logo

Toxic effects of metal oxide nanoparticles and their underlying mechanisms

More info
  • ReceivedNov 15, 2016
  • AcceptedJan 3, 2017
  • PublishedJan 17, 2017

Abstract

Nanomaterials have attracted considerable interest owing to their unique physicochemical properties. The wide application of nanomaterials has raised many concerns about their potential risks to human health and the environment. Metal oxide nanoparticles (MONPs), one of the main members of nanomaterials, have been applied in various fields, such as food, medicine, cosmetics, and sensors. This review highlights the bio-toxic effects of widely applied MONPs and their underlying mechanisms. Two main underlying toxicity mechanisms, reactive oxygen species (ROS)- and non-ROS-mediated toxicities, of MONPs have been widely accepted. ROS activates oxidative stress, which leads to lipid peroxidation and cell membrane damage. In addition, ROS can trigger the apoptotic pathway by activating caspase-9 and -3. Non-ROS-mediated toxicity mechanism includes the effect of released ions, excessive accumulation of NPs on the cell surface, and combination of NPs with specific death receptors. Furthermore, the combined toxicity evaluation of some MONPs is also discussed. Toxicity may dramatically change when nanomaterials are used in a combined system because the characteristics of NPs that play a key role in their toxicity such as size, surface properties, and chemical nature in the complex system are different from the pristine NPs.


Funded by

National Basic Research Program of China(2011CB933402)

National Natural Science Foundation of China(21371115,11025526,40830744,41073073,21101104)

Innovation Program of Shanghai Municipal Education Commission(14YZ025)

Program for Innovative Research Team in University(IRT13078)


Acknowledgment

This work was supported by the National Natural Science Foundation of China (21371115, 11025526, 40830744, 41073073, and 21101104), the National Basic Research Program of China (2011CB933402), the Innovation Program of Shanghai Municipal Education Commission (14YZ025), and the Program for Innovative Research Team in University (IRT13078).


Interest statement

The authors declare that they have no conflict of interest.


Contributions statement

Wang Y, Wu M and Ding L organized the references and wrote the paper. Ding L, Yao C, Li C, Xing X, Huang Y and Gu T finished the literature investigation. Ding L took the leadership of the literature investigation and organized the figures. All authors discussed the idea of the paper.


Author information

Yanli Wang is now working at the Institute of Nanochemistry and Nanobiology of Shanghai University as an associate professor since 2012. She obtained her PhD degree in environmental engineering from Shanghai University in 2010. Her research interests include bio-effects and safety evaluation of nanomaterials and their application in bio-imaging and cancer therapy.


Minghong Wu obtained her PhD degree from Shanghai Institute of Applied Physics of Chinese Academy of Sciences in 1999. She is the National outstanding youth and Yangtze River scholar of China. Based on her scientific contribution, she was selected as the Russian Academy of foreign academicians of Russian Academy of Engineering in 2008 and Russian Academy of Science in 2015. Her research interests mainly focus on bio-effects and safety evaluation of nanomaterials and environmental pollution analysis and control.


References

[1] Dykman L, Khlebtsov N. Gold nanoparticles in biomedical applications: recent advances and perspectives. Chem Soc Rev, 2012, 41: 2256-2282 CrossRef PubMed Google Scholar

[2] Wu QS, Liu JW, Wang GS, et al. A surfactant-free route to synthesize BaxSr1−xTiO3 nanoparticles at room temperature, their dielectric and microwave absorption properties. Sci China Mater, 2016, 59: 609-617 CrossRef Google Scholar

[3] Arvizo RR, Bhattacharyya S, Kudgus RA, et al. Intrinsic therapeutic applications of noble metal nanoparticles: past, present and future. Chem Soc Rev, 2012, 41: 2943 CrossRef PubMed Google Scholar

[4] Llevot A, Astruc D. Applications of vectorized gold nanoparticles to the diagnosis and therapy of cancer. Chem Soc Rev, 2012, 41: 242-257 CrossRef PubMed Google Scholar

[5] Sun Z, Liao T, Kou L. Strategies for designing metal oxide nanostructures. Sci China Mater, 2017, 60: 1-24 CrossRef Google Scholar

[6] Rana S, Bajaj A, Mout R, et al. Monolayer coated gold nanoparticles for delivery applications. Adv Drug Deliver Rev, 2012, 64: 200-216 CrossRef PubMed Google Scholar

[7] Lin X, Zuo YY, Gu N. Shape affects the interactions of nanoparticles with pulmonary surfactant. Sci China Mater, 2015, 58: 28-37 CrossRef Google Scholar

[8] Colvin VL. The potential environmental impact of engineered nanomaterials. Nat Biotechnol, 2003, 21: 1166-1170 CrossRef PubMed Google Scholar

[9] Zhao Y, Xing G, Chai Z. Nanotoxicology: are carbon nanotubes safe?. Nat Nanotech, 2008, 3: 191-192 CrossRef PubMed ADS Google Scholar

[10] Hoet PHM, Nemmar A, Nemery B. Health impact of nanomaterials?. Nat Biotechnol, 2004, 22: 19 CrossRef PubMed Google Scholar

[11] Service RF. Nanomaterials show signs of toxicity. Science, 2003, 300: 243 CrossRef PubMed Google Scholar

[12] Chen L, Remondetto GE, Subirade M. Food protein-based materials as nutraceutical delivery systems. Trends Food Sci Tech, 2006, 17: 272-283 CrossRef Google Scholar

[13] Donaldson K, Tran L, Jimenez LA, et al. Combustion-derived nanoparticles: a review of their toxicology following inhalation exposure. Part Fibre Toxicol, 2005, 2: 10 CrossRef PubMed Google Scholar

[14] Cortie MB, McDonagh AM. Synthesis and optical properties of hybrid and alloy plasmonic nanoparticles. Chem Rev, 2011, 111: 3713-3735 CrossRef PubMed Google Scholar

[15] Yang F, Li M, Cui H, et al. Altering the response of intracellular reactive oxygen to magnetic nanoparticles using ultrasound and microbubbles. Sci China Mater, 2015, 58: 467-480 CrossRef Google Scholar

[16] Koeneman BA, Zhang Y, Westerhoff P, et al. Toxicity and cellular responses of intestinal cells exposed to titanium dioxide. Cell Biol Toxicol, 2010, 26: 225-238 CrossRef PubMed Google Scholar

[17] Jani PU, McCarthy DE, Florence AT. Titanium dioxide (rutile) particle uptake from the rat GI tract and translocation to systemic organs after oral administration. Int J Pharm, 1994, 105: 157-168 CrossRef Google Scholar

[18] Liu X, Zhang J, Tang S, et al. Growth enhancing effect of LBL-assembled magnetic nanoparticles on primary bone marrow cells. Sci China Mater, 2016, 59: 901-910 CrossRef Google Scholar

[19] Ning Z, Sillanpää M, Pakbin P, et al. Field evaluation of a new particle concentrator-electrostatic precipitator system for measuring chemical and toxicological properties of particulate matter. Part Fibre Toxicol, 2008, 5: 15 CrossRef PubMed Google Scholar

[20] Wiesner MR, Lowry GV, Alvarez P, et al. Assessing the risks of manufactured nanomaterials. Environ Sci Technol, 2006, 40: 4336-4345 CrossRef Google Scholar

[21] Chen JL, Fayerweather WE. Epidemiologic study of workers exposed to titanium dioxide. J Occupational Environ Med, 1988, 30: 937-942 CrossRef Google Scholar

[22] Ghosh M, Chakraborty A, Mukherjee A. Cytotoxic, genotoxic and the hemolytic effect of titanium dioxide (TiO2) nanoparticles on human erythrocyte and lymphocyte cells in vitro. J Appl Toxicol, 2013, 33: 1097-1110 CrossRef PubMed Google Scholar

[23] Zhang J, Li S, Yang P, et al. Deposition of transparent TiO2 nanotubes-films via electrophoretic technique for photovoltaic applications. Sci China Mater, 2015, 58: 785-790 CrossRef Google Scholar

[24] Magdolenova Z, Bilaničová D, Pojana G, et al. Impact of agglomeration and different dispersions of titanium dioxide nanoparticles on the human related in vitro cytotoxicity and genotoxicity. J Environ Monit, 2012, 14: 455-464 CrossRef PubMed Google Scholar

[25] Thomas KV, Farkas J, Farmen E, et al. Effects of dispersed aggregates of carbon and titanium dioxide engineered nanoparticles on rainbow trout hepatocytes. J Toxicol Environ Health A, 2011, 74: 466-477 CrossRef PubMed Google Scholar

[26] Sha BY, Gao W, Wang SQ, et al. Cytotoxicity of titanium dioxide nanoparticles differs in four liver cells from human and rat. Composites Part B-Eng, 2011, 42: 2136-2144 CrossRef Google Scholar

[27] Pujalté I, Passagne I, Brouillaud B, et al. Cytotoxicity and oxidative stress induced by different metallic nanoparticles on human kidney cells. Part Fibre Toxicol, 2011, 8: 10 CrossRef PubMed Google Scholar

[28] Botelho MC, Costa C, Silva S, et al. Effects of titanium dioxide nanoparticles in human gastric epithelial cells in vitro. Biomed Pharmacother, 2014, 68: 59-64 CrossRef PubMed Google Scholar

[29] Butler KS, Casey BJ, Garborcauskas GVM, et al. Assessment of titanium dioxide nanoparticle effects in bacteria: association, uptake, mutagenicity, co-mutagenicity and DNA repair inhibition. Mutation Res/Genet Toxicol Environ Mutagenesis, 2014, 768: 14-22 CrossRef PubMed Google Scholar

[30] Valdiglesias V, Costa C, Sharma V, et al. Comparative study on effects of two different types of titanium dioxide nanoparticles on human neuronal cells. Food Chem Toxicol, 2013, 57: 352-361 CrossRef PubMed Google Scholar

[31] Wang Y, Yao C, Li C, et al. Excess titanium dioxide nanoparticles on the cell surface induce cytotoxicity by hindering ion exchange and disrupting exocytosis processes. Nanoscale, 2015, 7: 13105-13115 CrossRef PubMed ADS Google Scholar

[32] Yin Y, Zhu WW, Guo LP, et al. RGDC functionalized titanium dioxide nanoparticles induce less damage to plasmid DNA but higher cytotoxicity to HeLa cells. J Phys Chem B, 2013, 117: 125-131 CrossRef PubMed Google Scholar

[33] Venkatasubbu GD, Ramasamy S, Avadhani GS, et al. Size-mediated cytotoxicity of nanocrystalline titanium dioxide, pure and zinc-doped hydroxyapatite nanoparticles in human hepatoma cells. J Nanopart Res, 2012, 14: 819 CrossRef Google Scholar

[34] Liang G, Pu Y, Yin L, et al. Influence of different sizes of titanium dioxide nanoparticles on hepatic and renal functions in rats with correlation to oxidative stress. J Toxicol Environ Health A, 2009, 72: 740-745 CrossRef PubMed Google Scholar

[35] Zhang Y, Yu W, Jiang X, et al. Analysis of the cytotoxicity of differentially sized titanium dioxide nanoparticles in murine MC3T3-E1 preosteoblasts. J Mater Sci-Mater Med, 2011, 22: 1933-1945 CrossRef PubMed Google Scholar

[36] Xiong S, George S, Yu H, et al. Size influences the cytotoxicity of poly (lactic-co-glycolic acid) (PLGA) and titanium dioxide (TiO2) nanoparticles. Arch Toxicol, 2013, 87: 1075-1086 CrossRef PubMed Google Scholar

[37] Wang Y, Sui K, Fang J, et al. Cytotoxicity evaluation and subcellular location of titanium dioxide nanotubes. Appl Biochem Biotechnol, 2013, 171: 1568-1577 CrossRef PubMed Google Scholar

[38] Wang Y, Wang J, Deng X, et al. Direct imaging of titania nanotubes located in mouse neural stem cell nuclei. Nano Res, 2009, 2: 543-552 CrossRef Google Scholar

[39] Wang Y, Wu Q, Sui K, et al. A quantitative study of exocytosis of titanium dioxide nanoparticles from neural stem cells. Nanoscale, 2013, 5: 4737-4743 CrossRef PubMed ADS Google Scholar

[40] Tsuji JS, Maynard AD, Howard PC, et al. Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles. Toxicol Sci, 2005, 89: 42-50 CrossRef PubMed Google Scholar

[41] Lademann J, Weigmann HJ, Rickmeyer C, et al. Penetration of titanium dioxide microparticles in a sunscreen formulation into the horny layer and the follicular orifice. Skin Pharmacol Physiol, 1999, 12: 247-256 CrossRef Google Scholar

[42] Wu J, Liu W, Xue C, et al. Toxicity and penetration of TiO2 nanoparticles in hairless mice and porcine skin after subchronic dermal exposure. Toxicol Lett, 2009, 191: 1-8 CrossRef PubMed Google Scholar

[43] Hagens WI, Oomen AG, de Jong WH, et al. What do we (need to) know about the kinetic properties of nanoparticles in the body?. Regul Toxicol Pharm, 2007, 49: 217-229 CrossRef PubMed Google Scholar

[44] Namavar F, Cheung CL, Sabirianov RF, et al. Lotus effect in engineered zirconia. Nano Lett, 2008, 8: 988-996 CrossRef PubMed ADS Google Scholar

[45] Li J, Li Q, Xu J, et al. Comparative study on the acute pulmonary toxicity induced by 3 and 20 nm TiO2 primary particles in mice. Environ Toxicol Pharmacol, 2007, 24: 239-244 CrossRef PubMed Google Scholar

[46] Liu R, Yin L, Pu Y, et al. Pulmonary toxicity induced by three forms of titanium dioxide nanoparticles via intra-tracheal instillation in rats. Prog Nat Sci, 2009, 19: 573-579 CrossRef Google Scholar

[47] Hamilton RF, Wu N, Porter D, et al. Particle length-dependent titanium dioxide nanomaterials toxicity and bioactivity. Part Fibre Toxicol, 2009, 6: 35 CrossRef PubMed Google Scholar

[48] Chen XX, Cheng B, Yang YX, et al. Characterization and preliminary toxicity assay of nano-titanium dioxide additive in sugar-coated chewing gum. Small, 2013, 9: 1765-1774 CrossRef PubMed Google Scholar

[49] Wang Y, Chen Z, Ba T, et al. Susceptibility of young and adult rats to the oral toxicity of titanium dioxide nanoparticles. Small, 2013, 9: 1742-1752 CrossRef PubMed Google Scholar

[50] Fang J, Yuan LL, Yao CJ, et al. Biodistribution and toxicity study of titanium dioxide nanoparticles of different sizes after intravenous injection in mice. Adv Mater Res, 2014, 998-999: 196-199 CrossRef Google Scholar

[51] Yao C, Li C, Ding L, et al. Effects of exposure routes on the bio-distribution and toxicity of titanium dioxide nanoparticles in mice. J Nanosci Nanotechnol, 2016, 16: 7110-7117 CrossRef Google Scholar

[52] Zhang J, Lang HP, Huber F, et al. Rapid and label-free nanomechanical detection of biomarker transcripts in human RNA. Nat Nanotech, 2006, 1: 214-220 CrossRef PubMed ADS Google Scholar

[53] Dunphy Guzmán KA, Taylor MR, Banfield JF. Environmental risks of nanotechnology: National Nanotechnology Initiative Funding, 2000−2004. Environ Sci Technol, 2006, 40: 1401-1407 CrossRef Google Scholar

[54] He W, Wu H, Wamer WG, et al. Unraveling the enhanced photocatalytic activity and phototoxicity of ZnO/metal hybrid nanostructures from generation of reactive oxygen species and charge carriers. ACS Appl Mater Interfaces, 2014, 6: 15527-15535 CrossRef PubMed Google Scholar

[55] Wissing SA, Müller RH. Solid lipid nanoparticles (SLN)—a novel carrier for UV blockers. Die Pharmazie, 2001, 56: 783–786. Google Scholar

[56] Zhang Y, Kang Z, Yan X, et al. ZnO nanostructures in enzyme biosensors. Sci China Mater, 2015, 58: 60-76 CrossRef Google Scholar

[57] Chen S, Lou Z, Chen D, et al. Highly flexible strain sensor based on ZnO nanowires and P(VDF-TrFE) fibers for wearable electronic device. Sci China Mater, 2016, 59: 173-181 CrossRef Google Scholar

[58] Wang Y, Yuan L, Yao C, et al. A combined toxicity study of zinc oxide nanoparticles and vitamin C in food additives. Nanoscale, 2014, 6: 15333-15342 CrossRef PubMed ADS Google Scholar

[59] Mortimer M, Kasemets K, Kahru A. Toxicity of ZnO and CuO nanoparticles to ciliated protozoa Tetrahymena thermophila. Toxicol, 2010, 269: 182-189 CrossRef PubMed Google Scholar

[60] Suh KS, Lee YS, Seo SH, et al. Effect of zinc oxide nanoparticles on the function of MC3T3-E1 osteoblastic cells. Biol Trace Elem Res, 2013, 155: 287-294 CrossRef PubMed Google Scholar

[61] Xu M, Fujita D, Kajiwara S, et al. Contribution of physicochemical characteristics of nano-oxides to cytotoxicity. Biomaterials, 2010, 31: 8022-8031 CrossRef PubMed Google Scholar

[62] Chen R, Huo L, Shi X, et al. Endoplasmic reticulum stress induced by zinc oxide nanoparticles is an earlier biomarker for nanotoxicological evaluation. ACS Nano, 2014, 8: 2562-2574 CrossRef PubMed Google Scholar

[63] Moos PJ, Chung K, Woessner D, et al. ZnO particulate matter requires cell contact for toxicity in human colon cancer cells. Chem Res Toxicol, 2010, 23: 733-739 CrossRef PubMed Google Scholar

[64] Sahu D, Kannan GM, Vijayaraghavan R. Size-dependent effect of zinc oxide on toxicity and inflammatory potential of human monocytes. J Toxicol Environ Health A, 2014, 77: 177-191 CrossRef PubMed Google Scholar

[65] Yin H, Casey PS, McCall MJ. Surface modifications of ZnO nanoparticles and their cytotoxicity. J Nanosci Nanotech, 2010, 10: 7565-7570 CrossRef Google Scholar

[66] Gilbert E, Pirot F, Bertholle V, et al. Commonly used UV filter toxicity on biological functions: review of last decade studies. Int J Cosmet Sci, 2013, 35: 208-219 CrossRef PubMed Google Scholar

[67] Cross SE, Innes B, Roberts MS, et al. Human skin penetration of sunscreen nanoparticles: in-vitro assessment of a novel micronized zinc oxide formulation. Skin Pharmacol Physiol, 2007, 20: 148-154 CrossRef PubMed Google Scholar

[68] Filipe P, Silva JN, Silva R, et al. Stratum corneum is an effective barrier to TiO2 and ZnO nanoparticle percutaneous absorption. Skin Pharmacol Physiol, 2009, 22: 266-275 CrossRef PubMed Google Scholar

[69] Jang YS, Lee EY, Park YH, et al. The potential for skin irritation, phototoxicity, and sensitization of ZnO nanoparticles. Mol Cell Toxicol, 2012, 8: 171-177 CrossRef Google Scholar

[70] Prasad AS. Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Exp Gerontology, 2008, 43: 370-377 CrossRef PubMed Google Scholar

[71] Rincker MJ, Hill GM, Link JE, et al. Effects of dietary iron supplementation on growth performance, hematological status, and whole-body mineral concentrations of nursery pigs. J Anim Sci, 2004, 82: 3189-3197 CrossRef Google Scholar

[72] Sharma V, Singh P, Pandey AK, et al. Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles. Mutation Res-Genet Tox En, 2012, 745: 84-91 CrossRef PubMed Google Scholar

[73] Ko JW, Hong ET, Lee IC, et al. Evaluation of 2-week repeated oral dose toxicity of 100 nm zinc oxide nanoparticles in rats. Lab Anim Res, 2015, 31: 139-147 CrossRef PubMed Google Scholar

[74] Nie Z, Wang Y, Zhang Y, et al. Multi-shelled α-Fe2O3 microspheres for high-rate supercapacitors. Sci China Mater, 2016, 59: 247-253 CrossRef Google Scholar

[75] Li W, Feng X, Liu D, et al. In situ redox strategy for large-scale fabrication of surfactant-free M-Fe2O3 (M = Pt, Pd, Au) hybrid nanospheres. Sci China Mater, 2016, 59: 191-199 CrossRef Google Scholar

[76] Ling D, Hyeon T. Chemical design of biocompatible iron oxide nanoparticles for medical applications. Small, 2013, 9: 1450-1466 CrossRef PubMed Google Scholar

[77] Veiseh O, Gunn JW, Zhang M. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Adv Drug Deliver Rev, 2010, 62: 284-304 CrossRef PubMed Google Scholar

[78] Laurent S, Forge D, Port M, et al. Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications. Chem Rev, 2008, 108: 2064-2110 CrossRef PubMed Google Scholar

[79] Cai H, An X, Cui J, et al. Facile hydrothermal synthesis and surface functionalization of polyethyleneimine-coated iron oxide nanoparticles for biomedical applications. ACS Appl Mater Interfaces, 2013, 5: 1722-1731 CrossRef PubMed Google Scholar

[80] Berry CC, Wells S, Charles S, et al. Cell response to dextran-derivatised iron oxide nanoparticles post internalisation. Biomaterials, 2004, 25: 5405-5413 CrossRef PubMed Google Scholar

[81] Stroh A, Zimmer C, Gutzeit C, et al. Iron oxide particles for molecular magnetic resonance imaging cause transient oxidative stress in rat macrophages. Free Radical Biol Med, 2004, 36: 976-984 CrossRef PubMed Google Scholar

[82] Pawelczyk E, Arbab AS, Chaudhry A, et al. In vitro model of bromodeoxyuridine or iron oxide nanoparticle uptake by activated macrophages from labeled stem cells: implications for cellular therapy. Stem Cells, 2008, 26: 1366-1375 CrossRef PubMed Google Scholar

[83] Siglienti I, Bendszus M, Kleinschnitz C, et al. Cytokine profile of iron-laden macrophages: implications for cellular magnetic resonance imaging. J Neuroimmunol, 2006, 173: 166-173 CrossRef PubMed Google Scholar

[84] Mahmoudi M, Simchi A, Imani M, et al. An in vitro study of bare and poly(ethylene glycol)-co-fumarate-coated superparamagnetic iron oxide nanoparticles: a new toxicity identification procedure. Nanotechnology, 2009, 20: 225104 CrossRef PubMed ADS Google Scholar

[85] Huang G, Diakur J, Xu Z, et al. Asialoglycoprotein receptor-targeted superparamagnetic iron oxide nanoparticles. Int J Pharm, 2008, 360: 197-203 CrossRef PubMed Google Scholar

[86] Naqvi S, Samim M, Abdin M, et al. Concentration-dependent toxicity of iron oxide nanoparticles mediated by increased oxidative stress. Int J Nanomedicine, 2010, 5: 983-989 CrossRef PubMed Google Scholar

[87] Kunzmann A, Andersson B, Vogt C, et al. Efficient internalization of silica-coated iron oxide nanoparticles of different sizes by primary human macrophages and dendritic cells. Toxicol Appl Pharmacol, 2011, 253: 81-93 CrossRef PubMed Google Scholar

[88] Karlsson HL, Cronholm P, Gustafsson J, et al. Copper oxide nanoparticles are highly toxic: a comparison between metal oxide nanoparticles and carbon nanotubes. Chem Res Toxicol, 2008, 21: 1726-1732 CrossRef PubMed Google Scholar

[89] Hussain SM, Hess KL, Gearhart JM, et al. In vitro toxicity of nanoparticles in BRL 3A rat liver cells. Toxicol in Vitro, 2005, 19: 975-983 CrossRef PubMed Google Scholar

[90] Hohnholt MC, Dringen R. Uptake and metabolism of iron and iron oxide nanoparticles in brain astrocytes. Biochm Soc Trans, 2013, 41: 1588-1592 CrossRef PubMed Google Scholar

[91] Gu L, Fang RH, Sailor MJ, et al. In vivo clearance and toxicity of monodisperse iron oxide nanocrystals. ACS Nano, 2012, 6: 4947-4954 CrossRef PubMed Google Scholar

[92] Zhu MT, Feng WY, Wang Y, et al. Particokinetics and extrapulmonary translocation of intratracheally instilled ferric oxide nanoparticles in rats and the potential health risk assessment. Toxicol Sci, 2008, 107: 342-351 CrossRef PubMed Google Scholar

[93] Bellusci M, La Barbera A, Padella F, et al. Biodistribution and acute toxicity of a nanofluid containing manganese iron oxide nanoparticles produced by a mechanochemical process. Int J Nanomed, 2014, 9: 1919-1929 CrossRef PubMed Google Scholar

[94] Gupta AK, Gupta M. Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials, 2005, 26: 3995-4021 CrossRef PubMed Google Scholar

[95] Mahmoudi M, Hofmann H, Rothen-Rutishauser B, et al. Assessing the in vitro and in vivo toxicity of superparamagnetic iron oxide nanoparticles. Chem Rev, 2012, 112: 2323-2338 CrossRef PubMed Google Scholar

[96] Zhang YQ, Dringen R, Petters C, et al. Toxicity of dimercaptosuccinate-coated and un-functionalized magnetic iron oxide nanoparticles towards aquatic organisms. Environ Sci-Nano, 2016, 3: 754-767 CrossRef Google Scholar

[97] Zhu MT, Feng WY, Wang B, et al. Comparative study of pulmonary responses to nano- and submicron-sized ferric oxide in rats. Toxicology, 2008, 247: 102-111 CrossRef PubMed Google Scholar

[98] Di Bona KR, Xu Y, Ramirez PA, et al. Surface charge and dosage dependent potential developmental toxicity and biodistribution of iron oxide nanoparticles in pregnant CD-1 mice. Reprod Toxicol, 2014, 50: 36-42 CrossRef PubMed Google Scholar

[99] Hanini J, Schmitt J, Kacem K, et al. Evaluation of iron oxide nanoparticle biocompatibility. Int J Nanomedicine, 2011, 6: 787-794 CrossRef PubMed Google Scholar

[100] Sun T, Yan Y, Zhao Y, et al. Copper oxide nanoparticles induce autophagic cell death in A549 cells. PLoS ONE, 2012, 7: e43442 CrossRef PubMed ADS Google Scholar

[101] Dong E, Wang Y, Yang ST, et al. Toxicity of nano gamma alumina to neural stem cells. J Nanosci Nanotech, 2011, 11: 7848-7856 CrossRef Google Scholar

[102] Chattopadhyay S, Dash SK, Tripathy S, et al. Toxicity of cobalt oxide nanoparticles to normal cells an in vitro and in vivo study. Chemico-Biol Interactions, 2015, 226: 58-71 CrossRef PubMed Google Scholar

[103] Ates M, Demir V, Arslan Z, et al. Toxicity of engineered nickel oxide and cobalt oxide nanoparticles to Artemia salina in seawater. Water Air Soil Pollut, 2016, 227: 70 CrossRef PubMed Google Scholar

[104] Tedesco S, Doyle H, Blasco J, et al. Oxidative stress and toxicity of gold nanoparticles in Mytilus edulis. Aquatic Toxicol, 2010, 100: 178-186 CrossRef PubMed Google Scholar

[105] Zhuang W, Gao X. Methods, mechanisms and typical bio-indicators of engineered nanoparticle ecotoxicology: an overview. Clean Soil Air Water, 2014, 42: 377-385 CrossRef Google Scholar

[106] Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cellular Signalling, 2012, 24: 981-990 CrossRef PubMed Google Scholar

[107] Huang YW, Wu CH, Aronstam RS. Toxicity of transition metal oxide nanoparticles: recent insights from in vitro studies. Materials, 2010, 3: 4842-4859 CrossRef ADS Google Scholar

[108] Mocan T, Clichici S, Agoşton-Coldea L, et al. Implications of oxidative stress mechanisms in toxicity of nanoparticles. Acta Physiol Hung, 2010, 97: 247-255 CrossRef Google Scholar

[109] Risom L, Møller P, Loft S. Oxidative stress-induced DNA damage by particulate air pollution. Mutat Res-Fund Mol M, 2005, 592: 119-137 CrossRef PubMed Google Scholar

[110] Xiong D, Fang T, Yu L, et al. Effects of nano-scale TiO2, ZnO and their bulk counterparts on zebrafish: acute toxicity, oxidative stress and oxidative damage. Sci Total Environ, 2011, 409: 1444-1452 CrossRef PubMed Google Scholar

[111] Knaapen AM, Borm PJA, Albrecht C, et al. Inhaled particles and lung cancer. Part A: mechanisms. Int J Cancer, 2004, 109: 799-809 CrossRef PubMed Google Scholar

[112] Horie M, Komaba LK, Kato H, et al. Evaluation of cellular influences induced by stable nanodiamond dispersion the cellular influences of nanodiamond are small. Diamond Related Mater, 2012, 24: 15-24 CrossRef ADS Google Scholar

[113] Sharma V, Anderson D, Dhawan A. Zinc oxide nanoparticles induce oxidative DNA damage and ROS-triggered mitochondria mediated apoptosis in human liver cells (HepG2). Apoptosis, 2012, 17: 852-870 CrossRef PubMed Google Scholar

[114] Li N, Duan Y, Hong M, et al. Spleen injury and apoptotic pathway in mice caused by titanium dioxide nanoparticules. Toxicol Lett, 2010, 195: 161-168 CrossRef PubMed Google Scholar

[115] Cho Y, Gorina S, Jeffrey PD, et al. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science, 1994, 265: 346-355 CrossRef ADS Google Scholar

[116] Basu A. The relationship between BcI2, Bax and p53: consequences for cell cycle progression and cell death. Mol Human Reprod, 1998, 4: 1099-1109 CrossRef Google Scholar

[117] Haldar S, Negrini M, Monne M, et al. Down-regulation of bcl-2 by p53 in breast cancer cells. Cancer Res, 1994, 54: 2095–2097. Google Scholar

[118] Chipuk JE, Kuwana T, Bouchier-Hayes L, et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science, 2004, 303: 1010-1014 CrossRef PubMed ADS Google Scholar

[119] Antonsson B. Inhibition of Bax channel-forming activity by Bcl-2. Science, 1997, 277: 370-372 CrossRef Google Scholar

[120] Song MF, Li YS, Kasai H, et al. Metal nanoparticle-induced micronuclei and oxidative DNA damage in mice. J Clin Biochem Nutr, 2012, 50: 211-216 CrossRef PubMed Google Scholar

[121] Zaffaroni N, Pannati M, Diadone MG. Survivin as a target for new anticancer interventions. J Cellular Mol Med, 2005, 9: 360-372 CrossRef Google Scholar

[122] Fadeel B, Orrenius S. Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J Intern Med, 2005, 258: 479-517 CrossRef PubMed Google Scholar

[123] Manke A, Wang L, Rojanasakul Y. Mechanisms of nanoparticle-induced oxidative stress and toxicity. BioMed Res Int, 2013, 2013: 1-15 CrossRef PubMed Google Scholar

[124] Lankoff A, Sandberg WJ, Wegierek-Ciuk A, et al. The effect of agglomeration state of silver and titanium dioxide nanoparticles on cellular response of HepG2, A549 and THP-1 cells. Toxicol Lett, 2012, 208: 197-213 CrossRef PubMed Google Scholar

[125] Prasad RY, Simmons SO, Killius MG, et al. Cellular interactions and biological responses to titanium dioxide nanoparticles in HepG2 and BEAS-2B cells: role of cell culture media. Environ Mol Mutagen, 2014, 55: 336-342 CrossRef PubMed Google Scholar

[126] Li L, Jiang LL, Zeng Y, et al. Toxicity of superparamagnetic iron oxide nanoparticles: research strategies and implications for nanomedicine. Chin Phys B, 2013, 22: 127503 CrossRef Google Scholar

[127] Rousk J, Ackermann K, Curling SF, et al. Comparative toxicity of nanoparticulate CuO and ZnO to soil bacterial communities. PLoS ONE, 2012, 7: e34197 CrossRef PubMed ADS Google Scholar

[128] Zhang ZY, Xiong HM. Photoluminescent ZnO nanoparticles and their biological applications. Materials, 2015, 8: 3101-3127 CrossRef Google Scholar

[129] Franklin NM, Rogers NJ, Apte SC, et al. Comparative toxicity of nanoparticulate ZnO, Bulk ZnO, and ZnCl2 to a freshwater microalga (Pseudokirchneriella subcapitata): the importance of particle solubility. Environ Sci Technol, 2007, 41: 8484-8490 CrossRef ADS Google Scholar

[130] Adrain C, Creagh EM, Martin SJ. Defying death: showing Bcl-2 the way home. Nat Cell Biol, 2003, 5: 9-11 CrossRef PubMed Google Scholar

[131] Zhao J, Bowman L, Zhang X, et al. Titanium dioxide (TiO2) nanoparticles induce JB6 cell apoptosis through activation of the caspase-8/Bid and mitochondrial pathways. J Toxicol Environ Health A, 2009, 72: 1141-1149 CrossRef PubMed Google Scholar

[132] Cui Y, Liu H, Zhou M, et al. Signaling pathway of inflammatory responses in the mouse liver caused by TiO2 nanoparticles. J Biomed Mater Res, 2011, 96A: 221-229 CrossRef PubMed Google Scholar

[133] Tong T, Fang K, Thomas SA, et al. Chemical interactions between nano-ZnO and nano-TiO2 in a natural aqueous medium. Environ Sci Technol, 2014, 48: 7924-7932 CrossRef PubMed ADS Google Scholar

[134] Tong T, Wilke CM, Wu J, et al. Combined toxicity of nano-ZnO and nano-TiO2 : from single- to multinanomaterial systems. Environ Sci Technol, 2015, 49: 8113-8123 CrossRef PubMed ADS Google Scholar

[135] Wang Y, Yuan L, Yao C, et al. Caseinophosphopeptides cytoprotect human gastric epithelium cells against the injury induced by zinc oxide nanoparticles. RSC Adv, 2014, 4: 42168-42174 CrossRef Google Scholar

  • Figure 1

    (a–h) Microtubule dynamics following exposure to TiO2 NPs using immunofluorescence staining: (a–d) fluorescence images of 4T1 cells examined under a laser scanning confocal microscope and (e–h) phase contrast images of 4T1 cells. (a, e) Control group (treated in the absence of TiO2 NPs); (b, f) groups treated with 200 mg L−1 TiO2 NPs for 24 h; (c, g) 50 mg L−1 TiO2 NPs for 48 h, and (d, h) 200 mg L−1 TiO2 NPs for 48 h. (i–p) Representative histological photomicrographs of the liver in young and adult rats after gastrointestinal exposure to TiO2 NPs for 30 days. Circles: liver edema in young rats. Arrows: inflammatory cell infiltration in adult rat liver Y0–Y3: young rats, A0−A3: adult rats, Y0 & A0: control group (0 mg kg−1), Y1 & A1: low-dose exposure group (10 mg kg−1), Y2 & A2: middle-dose exposure group (50 mg kg−1), Y3 & A3: high-dose exposure group (200 mg kg−1). Reprinted with permission from: (a–h) Ref. [31], Copyright 2015, Royal Society of Chemistry; (i–p) Ref. [49], Copyright 2013, WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  • Figure 2

    ROS levels in HUVECs after exposure to NPs. (a–l) Fluorescence microscope images of intracellular ROS induced by NPs. HUVECs were treated with ZnO NPs/CeO2 NPs (240 µmol L−1) for 8 h; then the endoplasmatic reticulum (ER) and ROS were stained. (m) Image from ZnO NPs-treatment group shows the segmentation process of high-content analysis (HCA) method. (n) Quantitative analyses of ROS levels by HCA after HUVECs were treated with NPs for 8 h. Data is expressed as mean ± SD, (# p< 0.01 compared with that in blank, n = 6. Bars: 10 µm). The white arrows show bright and aggregated ER in ZnO NPs-treated cells. Reprinted with permission from Ref. [62], Copyright 2014, American Chemical Society.

  • Figure 3

    In vivo accumulation, degradation, and clearance of IONPs in mice. (a) Iron distributed in the liver, spleen, lung, kidney and brain after intravenous injection (5 mg Fe kg−1) of PEG-phospholipid-coated IO nanocrystals for 24 h, prepared via the organometallic route (sizes of ∼5, ∼15, and ∼30 nm), and Feridex (is a dextran-coated cluster of IONPs approved as a contrast agent for hepatic imaging). (b, c) Percent of IONPs (percent superparamagnetic/ferrimagnetic content) remaining in liver (b) and spleen (c). Reprinted with permission from Ref. [91], Copyright 2012, American Chemical Society.

  • Figure 4.

    Schematic diagram of MONP toxicity and mechanism. In vitro toxicity of MONPs is mainly caused by the damage of mitochondrial/DNA/protein and phospholipid bilayer, leading to cell toxicity. In vivo toxicity is caused by penetration of MONPs into the blood circulation through inhalation, oral, and dermal routes, and these MONPs finally reach the main organs of the body causing organ damage. Some nanomaterials also cause phototoxicity on the skin. MONP toxicity is induced mainly by four ways: the generation of ROS, effect of released ions, excessive accumulation of NPs on the cell surface, and combination of NPs with specific death receptors.

  • Figure 5

    Cytotoxicity evaluation of ZnO NPs (15 mg L−1), Vc (300 mg L−1), and ZnO NPs plus Vc treatment for 24 h (a, b). Cell viability of gastric epithelial cell line (GES-1) (a), and neural stem cell line (NSCs) (b) after 24 h co-incubation with ZnO NPs, Vc, and ZnO NPs plus Vc treatment. *p< 0.05 compared with cells exposed to ZnO NPs. Cell viability after treatment of various concentrations of ZnO NPs (c), various concentrations of CPP (d); (e) the effect of CPP (500 mg L−1) at various concentrations of ZnO NPs; (f) cell counts after treatment with 20 mg L−1 ZnO NPs, 500 mg L−1 CPP, 20 mg L−1 ZnO NPs & 500 mg L−1 CPP, respectively; (g) the effects of various concentrations of CPP and ZnO NPs (20 mg L−1); (h) the effects on LDH release at various concentrations of CPP with ZnO NPs (20 mg L−1). #p< 0.05 compared with control group; *p< 0.05 compared with cells exposed to ZnO NPs. Reprinted with permission from: (a, b) Ref. [58], Copyright 2014, Royal Society of Chemistry; (c–h) Ref. [135], Copyright 2014, Royal Society of Chemistry.

  • Table 2   Toxicities of IONPs with different surface coatings

    Coating material

    Cell types

    Size (nm)

    Concentration

    Incubation time

    Result

    Dextran

    Macrophages (human)

    100–150

    0.1 mg mL−1

    7 days

    20% cell viability after 7 days [82]

    Primary peritoneal macrophages (rats and mice)

    20, 60

    0.2–20 µmol L−1

    15 min–2 days

    Increased anti-inflammatory cytokines, reduced pro-inflammatory cytokines [83]

    Poly (vinyl alcohol)

    L929 (mouse fibroblasts)

    82

    0.2–20 mmol L−1

    2 days

    Toxicity depends on nanoparticles shape and size [84]

    Amine-surface

    HepG2 (human liver cancer cell)

    61–127

    0.03–3000 µg mL−1

    5 days

    High positive charge causes severe cytotoxicity [85]

    Tween

    macrophages J774 (mouse)

    30

    25–500 µg mL−1

    1–6 h

    Dose- and time-dependent damage [86]

    Silica

    A549 (human lung cancer cell)

    30–120

    10 µg mL−1

    2 days

    Dose- and size-dependent damage [87]

    Uncoated

    A549 (human lung cancer cell)

    20–30

    Up to 80 µg mL−1

    18 h

    No or low toxicity [88]

    Uncoated

    BRL 3A (rat liver derived cell)

    30, 47

    Up to 250 µg mL−1

    1 days

    No toxicity up to 100 µg mL−1, significant toxic effects at 250 µg mL−1 [89]

  • Table 1   Biochemistry assay of serum in rats after gastrointestinal exposure to TiO NPs for 30 days (mean ± SD, = 7)

    Group

    Exposure

    dose

    Glu

    [mmol L−1]

    TCHO

    [mmol L−1]

    TG

    [mmol L−1]

    HDL-C

    [mmol L−1]

    LDL-C

    [mmol L−1]

    TP

    [g L−1]

    ALB

    [g L−1]

    GLB

    [g L−1]

    ALB/GLB

    Youth

    Y0

    0 mg kg−1 BW

    5.04 ± 0.98

    1.59 ± 0.22

    0.82 ± 0.29

    0.60 ± 0.07

    0.23 ± 0.03

    70.86 ± 2.85

    36.51 ± 1.29

    34.34 ± 1.74

    1.06 ± 0.04

    Y1

    10 mg kg−1 BW

    5.20 ± 1.18

    1.76 ± 0.27

    1.04 ± 0.37

    0.61 ± 0.07

    0.29 ± 0.04

    70.43 ± 1.40

    35.60 ± 1.14

    34.83 ± 0.39

    1.02 ± 0.03

    Y2

    50 mg kg−1 BW

    6.61 ± 0.73**

    1.91 ± 0.30

    0.59 ± 0.13

    0.60 ± 0.07

    0.43 ± 0.09**

    1.57 ± 1.62

    36.54 ± 0.98

    35.03 ± 1.38

    1.04 ± 0.05

    Y3

    200 mg kg−1 BW

    6.44 ± 0.36**

    1.69 ± 0.36

    0.63 ± 0.13

    0.58 ± 0.08

    0.36 ± 0.05**

    69.86 ± 2.79

    35.99 ± 1.27

    33.87 ± 1.75

    1.06 ± 0.04

    Adult

    A0

    0 mg kg−1 BW

    5.73 ± 1.57

    1.65 ± 0.35

    0.84 ± 0.30

    0.62 ± 0.10

    0.26 ± 0.06

    70.43 ± 2.70

    35.66 ± 1.35

    34.77 ± 1.71

    1.03 ± 0.04

    A1

    10 mg kg−1 BW

    5.13 ± 1.09

    1.72 ± 0.25

    0.72 ± 0.20

    0.67 ± 0.06

    0.27 ± 0.06

    70.71 ± 3.64

    35.34 ± 1.67

    35.37 ± 2.23

    1.00 ± 0.04

    A2

    50 mg kg−1 BW

    4.88 ± 0.88

    1.83 ± 0.37

    0.52 ± 0.11

    0.64 ± 0.07

    0.29 ± 0.05

    72.17 ± 2.23

    35.67 ± 1.03

    36.50 ± 2.35

    0.98 ± 0.08

    A3

    200 mg kg−1 BW

    5.06 ± 0.36

    1.61 ± 0.28

    0.82 ± 0.37

    0.59 ± 0.07

    0.24 ± 0.05

    68.86 ± 2.54

    34.54 ± 1.58

    34.31 ± 1.60

    1.01 ± 0.06

    Group

    Exposure

    dose

    ALT [U L−1]

    AST

    [U L−1]

    ALT/AST

    TBIL

    [µmol L−1]

    LDH

    [U L−1]

    HBDH

    [U L−1]

    CK

    [U L−1]

    BUN

    [mmol L−1]

    Crea

    [µmol L−1]

    Youth

    Y0

    0 mg kg−1 BW

    47.57 ± 4.83

    209.14 ± 31.91

    0.23 ± 0.04

    1.27 ± 0.21

    1852.86 ±467.30

    890.43 ±344.28

    2792.00 ±294.97

    6.93 ± 1.08

    52.57 ± 5.32

    Y1

    10 mg kg−1 BW

    44.43 ± 7.68

    179.71 ± 36.59

    0.25 ± 0.06

    1.23 ± 0.19

    1731.29 ±306.55

    770.71 ±206.29

    2083.29 ±622.24

    7.13 ± 1.26

    52.29 ± 3.73

    Y2

    50 mg kg−1 BW

    54.43 ± 7.09

    152.14 ± 28.20**

    0.37 ± 0.07**

    1.47 ± 0.18

    1313.86 ±346.95

    510.86 ±168.34**

    2154.43 ±914.55

    6.49 ± 1.10

    52.86 ± 3.07

    Y3

    200 mg kg−1 BW

    48.86 ± 6.39

    157.57 ± 31.83**

    0.32 ± 0.06*

    2.11 ± 0.30**

    1499.43 ±383.68

    617.28 ±222.54*

    1658.00 ±685.07*

    6.44 ± 1.11

    49.71 ± 2.75

    Adult

    A0

    0 mg kg−1 BW

    52.43 ± 6.16

    170.43 ± 38.31

    0.32 ± 0.07

    1.81 ± 0.13

    1548.86 ±393.39

    692.86 ±328.89

    2045.86 ±520.32

    5.60 ± 0.91

    53.43 ± 3.10

    A1

    10 mg kg−1 BW

    47.43 ± 5.65

    178.57 ± 54.36

    0.28 ± 0.05

    2.09 ± 0.41

    1753.71 ±545.80

    835.71 ±439.23

    2176.86 ±777.33

    6.43 ± 0.94

    53.00 ± 8.74

    A2

    50 mg kg−1 BW

    46.00 ± 5.66

    167.83 ± 31.24

    0.29 ± 0.08

    1.90 ± 0.29

    1560.33 ±336.45

    690.83 ±232.51

    1789.17 ±459.89

    8.42 ± 1.96++

    54.33 ± 5.96

    A3

    200 mg kg−1 BW

    51.57 ± 9.05

    177.00 ± 19.21

    0.29 ± 0.03

    1.37 ± 0.50+

    1647.29 ±44.32

    709.29 ±27.40

    2041.86 ±337.52

    7.26 ± 0.61+

    50.29 ± 4.57

Copyright 2019 Science China Press Co., Ltd. 《中国科学》杂志社有限责任公司 版权所有

京ICP备18024590号-1