Abstract
Silver nanoparticles (AgNPs) are widely used in a variety of consumer products because of their antibacterial and antifungal characteristics, but little is known about their toxicity to the brain. In this study, we investigated AgNP-induced neurotoxicity using the human neuroblastoma cancer (SH-SY5Y) cell line. After a 24 h treatment of AgNPs with two primary sizes (5 and 50 nm labeled as Ag-5 and Ag-50, respectively), a series of toxicological endpoints including cell viability, expression of proteins and genes in amyloid precursor protein (APP) amyloid hydrolysis process and ferritinophagy signaling pathways, oxidative stress, intracellular iron levels, and molecular regulators of iron metabolism were evaluated. Our results showed that both Ag-5 and Ag-50 induced notable neurotoxic effects on SH-SY5Y cells indicated by cell proliferation inhibition, increased BACE1 protein expression, and decreased APP and ADAM10 gene expression. Activation of nuclear receptor coactivator 4-mediated ferritinophagy and blockade of autophagic flux were induced by AgNPs, accompanied by intracellular iron accumulation and overexpression of divalent metal-ion transporter-1 and ferroportin1 in SH-SY5Y cells. In addition, AgNPs significantly decreased glutathione peroxidase 4 protein expression but increased malondialdehyde concentration, suggesting that AgNP-induced iron accumulation may trigger oxidative stress by disruption of the intracellular oxidant and antioxidant systems. In addition, compared with Ag-50, Ag-5 with higher cellular uptake efficiency caused more detrimental effects on SH-SY5Y cells. In conclusion, our findings demonstrated a size-dependent neurotoxicity in SH-SY5Y cells by AgNPs via ferritinophagy-mediated oxidative stress.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Antsiferova A, Kopaeva M, Kashkarov P (2018) Effects of prolonged silver nanoparticle exposure on the contextual cognition and behavior of mammals. Materials (basel) 11(4):558. https://doi.org/10.3390/ma11040558
Aring L, Choi EK, Kopera H, Lanigan T, Iwase S, Klionsky DJ, Seo YA (2022) A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation. J Neurochem 160(3):356–375. https://doi.org/10.1111/jnc.15548
Asadi Dokht Lish R, Johari SA, Sarkheil M, Yu IJ (2019) On how environmental and experimental conditions affect the results of aquatic nanotoxicology on brine shrimp (Artemia salina): a case of silver nanoparticles toxicity. Environ Pollut 255(Pt 3):113358. https://doi.org/10.1016/j.envpol.2019.113358
Chang X, Wang X, Li J, Shang M, Niu S, Zhang W, Li Y, Sun Z, Gan J, Li W, Tang M, Xue Y (2021) Silver nanoparticles induced cytotoxicity in HT22 cells through autophagy and apoptosis via PI3K/AKT/mTOR signaling pathway. Ecotoxicol Environ Saf 208:111696. https://doi.org/10.1016/j.ecoenv.2020.111696
Cheung YT, Lau WK, Yu MS, Lai CS, Yeung SC, So KF, Chang RC (2009) Effects of all-trans-retinoic acid on human SH-SY5Y neuroblastoma as in vitro model in neurotoxicity research. Neurotoxicology 30(1):127–135. https://doi.org/10.1016/j.neuro.2008.11.001
Dabrowska-Bouta B, Sulkowski G, Struzynski W, Struzynska L (2019) Prolonged exposure to silver nanoparticles results in oxidative stress in cerebral myelin. Neurotox Res 35(3):495–504. https://doi.org/10.1007/s12640-018-9977-0
Dan M, Wen H, Shao A, Xu L (2018) Silver nanoparticle exposure induces neurotoxicity in the rat hippocampus without increasing the blood-brain barrier permeability. J Biomed Nanotechnol 14(7):1330–1338. https://doi.org/10.1166/jbn.2018.2563
Davenport LL, Hsieh H, Eppert BL, Carreira VS, Krishan M, Ingle T, Howard PC, Williams MT, Vorhees CV, Genter MB (2015) Systemic and behavioral effects of intranasal administration of silver nanoparticles. Neurotoxicol Teratol 51:68–76. https://doi.org/10.1016/j.ntt.2015.08.006
Du J, Tang J, Xu S, Ge J, Dong Y, Li H, Jin M (2018) A review on silver nanoparticles-induced ecotoxicity and the underlying toxicity mechanisms. Regul Toxicol Pharmacol 98:231–239. https://doi.org/10.1016/j.yrtph.2018.08.003
Dziendzikowska K, Wilczak J, Grodzicki W, Gromadzka-Ostrowska J, Węsierska M, Kruszewski M (2022) Coating-dependent neurotoxicity of silver nanoparticles-an in vivo study on hippocampal oxidative stress and neurosteroids. Int J Mol Sci 23(3):1365. https://doi.org/10.3390/ijms23031365
Fang Y, Chen X, Tan Q, Zhou H, Xu J, Gu Q (2021) Inhibiting ferroptosis through disrupting the ncoa4-fth1 interaction: a new mechanism of action. ACS Cent Sci 7(6):980–989. https://doi.org/10.1021/acscentsci.0c01592
Ferdous Z, Nemmar A (2020) Health impact of silver nanoparticles: a review of the biodistribution and toxicity following various routes of exposure. Int J Mol Sci 21(7):2375. https://doi.org/10.3390/ijms21072375
Gong JY, Holt MG, Hoet PHM, Ghosh M (2022) Neurotoxicity of four frequently used nanoparticles: a systematic review to reveal the missing data. Arch Toxicol 96(5):1141–1212. https://doi.org/10.1007/s00204-022-03233-1
Greish K, Alqahtani AA, Alotaibi AF, Abdulla AM, Bukelly AT, Alsobyani FM, Alharbi GH, Alkiyumi IS, Aldawish MM, Alshahrani TF, Pittala V, Taurin S, Kamal A (2019) The effect of silver nanoparticles on learning, memory and social interaction in BALB/C mice. Int J Environ Res Public Health 16(1):148. https://doi.org/10.3390/ijerph16010148
Gurunathan S, Jeyaraj M, Kang MH, Kim JH (2019) Mitochondrial peptide humanin protects silver nanoparticles-induced neurotoxicity in human neuroblastoma cancer cells (SH-SY5Y). Int J Mol Sci 20(18):4439. https://doi.org/10.3390/ijms20184439
Kang S, Lee YH, Lee JE (2017) Metabolism-centric overview of the pathogenesis of Alzheimer’s disease. Yonsei Med J 58(3):479–488. https://doi.org/10.3349/ymj.2017.58.3.479
Krawczyńska A, Dziendzikowska K, Gromadzka-Ostrowska J, Lankoff A, Herman AP, Oczkowski M, Królikowski T, Wilczak J, Wojewodzka M, Kruszewski M (2015) Silver and titanium dioxide nanoparticles alter oxidative/inflammatory response and renin-angiotensin system in brain. Food Chem Toxicol 85:96–105. https://doi.org/10.1016/j.fct.2015.08.005
Kuhn LC (2015) Iron regulatory proteins and their role in controlling iron metabolism. Metallomics 7(2):232–243. https://doi.org/10.1039/c4mt00164h
Li D, Liu B, Fan Y, Liu M, Han B, Meng Y, Xu X, Song Z, Liu X, Hao Q, Duan X, Nakai A, Chang Y, Cao P, Tan K (2021) Nuciferine protects against folic acid-induced acute kidney injury by inhibiting ferroptosis. Br J Pharmacol 178(5):1182–1199. https://doi.org/10.1111/bph.15364
Li K, Reichmann H (2016) Role of iron in neurodegenerative diseases. J Neural Transm (vienna) 123(4):389–399. https://doi.org/10.1007/s00702-016-1508-7
Lojk J, Repas J, Veranic P, Bregar VB, Pavlin M (2020) Toxicity mechanisms of selected engineered nanoparticles on human neural cells in vitro. Toxicology 432:152364. https://doi.org/10.1016/j.tox.2020.152364
Lundgren JL, Ahmed S, Schedin-Weiss S, Gouras GK, Winblad B, Tjernberg LO, Frykman S (2015) ADAM10 and BACE1 are localized to synaptic vesicles. J Neurochem 135(3):606–615. https://doi.org/10.1111/jnc.13287
Lundgren JL, Vandermeulen L, Sandebring-Matton A, Ahmed S, Winblad B, Di Luca M, Tjernberg LO, Marcello E, Frykman S (2020) Proximity ligation assay reveals both pre- and postsynaptic localization of the APP-processing enzymes ADAM10 and BACE1 in rat and human adult brain. BMC Neurosci 21(1):6. https://doi.org/10.1186/s12868-020-0554-0
Mao BH, Tsai JC, Chen CW, Yan SJ, Wang YJ (2016) Mechanisms of silver nanoparticle-induced toxicity and important role of autophagy. Nanotoxicology 10(8):1021–1040. https://doi.org/10.1080/17435390.2016.1189614
Massarsky A, Trudeau VL, Moon TW (2014) Predicting the environmental impact of nanosilver. Environ Toxicol Pharmacol 38(3):861–873. https://doi.org/10.1016/j.etap.2014.10.006
Nai A, Lidonnici MR, Federico G, Pettinato M, Olivari V, Carrillo F, Geninatti Crich S, Ferrari G, Camaschella C, Silvestri L, Carlomagno F (2021) NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice. Haematologica 106(3):795–805. https://doi.org/10.3324/haematol.2019.241232
Pareek V, Gupta R, Devineau S, Sivasankaran SK, Bhargava A, Khan MA, Srikumar S, Fanning S, Panwar J (2022) Does silver in different forms affect bacterial susceptibility and resistance? A mechanistic perspective. ACS Appl Bio Mater 5(2):801–817. https://doi.org/10.1021/acsabm.1c01179
Pareek V, Gupta R, Panwar J (2018) Do physico-chemical properties of silver nanoparticles decide their interaction with biological media and bactericidal action? A review. Mater Sci Eng C Mater Biol Appl 90:739–749. https://doi.org/10.1016/j.msec.2018.04.093
Pavičić I, Milić M, Pongrac IM, Brkić Ahmed L, Matijević Glavan T, Ilić K, Zapletal E, Ćurlin M, Mitrečić D, Vinković Vrček I (2020) Neurotoxicity of silver nanoparticles stabilized with different coating agents: in vitro response of neuronal precursor cells. Food Chem Toxicol 136:110935. https://doi.org/10.1016/j.fct.2019.110935
Pimentel-Acosta CA, Ramírez-Salcedo J, Morales-Serna FN, Fajer-Ávila EJ, Chávez-Sánchez C, Lara HH, Garciá-Gasca A (2020) Molecular effects of silver nanoparticles on monogenean parasites: lessons from Caenorhabditis elegans. Int J Mol Sci 21(16):5889. https://doi.org/10.3390/ijms21165889
Repar N, Li H, Aguilar JS, Li QQ, Drobne D, Hong Y (2018) Silver nanoparticles induce neurotoxicity in a human embryonic stem cell-derived neuron and astrocyte network. Nanotoxicology 12(2):104–116. https://doi.org/10.1080/17435390.2018.1425497
Santana-Codina N, Mancias JD (2018) The role of NCOA4-mediated ferritinophagy in health and disease. Pharmaceuticals (basel) 11(4):114. https://doi.org/10.3390/ph11040114
Singh N, Haldar S, Tripathi AK, Horback K, Wong J, Sharma D, Beserra A, Suda S, Anbalagan C, Dev S, Mukhopadhyay CK, Singh A (2014) Brain iron homeostasis: from molecular mechanisms to clinical significance and therapeutic opportunities. Antioxid Redox Signal 20(8):1324–1363. https://doi.org/10.1089/ars.2012.4931
Thirupathi A, Chang YZ (2019) Brain iron metabolism and CNS diseases. Adv Exp Med Biol 1173:1–19. https://doi.org/10.1007/978-981-13-9589-5_1
Xin L, Wang J, Zhang LW, Che B, Dong G, Fan G, Cheng K (2016) Development of HSPA1A promoter-driven luciferase reporter gene assays in human cells for assessing the oxidative damage induced by silver nanoparticles. Toxicol Appl Pharmacol 304:9–17. https://doi.org/10.1016/j.taap.2016.05.010
Yu P, Chang YZ (2019) Brain iron metabolism and regulation. Adv Exp Med Biol 1173:33–44. https://doi.org/10.1007/978-981-13-9589-5_3
Zhang B, Liu N, Liu QS, Zhang J, Zhou Q, Jiang G (2020) Silver nanoparticles induce size-dependent and particle-specific neurotoxicity to primary cultures of rat cerebral cortical neurons. Ecotoxicol Environ Saf 198:110674. https://doi.org/10.1016/j.ecoenv.2020.110674
Zuo Y, Xie J, Li X, Li Y, Thirupathi A, Zhang J, Yu P, Gao G, Chang Y, Shi Z (2021) Ferritinophagy-mediated ferroptosis involved in paraquat-induced neurotoxicity of dopaminergic neurons: implication for neurotoxicity in PD. Oxid Med Cell Longev 2021:9961628. https://doi.org/10.1155/2021/9961628
Acknowledgements
We would like to thank Dr. Anthony L. Kiorpes for manuscript editing and proofreading.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by XDZ, SS, and JMW, with overall guidance from LLX, JSW, and HLT. The first draft of the manuscript was written by XDZ and SS, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Ethics Approval
Not applicable.
Consent to Participate
Not applicable.
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhai, X., Shan, S., Wan, J. et al. Silver Nanoparticles Induce a Size-dependent Neurotoxicity to SH-SY5Y Neuroblastoma Cells via Ferritinophagy-mediated Oxidative Stress. Neurotox Res 40, 1369–1379 (2022). https://doi.org/10.1007/s12640-022-00570-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-022-00570-y