotoxic properties of nickel oxide nanoparticles in vitro and in vivo. Mutat. Res. Genet. Toxicol. Environ. Mutagen, 2018, vol. 836, pt. B, pp. 47–53. DOI: 10.1016/j.mrgentox.2018.06.003
  24. Capasso L., Camatini M., Gualtieri M. Nickel oxide nanoparticles induce inflammation and genotoxic effect in lung epithelial cells. Toxicol. Lett, 2014, vol. 226, no. 1, pp. 28–34. DOI: 10.1016/j.toxlet.2014.01.040
  25. Latvala S., Hedberg J., Di Bucchianico S., Moller L., Odnevall Wallinder I., Elihn K., Karlsson H.L. Nickel release, ROS generation and toxicity of Ni and NiO micro- and nanoparticles. PLoS ONE, 2016, vol. 11, no. 7, pp. e0159684. DOI: 10.1371/journal.pone.0159684
  26. Magaye R., Gu Y., Wang Y., Su H., Zhou Q., Mao G., Shi H., Yue X. [et al.]. In vitro and in vivo evaluation of the toxicities induced by metallic nickel nano and fine particles. J. Mol. Histol, 2016, vol. 47, no. 3, pp. 273–286. DOI: 10.1007/s10735-016-9671-6
  27. Chang X., Tian M., Zhang Q., Gao J., Li S., Sun Y. Nano nickel oxide promotes epithelial-mesenchymal transition through transforming growth factor 1/smads signaling pathway in A549 cells. Environ Toxicol, 2020, vol. 35, no. 12, pp. 1308–1317. DOI: 10.1002/tox.22995
  28. Horie M., Fukui H., Nishio K., Endoh S., Kato H., Fujita K., Miyauchi A., Shichiri M. [et al.]. Evaluation of acute oxidative stress induced by NiO nanoparticles in vivo and in vitro. J. Occup. Health, 2011, vol. 53, no. 2, pp. 64–74. DOI: 10.1539/joh.L10121
  29. Khiari M., Kechrid Z., Klibet F., Elfeki A., Shaarani M.S., Krishnaiah D. NiO nanoparticles induce cytotoxicity mediated through ROS generation and impairing the antioxidant defense in the human lung epithelial cells, A549: preventive effect of Pistacia lentiscus essential oil. Toxicol. Rep, 2018, vol. 21, no. 5, pp. 480–488. DOI: 10.1016/j.toxrep.2018.03.012
  30. Duan W.-X., He M.-D., Mao L., Qian F.-H., Li Y.-M., Pi H.-F., Liu C., Chen C.-H .[et al.]. NiO nanoparticles induce apoptosis through repressing SIRT1 in human bronchial epithelial cells. Toxicol. Appl. Pharmacol, 2015, vol. 286, no. 2, pp. 80–91. DOI: 10.1016/j.taap.2015.03.024
  31. Gliga A.R., Di Bucchianico S., Åkerlund E., Karlsson H.L. Transcriptome profiling and toxicity following long-term, low dose exposure of human lung cells to Ni and NiO nanoparticles-comparison with NiCl2. Nanomaterials (Basel), 2020, vol. 10, no. 4, pp. 649. DOI: 10.3390/nano10040649
  32. Di Bucchianico S., Gliga A.R., Åkerlund E., Skoglund S., Wallinder I.O., Fadeel B., Karlsson H.L. Calcium-dependent cyto- and genotoxicity of nickel metal and nickel oxide nanoparticles in human lung cells. Part. Fibre Toxicol, 2018, vol. 15, no. 1, pp. 32. DOI: 10.1186/s12989-018-0268-y
  33. Åkerlund E., Cappellini F., Di Bucchianico S., Islam S., Skoglund S., Derr R., Wallinder I.O., Hendriks G., Karlsson H.L. Genotoxic and mutagenic properties of Ni and NiO nanoparticles investigated by comet assay, γ-H2AX staining, Hprt mutation assay and Tox Tracker reporter cell lines. Environ. Mol. Mutagen, 2018, vol. 59, no. 3, pp. 211–222. DOI: 10.1002/em.22163
  34. Abudayyak M., Guzel E., Özhan G. Cytotoxic, genotoxic, and apoptotic effects of nickel oxide nanoparticles in intestinal epithelial cells. Turk. J. Pharm. Sci, 2020, vol. 17, no. 4, pp. 446–451. DOI: 10.4274/tjps.galenos.2019.76376
  35. Ahamed M., Ali D., Alhadlaq H.A., Akhtar M.J. Nickel oxide nanoparticles exert cytotoxicity via oxidative stress and induce apoptotic response in human liver cells, HepG2. Chemosphere, 2013, vol. 93, no. 10, pp. 2514–2522. DOI: 10.1016/j.chemosphere.2013.09.047
  36. Ahmad J., Alhadlaq H.A., Siddiqui M.A., Saquib Q., Al-Khedhairy A.A., Musarrat J., Ahamed M. Concentration-dependent induction of reactive oxygen species, cell cycle arrest and apoptosis in human liver cells after nickel nanoparticles exposure. Environ. Toxicol, 2015, vol. 30, no. 2, pp. 137–148. DOI:10.1002/tox.21879
  37. Saquib Q., Siddiqui M., Ahmad J., Ansari S., Faisal M., Wahab R., Alatar A., Al-Khedhairy A.A., Musarrat J. Nickel oxide nanoparticles induced transcriptomic alterations in HEPG2 cells. Adv. Exp. Med. Biol, 2018, vol. 1048, pp. 163–174. DOI: 10.1007/978-3-319-72041-8_10
  38. Saquib Q., Xia P., Siddiqui M.A., Zhang J., Xie Y., Faisal M., Ansari S.M., Alwathnani H.A. [et al.]. High-throughput transcriptomics: an insight on the pathways affected in HepG2 cells exposed to nickel oxide nanoparticles. Chemosphere, 2020, vol. 244, pp. 125488. DOI: 10.1016/j.chemosphere.2019.125488
  39. Zhang Q., Chang X., Wang H., Liu Y., Wang X., Wu M., Zhan H., Li S., Sun Y. TGF-β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro. Environ. Toxicol, 2020, vol. 35, no. 4, pp. 419–429. DOI: 10.1002/tox.22878
  40. Cambre M.H., Holl N.J., Wang B., Harper L., Lee H.-J., Chusuei C.C., Hou F.Y.S., Williams E.T. [et al.]. Cytotoxicity of NiO and Ni(OH)2 nanoparticles is mediated by oxidative stress-induced cell death and suppression of cell proliferation. Int. J. Mol Sci, 2020, vol. 21, no. 7, pp. 2355. DOI: 10.3390/ijms21072355
  41. Abudayyak M., Guzel E., Özhan G. Nickel oxide nanoparticles induce oxidative DNA damage and apoptosis in kidney cell line, NRK-52E. Biol. Trace Elem. Res, 2017, vol. 178, no. 1, pp. 98–104. DOI: 10.1007/s12011-016-0892-z
  42. Alarifi S., Ali D., Alakhtani S., Al Suhaibani E.S., Al-Qahtani A.A. Reactive oxygen species-mediated DNA damage and apoptosis in human skin epidermal cells after exposure to nickel nanoparticles. Biol. Trace Elem. Res, 2014, vol. 157, no. 1, pp. 84–93. DOI: 10.1007/s12011-013-9871-9
  43. Zhao J., Bowman L., Zhang X., Shi X., Jiang B., Castranova V., Ding M. Metallic nickel nano- and fine particles induce JB6 cell apoptosis through a caspase-8/AIF mediated cytochrome c-independent pathway. J Nanobiotechnol, 2009, vol. 7, pp. 2. DOI: 10.1186/1477-3155-7-2
  44. Gu Y., Wang Y., Zhou Q., Bowman L., Mao G., Zou B., Xu J., Liu Y. [et al.]. Inhibition of nickel nanoparticles-induced toxicity by epigallocatechin-3-gallate in JB6 cells may be through down-regulation of the MAPK signaling pathways. PLoS One, 2016, vol. 11, no. 3, pp. e0150954. DOI: 10.1371/journal.pone.0150954
  45. Dumala N., Mangalampalli B., Grover P. In vitro genotoxicity assessment of nickel(II)oxide nanoparticles on lymphocytes of human peripheral blood. J. Appl. Toxicol, 2019, vol. 39, no. 7, pp. 955–965. DOI: 10.1002/jat.3784
  46. Mo Y., Zhang Y., Mo L., Wan R., Jiang M., Zhang Q. The role of miR-21 in nickel nanoparticle-induced MMP-2 and MMP-9 production in mouse primary monocytes: in vitro and in vivo studies. Environ. Pollut, 2020, vol. 267, pp. 115597. DOI: 10.1016/j.envpol.2020.115597
  47. Kong L., Hu W., Gao X., Wu Y., Xue Y., Cheng K., Tang M. Molecular mechanisms underlying nickel nanoparticle induced rat Sertoli-germ cells apoptosis. Sci. Total Environ, 2019, vol. 692, pp. 240–248. DOI: 10.1016/j.scitotenv.2019.07.107
  48. Wu Y., Ma J., Sun Y., Tang M., Kong L. Effect and mechanism of PI3K/AKT/mTOR signaling pathway in the apoptosis of GC-1 cells induced by nickel nanoparticles. Chemosphere, 2020, vol. 255, pp. 126913. DOI: 10.1016/j.chemosphere.2020.126913
  49. Latvala S., Vare D., Karlsson H.L., Elihn K. In vitro genotoxicity of airborne Ni-NP in air-liquid interface. J. Appl. Toxicol, 2017, vol. 37, no. 12, pp. 1420–1427. DOI: 10.1002/jat.3510
  50. Abudayyak M., Guzel E., Özhan G. Nickel oxide nanoparticles are highly toxic to SH-SY5Y neuronal cells. Neurochem. Int, 2017, vol. 108, pp. 7–14. DOI: 10.1016/j.neuint.2017.01.017
  51. Hajimohammadjafartehrani M., Hosseinali S.H., Dehkohneh A., Ghoraeian P., Ale-Ebrahim M., Akhtari K., Shahpasand K., Saboury A.A., Attar F., Falahati M. The effects of nickel oxide nanoparticles on tau protein and neuron-like cells: biothermodynamics and molecular studies. Int. J. Biol. Macromol, 2019, vol. 127, pp. 330–339. DOI: 10.1016/j.ijbiomac.2019.01.050
  52. Hosseinali S.H., Boushehri Z.P., Rasti B., Mirpour M., Shahpasand K., Falahati M. Biophysical, molecular dynamics and cellular studies on the interaction of nickel oxide nanoparticles with tau proteins and neuron-like cells. Int. J. Biol. Macromol, 2019, vol. 125, pp. 778–784. DOI: 10.1016/j.ijbiomac.2018.12.062
  53. Minigalieva I., Bushueva T., Fröhlich E., Meindl C., Öhlinger K., Panov V., Varaksin A., Shur V. [et al.]. Are in vivo and in vitro assessments of comparative and combined toxicity of the same metallic nanoparticles compatible, or contradictory, or both? A juxtaposition of data obtained in respective experiments with NiO and Mn3O4 nanoparticles. Food Chem Toxicol, 2017, vol. 109, pt. 1, pp. 393–404. DOI: 10.1016/j.fct.2017.09.032
  54. Magaye R., Zhou Q., Bowman L., Zou B., Mao G., Xu J., Castranova V., Zhao J., Ding M. Metallic nickel nanoparticles may exhibit higher carcinogenic potential than fine particles in JB6 cells. PLoS One, 2014, vol. 9, no. 4, pp. e92418. DOI: 10.1371/journal.pone.0092418
  55. Muñoz A., Costa M. Elucidating the mechanisms of nickel compound uptake– a review of particulate and nano-nickel endocytosis and toxicity. Toxicol. Appl. Pharmacol, 2012, vol. 260, no. 1, pp. 1–16. DOI: 10.1016/j.taap.2011.12.014
  56. Manke A., Wang L., Rojanasakul Y. Mechanisms of nanoparticle-induced oxidative stress and toxicity. Biomed. Res. Int, 2013, vol. 2013, pp. 942916. DOI: 10.1155/2013/942916
  57. Cameron K.S., Buchner V., Tchounwou P.B. Exploring the molecular mechanisms of nickel-induced genotoxicity and carcinogenicity: a literature review. Rev. Environ. Health, 2011, vol. 26, no. 2, pp. 81–92. DOI: 10.1515/reveh.2011.012
  58. Kong L., Gao X., Zhu J., Cheng K., Tang M. Mechanisms involved in reproductive toxicity caused by nickel nanoparticle in female rats. Environ. Toxicol, 2016, vol. 31, no. 11, pp. 1674–1683. DOI: 10.1002/tox.22288
  59. Magaye R.R., Yue X., Zou B., Shi H., Yu H., Liu K., Lin X., Xu J. [et al.]. Acute toxicity of nickel nanoparticles in rats after intravenous injection. Int. J. Nanomed, 2014, vol. 9, pp. 1393–1402. DOI: 10.2147/ijn.S56212
  60. Wan R., Mo Y., Chien S., Li Y., Tollerud D.J., Zhang Q. The role of hypoxia inducible factor-1alpha in the increased MMP-2 and MMP-9 production by human monocytes exposed to nickel nanoparticles. Nanotoxicology, 2011, vol. 5, no. 4, pp. 568–582. DOI: 10.3109/17435390.2010.537791
  61. Shumakova A.A., Shipelin V.A., Trushina E.N., Mustafina O.K., Gmoshinskii I.V., Khanfer'yan R.A., Khotimchenko S.A., Tutel'yan V.A. Toxicological assessment of nanostructured silica. IV. Immunological and allergological indices in animals sensitized with food allergen and final discussion. Voprosy pitaniya, 2015, vol. 84, no. 5, pp. 102–111 (in Russian).
  62. Gmoshinski I.V., Shumakova A.A., Shipelin V.A., Maltsev G.Yu., Khotimchenko S.A. Influence of orally introduced silver nanoparticles on content of essential and toxic trace elements in organism. Nanotechnologies in Russia, 2016, vol. 11, no. 9–10, pp. 646–652. DOI: 10.1134/S1995078016050074

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