Hormesis Effects of Silver Nanoparticles at Non-Cytotoxic Doses to Human Hepatoma Cells

Silver nanoparticles (AgNPs) have attracted considerable attentions due to their unique properties and diverse applications. Although it has been reported that AgNPs have acute toxic effects on a variety of cultured mammalian cells and animal models, few studies have been conducted to evaluate the associated risk of AgNPs to human health at non-cytotoxic doses. In this paper, HepG2 cells were exposed to 10 nm and 100 nm AgNPs under non-cytotoxic conditions, and cell viability was assessed. At low doses, AgNPs displayed “hormesis” effects by accelerating cell proliferation. Further studies indicated that the activation states of MAPKs were differentially regulated in this process. Specifically, by increasing the expression of downstream genes, p38 MAPK played a central role in non-cytotoxic AgNP-induced hormesis. Moreover, the treatment of HepG2 cells with silver ions (Ag+) at the same dose levels induced distinct biological effects, suggesting that different intrinsic properties exist for AgNPs and Ag+.

[1]  A. Stebbing,et al.  Hormesis--the stimulation of growth by low levels of inhibitors. , 1982, The Science of the total environment.

[2]  W. D. de Jong,et al.  The effect of particle size on the cytotoxicity, inflammation, developmental toxicity and genotoxicity of silver nanoparticles. , 2011, Biomaterials.

[3]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[4]  Beena Vallanat,et al.  The Physicochemistry of Capped Nanosilver Predicts Its Biological Activity in Rat Brain Endothelial Cells (RBEC4) , 2014 .

[5]  Seung-Heon Shin,et al.  The effects of nano-silver on the proliferation and cytokine expression by peripheral blood mononuclear cells. , 2007, International immunopharmacology.

[6]  T. Xi,et al.  Distribution, translocation and accumulation of silver nanoparticles in rats. , 2009, Journal of nanoscience and nanotechnology.

[7]  R. P. Nachane,et al.  Functional finishing of cotton fabrics using silver nanoparticles. , 2007, Journal of nanoscience and nanotechnology.

[8]  T. Xia,et al.  Toxic Potential of Materials at the Nanolevel , 2006, Science.

[9]  J. Blenis,et al.  ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions , 2004, Microbiology and Molecular Biology Reviews.

[10]  P. Angel,et al.  AP-1 subunits: quarrel and harmony among siblings , 2004, Journal of Cell Science.

[11]  Tung-Sheng Shih,et al.  The apoptotic effect of nanosilver is mediated by a ROS- and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells. , 2008, Toxicology letters.

[12]  Aneta Wegierek-Ciuk,et al.  The effect of agglomeration state of silver and titanium dioxide nanoparticles on cellular response of HepG2, A549 and THP-1 cells. , 2012, Toxicology letters.

[13]  Jinhee Choi,et al.  Oxidative stress‐related PMK‐1 P38 MAPK activation as a mechanism for toxicity of silver nanoparticles to reproduction in the nematode Caenorhabditis elegans , 2012, Environmental toxicology and chemistry.

[14]  Il Je Yu,et al.  Lung function changes in Sprague-Dawley rats after prolonged inhalation exposure to silver nanoparticles. , 2008, Inhalation toxicology.

[15]  S. Okabe,et al.  In vitro toxicity of silver nanoparticles at noncytotoxic doses to HepG2 human hepatoma cells. , 2009, Environmental science & technology.

[16]  C. Widmann,et al.  Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. , 1999, Physiological reviews.

[17]  Rawiwan Maniratanachote,et al.  Silver nanoparticles induce toxicity in A549 cells via ROS-dependent and ROS-independent pathways. , 2013, Toxicology in vitro : an international journal published in association with BIBRA.

[18]  E. Calabrese,et al.  Exposure to Nanoparticles and Hormesis , 2010, Dose-response : a publication of International Hormesis Society.

[19]  Jasmine Kaur,et al.  Evaluating cell specific cytotoxicity of differentially charged silver nanoparticles. , 2013, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[20]  A C Upton,et al.  Comments on the article ‘Defining hormesis’, by EJ Calabrese and LA Baldwin , 2002, Human & experimental toxicology.

[21]  D. Evanoff,et al.  Synthesis and optical properties of silver nanoparticles and arrays. , 2005, Chemphyschem : a European journal of chemical physics and physical chemistry.

[22]  M. Karin,et al.  AP-1 in cell proliferation and survival , 2001, Oncogene.

[23]  S. Oldenburg,et al.  Evaluation of Silver Nanoparticle Toxicity in Skin in Vivo and Keratinocytes in Vitro , 2009, Environmental health perspectives.

[24]  K. Paknikar,et al.  Cellular responses induced by silver nanoparticles: In vitro studies. , 2008, Toxicology letters.

[25]  G. Sharma,et al.  p38 and ERK1/2 Coordinate Cellular Migration and Proliferation in Epithelial Wound Healing , 2003, Journal of Biological Chemistry.

[26]  R. Albrecht,et al.  Toxicity assessments of multisized gold and silver nanoparticles in zebrafish embryos. , 2009, Small.

[27]  M. Cobb,et al.  Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. , 2001, Endocrine reviews.

[28]  Jing-fu Liu,et al.  Quantification of the uptake of silver nanoparticles and ions to HepG2 cells. , 2013, Environmental science & technology.

[29]  Jin Sik Kim,et al.  Twenty-eight-day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in Sprague-Dawley rats. , 2008, Inhalation toxicology.

[30]  Jong Hoon Park,et al.  Comparison of acute responses of mice livers to short-term exposure to nano-sized or micro-sized silver particles , 2008, Biotechnology Letters.

[31]  W. Liu,et al.  Impact of silver nanoparticles on human cells: Effect of particle size , 2010, Nanotoxicology.

[32]  X. Chen,et al.  Nanosilver: a nanoproduct in medical application. , 2008, Toxicology letters.

[33]  Huitu Liu,et al.  MAPK signal pathways in the regulation of cell proliferation in mammalian cells , 2002, Cell Research.

[34]  Ivo Iavicoli,et al.  Defining hormesis. Commentary. Authors reply , 2002 .

[35]  Pedro J J Alvarez,et al.  Negligible particle-specific antibacterial activity of silver nanoparticles. , 2012, Nano letters.

[36]  Philip R. Cohen,et al.  SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin‐1 , 1995, FEBS letters.

[37]  E J Calabrese,et al.  Defining hormesis , 2002, Human & experimental toxicology.

[38]  S. Dubas,et al.  Humic acid assisted synthesis of silver nanoparticles and its application to herbicide detection , 2008 .

[39]  Naomi Lubick,et al.  Nanosilver toxicity: ions, nanoparticles--or both? , 2008, Environmental science & technology.

[40]  Byung-Hoon Lee,et al.  Genomics-based screening of differentially expressed genes in the brains of mice exposed to silver nanoparticles via inhalation , 2010 .

[41]  Dae Hong Jeong,et al.  Antimicrobial effects of silver nanoparticles. , 2007, Nanomedicine : nanotechnology, biology, and medicine.

[42]  U. Heinzmann,et al.  Pulmonary and systemic distribution of inhaled ultrafine silver particles in rats. , 2001, Environmental health perspectives.

[43]  J. Schlager,et al.  In vitro cytotoxicity of nanoparticles in mammalian germline stem cells. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[44]  S. Hussain,et al.  Silver nanoparticles induced heat shock protein 70, oxidative stress and apoptosis in Drosophila melanogaster. , 2010, Toxicology and applied pharmacology.

[45]  K. Paknikar,et al.  Interactions of silver nanoparticles with primary mouse fibroblasts and liver cells. , 2009, Toxicology and applied pharmacology.

[46]  H. Autrup,et al.  PVP-coated silver nanoparticles and silver ions induce reactive oxygen species, apoptosis and necrosis in THP-1 monocytes. , 2009, Toxicology letters.

[47]  Kyunghee Choi,et al.  Silver nanoparticles induce cytotoxicity by a Trojan-horse type mechanism. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[48]  Kiril Hristovski,et al.  The release of nanosilver from consumer products used in the home. , 2010, Journal of environmental quality.

[49]  Kianoush Khosravi-Darani,et al.  The Applications of Nanotechnology in Food Industry , 2011, Critical reviews in food science and nutrition.

[50]  J. Yi,et al.  Oxidative stress-dependent toxicity of silver nanoparticles in human hepatoma cells. , 2009, Toxicology in vitro : an international journal published in association with BIBRA.

[51]  J. Schlager,et al.  DNA damage response to different surface chemistry of silver nanoparticles in mammalian cells. , 2008, Toxicology and applied pharmacology.

[52]  H. Lang,et al.  How the doors to the nanoworld were opened , 2006, Nature nanotechnology.

[53]  M. Mattson.  Hormesis defined , 2008, Ageing Research Reviews.

[54]  Kirk G Scheckel,et al.  Surface charge-dependent toxicity of silver nanoparticles. , 2011, Environmental science & technology.

[55]  M. Ahamed,et al.  Silver nanoparticle applications and human health. , 2010, Clinica chimica acta; international journal of clinical chemistry.

[56]  R. L. Jones,et al.  Unique cellular interaction of silver nanoparticles: size-dependent generation of reactive oxygen species. , 2008, The journal of physical chemistry. B.

[57]  Paul Westerhoff,et al.  Nanoparticle silver released into water from commercially available sock fabrics. , 2008, Environmental science & technology.

[58]  J. Gearhart,et al.  In vitro toxicity of nanoparticles in BRL 3A rat liver cells. , 2005, Toxicology in vitro : an international journal published in association with BIBRA.

[59]  A. Porras,et al.  p38 MAP kinases: beyond the stress response. , 2000, Trends in biochemical sciences.

[60]  S. Ghosh,et al.  Signaling gene cascade in silver nanoparticle induced apoptosis. , 2010, Colloids and surfaces. B, Biointerfaces.

[61]  Vicki Stone,et al.  Effects of aqueous exposure to silver nanoparticles of different sizes in rainbow trout. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[62]  David M. Brown,et al.  Proinflammogenic Effects of Low-Toxicity and Metal Nanoparticles In Vivo and In Vitro: Highlighting the Role of Particle Surface Area and Surface Reactivity , 2007, Inhalation toxicology.

[63]  Jinhee Choi,et al.  p38 MAPK activation, DNA damage, cell cycle arrest and apoptosis as mechanisms of toxicity of silver nanoparticles in Jurkat T cells. , 2010, Environmental science & technology.