Toxicity of Transition Metal Oxide Nanoparticles: Recent Insights from in vitro Studies

Nanotechnology has evolved to play a prominent role in our economy. Increased use of nanomaterials poses potential human health risk. It is therefore critical to understand the nature and origin of the toxicity imposed by nanomaterials (nanotoxicity). In this article we review the toxicity of the transition metal oxides in the 4th period that are widely used in industry and biotechnology. Nanoparticle toxicity is compellingly related to oxidative stress and alteration of calcium homeostasis, gene expression, pro-inflammatory responses, and cellular signaling events. The precise physicochemical properties that dictate the toxicity of nanoparticles have yet to be defined, but may include element-specific surface catalytic activity (e.g., metallic, semiconducting properties), nanoparticle uptake, or nanoparticle dissolution. These in vitro studies substantially advance our understanding in mechanisms of toxicity, which may lead to safer design of nanomaterials.

[1]  A. Khachatryan,et al.  Synthesis and Some Characteristics of Magnetic Matrices for Fixation of Biologically Active Substances , 2001 .

[2]  E. Kahn,et al.  Iron nanoparticles increase 7-ketocholesterol-induced cell death , inflammation , and oxidation on murine cardiac hL 1NB cells , 2010 .

[3]  H. Karlsson,et al.  Copper oxide nanoparticles are highly toxic: a comparison between metal oxide nanoparticles and carbon nanotubes. , 2008, Chemical research in toxicology.

[4]  Yue-Wern Huang,et al.  Cellular internalization of quantum dots noncovalently conjugated with arginine-rich cell-penetrating peptides. , 2010, Journal of nanoscience and nanotechnology.

[5]  K. Itoh,et al.  An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. , 1997, Biochemical and biophysical research communications.

[6]  P. Borm,et al.  In vitro effects of coal fly ashes: hydroxyl radical generation, iron release, and DNA damage and toxicity in rat lung epithelial cells. , 1999, Inhalation toxicology.

[7]  H. Dai,et al.  Carbon nanotubes as intracellular protein transporters: generality and biological functionality. , 2005, Journal of the American Chemical Society.

[8]  Roel P F Schins,et al.  Inhaled particles and lung cancer. Part A: Mechanisms , 2004, International journal of cancer.

[9]  S. Kang,et al.  Oxygen Tension Regulates the Stability of Insulin Receptor Substrate-1 (IRS-1) through Caspase-mediated Cleavage* , 2007, Journal of Biological Chemistry.

[10]  E. Dopp,et al.  Titanium dioxide nanoparticles induce oxidative stress and DNA-adduct formation but not DNA-breakage in human lung cells , 2009, Particle and Fibre Toxicology.

[11]  Kaja Kasemets,et al.  Toxicity of nanoparticles of ZnO, CuO and TiO2 to yeast Saccharomyces cerevisiae. , 2009, Toxicology in vitro : an international journal published in association with BIBRA.

[12]  W. Whong,et al.  Detection of mineral-dust-induced DNA damage in two mammalian cell lines using the alkaline single cell gel/comet assay. , 1997, Mutation research.

[13]  Sourav Bhattacharjee,et al.  Role of surface charge and oxidative stress in cytotoxicity of organic monolayer-coated silicon nanoparticles towards macrophage NR8383 cells , 2010, Particle and Fibre Toxicology.

[14]  A. Marcus,et al.  Imaging and tracking of tat peptide-conjugated quantum dots in living cells: new insights into nanoparticle uptake, intracellular transport, and vesicle shedding. , 2007, Journal of the American Chemical Society.

[15]  Giorgio Sberveglieri,et al.  Stable and highly sensitive gas sensors based on semiconducting oxide nanobelts , 2002 .

[16]  Shen-Ming Chen,et al.  Nanostructured Zinc Oxide Particles in Chemically Modified Electrodes for Biosensor Applications , 2008 .

[17]  J. Putney,et al.  Ca2+-store-dependent and -independent reversal of Stim1 localization and function , 2008, Journal of Cell Science.

[18]  Vicki Stone,et al.  Particle and Fibre Toxicology Ultrafine Particles Cause Cytoskeletal Dysfunctions in Macrophages: Role of Intracellular Calcium , 2022 .

[19]  D. Girard,et al.  Activation of human neutrophils by titanium dioxide (TiO2) nanoparticles. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[20]  M A Howard,et al.  Experimental study of the magnetic stereotaxis system for catheter manipulation within the brain. , 2000, Journal of neurosurgery.

[21]  Yinfa Ma,et al.  Toxicity of nano- and micro-sized ZnO particles in human lung epithelial cells , 2009 .

[22]  Urs O. Häfeli,et al.  Scientific and clinical applications of magnetic carriers , 1997 .

[23]  Katsuhide Fujita,et al.  Protein adsorption of ultrafine metal oxide and its influence on cytotoxicity toward cultured cells. , 2009, Chemical research in toxicology.

[24]  N. Ljubešić,et al.  Cytotoxicity of nanosize V2O5 particles to selected fibroblast and tumor cells , 2006 .

[25]  Jeremy C Simpson,et al.  Cellular uptake of arginine-rich peptides: roles for macropinocytosis and actin rearrangement. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[26]  Robert N Grass,et al.  Oxide nanoparticle uptake in human lung fibroblasts: effects of particle size, agglomeration, and diffusion at low concentrations. , 2005, Environmental science & technology.

[27]  Ken Takeda,et al.  The effects of nanoparticles on mouse testis Leydig cells in vitro. , 2008, Toxicology in vitro : an international journal published in association with BIBRA.

[28]  Jinhee Choi,et al.  Oxidative stress of CeO2 nanoparticles via p38-Nrf-2 signaling pathway in human bronchial epithelial cell, Beas-2B. , 2009, Toxicology letters.

[29]  Y. Kan,et al.  Nrf2 is essential for protection against acute pulmonary injury in mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[30]  H. Jeng,et al.  Toxicity of Metal Oxide Nanoparticles in Mammalian Cells , 2006, Journal of environmental science and health. Part A, Toxic/hazardous substances & environmental engineering.

[31]  Sue-N. Park,et al.  Pulmonary toxicity and kinetic study of Cy5.5-conjugated superparamagnetic iron oxide nanoparticles by optical imaging. , 2009, Toxicology and applied pharmacology.

[32]  J. Carter,et al.  Effects of particle exposure and particle-elicited inflammatory cells on mutation in rat alveolar epithelial cells. , 1997, Carcinogenesis.

[33]  Qamar Rahman,et al.  Evidence that ultrafine titanium dioxide induces micronuclei and apoptosis in Syrian hamster embryo fibroblasts. , 2002, Environmental health perspectives.

[34]  H. Lindberg,et al.  Genotoxic effects of nanosized and fine TiO2 , 2009, Human & experimental toxicology.

[35]  S. Hussain,et al.  Nanosized aluminum altered immune function. , 2010, ACS nano.

[36]  J. Putney Recent breakthroughs in the molecular mechanism of capacitative calcium entry (with thoughts on how we got here). , 2007, Cell calcium.

[37]  Da-Ren Chen,et al.  Oxidative stress, calcium homeostasis, and altered gene expression in human lung epithelial cells exposed to ZnO nanoparticles. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[38]  K. Shadan,et al.  Available online: , 2012 .

[39]  Q. Lu,et al.  Cytotoxicity of titanium dioxide nanoparticles in mouse fibroblast cells. , 2008, Chemical research in toxicology.

[40]  Matthew A. Howard,et al.  Magnetically guided interventional medicine , 1998, Photonics West - Biomedical Optics.

[41]  M. Giacca,et al.  Internalization of HIV-1 Tat Requires Cell Surface Heparan Sulfate Proteoglycans* , 2001, The Journal of Biological Chemistry.

[42]  Mary Gulumian,et al.  The limits of testing particle-mediated oxidative stress in vitro in predicting diverse pathologies; relevance for testing of nanoparticles , 2009, Particle and Fibre Toxicology.

[43]  Benjamin Gilbert,et al.  Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. , 2008, ACS nano.

[44]  Chien-Tsung Wang,et al.  ZnO nanoparticle-modified infrared internal reflection elements for selective detection of volatile organic compounds. , 2006, Analytical chemistry.

[45]  Weidong Wu,et al.  Phosphorylation of p65 Is Required for Zinc Oxide Nanoparticle–Induced Interleukin 8 Expression in Human Bronchial Epithelial Cells , 2010, Environmental health perspectives.

[46]  K. Itoh,et al.  Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust. , 2001, Toxicology and applied pharmacology.

[47]  Zhong Lin Wang,et al.  Structure Analysis of Nanowires and Nanobelts by Transmission Electron Microscopy , 2004 .

[48]  Catrin Albrecht,et al.  Inhaled particles and lung cancer, part B: Paradigms and risk assessment , 2004, International journal of cancer.

[49]  Xiao-Dong Zhou,et al.  Toxicity of Cerium Oxide Nanoparticles in Human Lung Cancer Cells , 2006, International journal of toxicology.

[50]  Enge Wang,et al.  Dual-mode mechanical resonance of individual ZnO nanobelts , 2003 .

[51]  A. Bhushan,et al.  Exposure to titanium dioxide and other metallic oxide nanoparticles induces cytotoxicity on human neural cells and fibroblasts , 2008, International journal of nanomedicine.

[52]  Robert N Grass,et al.  Exposure of engineered nanoparticles to human lung epithelial cells: influence of chemical composition and catalytic activity on oxidative stress. , 2007, Environmental science & technology.

[53]  W. MacNee,et al.  The pro-inflammatory effects of low-toxicity low-solubility particles, nanoparticles and fine particles, on epithelial cells in vitro: the role of surface area , 2007, Occupational and Environmental Medicine.

[54]  F. Porta,et al.  Phagocytosis of biocompatible gold nanoparticles. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[55]  Bice Fubini,et al.  Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. , 2003, Free radical biology & medicine.

[56]  Pratim Biswas,et al.  Does nanoparticle activity depend upon size and crystal phase? , 2008, Nanotoxicology.

[57]  Suwei Wang,et al.  Activation of nuclear factor-kappaB during doxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide. , 2002, The Biochemical journal.

[58]  S. Sarkar,et al.  Analysis of stress responsive genes induced by single-walled carbon nanotubes in BJ Foreskin cells. , 2007, Journal of nanoscience and nanotechnology.

[59]  Xiao-Dong Zhou,et al.  Cytotoxicity and cell membrane depolarization induced by aluminum oxide nanoparticles in human lung epithelial cells A549 , 2008 .

[60]  C. Xie,et al.  Investigation of gas sensitivity of Sb-doped ZnO nanoparticles , 2005 .

[61]  Benjamin Gilbert,et al.  Use of a rapid cytotoxicity screening approach to engineer a safer zinc oxide nanoparticle through iron doping. , 2010, ACS nano.

[62]  Emmanuel P. Giannelis,et al.  Magnetic and Optical Properties of γ-Fe2O3 Nanocrystals , 1993 .

[63]  N. Gjerdet,et al.  Induction of cell death by TiO2 nanoparticles: studies on a human monoblastoid cell line. , 2008, Toxicology in vitro : an international journal published in association with BIBRA.

[64]  C Tagesson,et al.  Hydrogen peroxide release and hydroxyl radical formation in mixtures containing mineral fibres and human neutrophils. , 1992, British journal of industrial medicine.

[65]  C. Wolf,et al.  The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin. , 2000, Biochemical Society transactions.

[66]  Xiao-Dong Zhou,et al.  In vitro toxicity of silica nanoparticles in human lung cancer cells. , 2006, Toxicology and applied pharmacology.

[67]  Peng Wang,et al.  In vitro evaluation of cytotoxicity of engineered metal oxide nanoparticles. , 2009, The Science of the total environment.

[68]  Roel P F Schins,et al.  MECHANISMS OF GENOTOXICITY OF PARTICLES AND FIBERS , 2002, Inhalation toxicology.

[69]  Kyunghee Choi,et al.  Inflammatory responses may be induced by a single intratracheal instillation of iron nanoparticles in mice. , 2010, Toxicology.

[70]  Martinus Løvik,et al.  Single-walled and multi-walled carbon nanotubes promote allergic immune responses in mice. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[71]  A. Churg,et al.  Mechanisms in the pathogenesis of asbestosis and silicosis. , 1998, American journal of respiratory and critical care medicine.

[72]  H. Ghosh,et al.  Effect of Particle Size on the Reactivity of Quantum Size ZnO Nanoparticles and Charge-Transfer Dynamics with Adsorbed Catechols , 2003 .

[73]  F. B. Noronha,et al.  Characterization of graphite-supported palladium-cobalt catalysts by temperature-programmed reduction and magnetic measurements , 1997 .

[74]  David M. Brown,et al.  Increased calcium influx in a monocytic cell line on exposure to ultrafine carbon black. , 2000, The European respiratory journal.

[75]  Simmons Tw,et al.  Relative importance of intracellular glutathione peroxidase and catalase in vivo for prevention of peroxidation to the heart. , 1989 .

[76]  Jiao Sun,et al.  Endothelial cells dysfunction induced by silica nanoparticles through oxidative stress via JNK/P53 and NF-kappaB pathways. , 2010, Biomaterials.

[77]  Spomenka Kobe,et al.  The influence of the magnetic field on the crystallisation form of calcium carbonate and the testing of a magnetic water-treatment device , 2001 .

[78]  Yue-Wern Huang,et al.  Nona-Arginine Facilitates Delivery of Quantum Dots into Cells via Multiple Pathways , 2010, Journal of biomedicine & biotechnology.

[79]  D. C. Agrawal,et al.  Magnetic properties of glass‐metal nanocomposites prepared by the sol‐gel route and hot pressing , 1993 .

[80]  S. Cormier,et al.  Copper oxide nanoparticles induce oxidative stress and cytotoxicity in airway epithelial cells. , 2009, Toxicology in vitro : an international journal published in association with BIBRA.

[81]  Mark R Wiesner,et al.  Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. , 2006, Nano letters.

[82]  Steven F Dowdy,et al.  Transmembrane delivery of protein and peptide drugs by TAT-mediated transduction in the treatment of cancer. , 2005, Advanced drug delivery reviews.

[83]  S. Sheikpranbabu,et al.  Gold nanoparticles downregulate VEGF-and IL-1β-induced cell proliferation through Src kinase in retinal pigment epithelial cells. , 2010, Experimental eye research.

[84]  P. Borm,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. , 2007, Toxicology and applied pharmacology.