title: Cyto- and genotoxic effects of metallic nanoparticles in untransformed human fibroblast.
abstract: Metallic nanoparticles such as silver (Ag), cerium dioxide (CeO2) and titanium dioxide (TiO2) are produced at a large scale and included in many consumer products. It is well known that most metallic NPs are toxic to humans which raise concerns about these engineered particles. Various studies have already been published on the subject, however, almost all of these studies have been conducted in cancer or transformed cell lines. In this work we performed a comparative evaluation of these metallic NPs on normal untransformed human fibroblasts (GM07492) detecting cyto- and geno-toxic responses after exposure to these NPs. Our results showed that all three metallic NPs were able to cross the plasma membrane and were mainly found in endocytic vesicles. The Ag and TiO2 NPs affected mitochondrial enzymatic activity (XTT), increased DNA fragmentation, oxidative damage (Comet assay) and induced cell death mainly by the apoptotic pathway. Ag NPs increased GADD45α transcript levels and the phosphorylation of proteins γH2AX. Transient genotoxicity was also observed from exposure to CeO2 NPs while TiO2 NPs showed no increase in DNA damage at sub-cytotoxic concentrations. In comparison, Ag NPs were found to be the most cyto-genotoxic NPs to fibroblasts. Thus, these results support the use of normal fibroblast as a more informative tool to detect the mechanisms of action induced by metallic NPs.
authors.affiliation: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, USP, RibeirãoPreto, SP, Brazil. Electronic address: leonardofranchi@yahoo.com.br.
authors.forename: Leonardo P
authors.initials: LP
authors.lastname: Franchi
authors.affiliation: MoSAIC/Biomedical MRI Unit, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Bella B
authors.initials: BB
authors.lastname: Manshian
authors.affiliation: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, USP, RibeirãoPreto, SP, Brazil.
authors.forename: Tiago A J
authors.initials: TA
authors.lastname: de Souza
authors.affiliation: MoSAIC/Biomedical MRI Unit, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Stefaan J
authors.initials: SJ
authors.lastname: Soenen
authors.affiliation: Department of Chemistry, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil.
authors.forename: Elaine Y
authors.initials: EY
authors.lastname: Matsubara
authors.affiliation: Department of Chemistry, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil.
authors.forename: J Mauricio
authors.initials: JM
authors.lastname: Rosolen
authors.affiliation: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, USP, RibeirãoPreto, SP, Brazil; Department of Biology, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil.
authors.forename: Catarina S
authors.initials: CS
authors.lastname: Takahashi
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002563:Cerium / Q000633:toxicity*; D020552:Comet Assay; D004249:DNA Damage; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D053768:Metal Nanoparticles / Q000633:toxicity*; D009687:Nuclear Proteins / Q000235:genetics; D012834:Silver / Q000633:toxicity*; D014025:Titanium / Q000633:toxicity*; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D002563:Cerium; D006657:Histones; D009687:Nuclear Proteins; D012834:Silver; D014025:Titanium; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C468783:H2AX protein, human; C009495:titanium dioxide; C030583:ceric oxide
keywords: Cytotoxicity; Flow cytometry; Genotoxicity; Human fibroblasts; Metallic nanoparticles