title: Differential genotoxicity mechanisms of silver nanoparticles and silver ions.
abstract: In spite of many reports on the toxicity of silver nanoparticles (AgNPs), the mechanisms underlying the toxicity are far from clear. A key question is whether the observed toxicity comes from the silver ions (Ag+) released from the AgNPs or from the nanoparticles themselves. In this study, we explored the genotoxicity and the genotoxicity mechanisms of Ag+and AgNPs. Human TK6 cells were treated with 5 nM AgNPs or silver nitrate (AgNO3) to evaluate their genotoxicity and induction of oxidative stress. AgNPs and AgNO3induced cytotoxicity and genotoxicity in a similar range of concentrations (1.00-1.75 µg/ml) when evaluated using the micronucleus assay, and both induced oxidative stress by measuring the gene expression and reactive oxygen species in the treated cells. Addition of N-acetylcysteine (NAC, an Ag+chelator) to the treatments significantly decreased genotoxicity of Ag+, but not AgNPs, while addition of Trolox (a free radical scavenger) to the treatment efficiently decreased the genotoxicity of both agents. In addition, the Ag+released from the highest concentration of AgNPs used for the treatment was measured. Only 0.5 % of the AgNPs were ionized in the culture medium and the released silver ions were neither cytotoxic nor genotoxic at this concentration. Further analysis using electron spin resonance demonstrated that AgNPs produced hydroxyl radicals directly, while AgNO3did not. These results indicated that although both AgNPs and Ag+can cause genotoxicity via oxidative stress, the mechanisms are different, and the nanoparticles, but not the released ions, mainly contribute to the genotoxicity of AgNPs.
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR, USA.|Covance Laboratories Inc., 671 South Meridian Rd, Greenfield, IN, 46140, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR, USA.|Bio-Medical Pharmaceutical Manufacturing Corporation, 4311 South Drive, Houston, TX, 77053, USA.
authors.forename: Taichun
authors.initials: T
authors.lastname: Qin
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Ingle
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Division of Analytical Chemistry, Office of Regulatory Science, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, MD, USA.|Key Laboratory of Micro-Nano Materials for Energy Storage and Conversion of Henan Province, Institute of Surface Micro and Nano Materials, Kuching University, Henan, 461000, People's Republic of China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: He
authors.affiliation: Division of Analytical Chemistry, Office of Regulatory Science, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, MD, USA.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Yin
authors.affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR, USA. tao.chen@fda.hhs.gov.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D053768:Metal Nanoparticles / Q000633:toxicity*; D015162:Micronucleus Tests; D009153:Mutagens / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D010316:Particle Size; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012834:Silver / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*; D012835:Silver Nitrate / Q000037:antagonists & inhibitors / Q000633:toxicity; D012995:Solubility; D013499:Surface Properties
chemical_list: D002614:Chelating Agents; D002839:Chromans; D016166:Free Radical Scavengers; D009153:Mutagens; D017382:Reactive Oxygen Species; D012834:Silver; D012835:Silver Nitrate; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D000111:Acetylcysteine
keywords: Cytotoxicity; Genotoxicity; In vitro micronucleus assay; Oxidative stress; Silver ion; Silver nanoparticles