title: Genotoxicity and molecular response of silver nanoparticle (NP)-based hydrogel.
abstract: BACKGROUND
  Since silver-nanoparticles (NPs) possess an antibacterial activity, they were commonly used in medical products and devices, food storage materials, cosmetics, various health care products, and industrial products. Various silver-NP based medical devices are available for clinical uses, such as silver-NP based dressing and silver-NP based hydrogel (silver-NP-hydrogel) for medical applications. Although the previous data have suggested silver-NPs induced toxicity in vivo and in vitro, there is lack information about the mechanisms of biological response and potential toxicity of silver-NP-hydrogel.
  
  
  METHODS
  In this study, the genotoxicity of silver-NP-hydrogel was assayed using cytokinesis-block micronucleus (CBMN). The molecular response was studied using DNA microarray and GO pathway analysis.
  
  
  CONCLUSIONS
  The results of global gene expression analysis in HeLa cells showed that thousands of genes were up- or down-regulated at 48 h of silver-NP-hydrogel exposure. Further GO pathway analysis suggested that fourteen theoretical activating signaling pathways were attributed to up-regulated genes; and three signal pathways were attributed to down-regulated genes. It was discussed that the cells protect themselves against silver NP-mediated toxicity through up-regulating metallothionein genes and anti-oxidative stress genes. The changes in DNA damage, apoptosis and mitosis pathway were closely related to silver-NP-induced cytotoxicity and chromosome damage. The down-regulation of CDC14A via mitosis pathway might play a role in potential genotoxicity induced by silver-NPs.
  
  
  CONCLUSIONS
  The silver-NP-hydrogel induced micronuclei formation in cellular level and broad spectrum molecular responses in gene expression level. The results of signal pathway analysis suggested that the balances between anti-ROS response and DNA damage, chromosome instability, mitosis inhibition might play important roles in silver-NP induced toxicity. The inflammatory factors were likely involved in silver-NP-hydrogel complex-induced toxic effects via JAK-STAT signal transduction pathway and immune response pathway. These biological responses eventually decide the future of the cells, survival or apoptosis.
authors.affiliation: Institute for Medical Devices Control, National Institutes for Food and Drug Control, Beijing 100050, China. xuliming@nifdc.org.cn
authors.forename: Liming
authors.initials: L
authors.lastname: Xu
authors.forename: Xuefei
authors.initials: X
authors.lastname: Li
authors.forename: Taro
authors.initials: T
authors.lastname: Takemura
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hanagata
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Laisheng Lee
authors.initials: LL
authors.lastname: Chou
mesh_terms: D048430:Cell Shape / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000633:toxicity*; D053768:Metal Nanoparticles / Q000633:toxicity* / Q000648:ultrastructure; D015162:Micronucleus Tests; D008954:Models, Biological; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D012834:Silver / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D009153:Mutagens; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D012834:Silver