title: A combined proteomic and targeted analysis unravels new toxic mechanisms for zinc oxide nanoparticles in macrophages.
abstract: The cellular responses of the J774 macrophage cell line to zinc oxide and zirconium oxide nanoparticles have been studied by a comparative quantitative, protein level based proteomic approach. The most prominent results have been validated by targeted approaches. These approaches have been carried out under culture conditions that stimulate mildly the aryl hydrocarbon receptor, thereby mimicking conditions that can be encountered in vivo in complex environments. The comparative approach with two nanoparticles allows to separate the common responses, which can be attributed to the phagocytosis event per se, from the response specific to each type of nanoparticles. The zinc-specific responses are the most prominent ones and include mitochondrial proteins too, but also signaling molecules such as MyD88, proteins associated with methylglyoxal detoxification (glyoxalase 2, aldose reductase) and deoxyribonucleotide hydrolases. The in cellulo inhibition of GAPDH by zinc was also documented, representing a possible source of methylglyoxal in the cells, leading to an increase in methylglyoxal-modified DNA bases. These observations may be mechanistically associated with the genotoxic effect of zinc and its selective effects on cancer cells.
  
  
  CONCLUSIONS
  The responses of the murine J774 macrophage cell lines to two types of metallic oxide nanoparticles (zinc oxide and zirconium dioxide) were studied by a comparative 2D gel based approach. This allows sorting of shared responses from nanoparticle-specific responses. Zinc oxide nanoparticles induced specifically a strong decrease in the mitochondrial function, in phagocytosis and also an increase in the methylglyoxal-associated DNA damage, which may explain the well known genotoxicity of zinc. In conclusion, this study allows highlighting of pathways that may play an important role in the toxicity of the zinc oxide nanoparticles.
authors.affiliation: CEA Grenoble, iRTSV/CBM, Laboratory of Chemistry and Biology of Metals, Grenoble, France; Univ. Grenoble Alpes, Laboratory of Chemistry and Biology of Metals, Grenoble, France; CNRS UMR 5249, Laboratory of Chemistry and Biology of Metals, Grenoble, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Aude-Garcia
authors.affiliation: CEA Grenoble, iRTSV/CBM, Laboratory of Chemistry and Biology of Metals, Grenoble, France; Univ. Grenoble Alpes, Laboratory of Chemistry and Biology of Metals, Grenoble, France; CNRS UMR 5249, Laboratory of Chemistry and Biology of Metals, Grenoble, France.
authors.forename: Bastien
authors.initials: B
authors.lastname: Dalzon
authors.affiliation: Univ. Grenoble Alpes, INAC, SCIB, F-38000 Grenoble, France; CEA, INAC-SCIB/LAN, F-38000 Grenoble, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Ravanat
authors.affiliation: CEA Grenoble, iRTSV/CBM, Laboratory of Chemistry and Biology of Metals, Grenoble, France; Univ. Grenoble Alpes, Laboratory of Chemistry and Biology of Metals, Grenoble, France; CNRS UMR 5249, Laboratory of Chemistry and Biology of Metals, Grenoble, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Collin-Faure
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg, IPHC, 25 rue Becquerel, 67087 Strasbourg, France; CNRS, UMR7178, 67037 Strasbourg, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Diemer
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg, IPHC, 25 rue Becquerel, 67087 Strasbourg, France; CNRS, UMR7178, 67037 Strasbourg, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Strub
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg, IPHC, 25 rue Becquerel, 67087 Strasbourg, France; CNRS, UMR7178, 67037 Strasbourg, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Cianferani
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg, IPHC, 25 rue Becquerel, 67087 Strasbourg, France; CNRS, UMR7178, 67037 Strasbourg, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Van Dorsselaer
authors.affiliation: Univ. Grenoble Alpes, INAC, SCIB, F-38000 Grenoble, France; CEA, INAC-SCIB/LAN, F-38000 Grenoble, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Carrière
authors.affiliation: CEA Grenoble, iRTSV/CBM, Laboratory of Chemistry and Biology of Metals, Grenoble, France; Univ. Grenoble Alpes, Laboratory of Chemistry and Biology of Metals, Grenoble, France; CNRS UMR 5249, Laboratory of Chemistry and Biology of Metals, Grenoble, France. Electronic address: thierry.rabilloud@cea.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Rabilloud
mesh_terms: D000818:Animals; D002460:Cell Line; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D053758:Nanoparticles / Q000009:adverse effects* / Q000737:chemistry; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics; D015034:Zinc Oxide / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020543:Proteome; D015034:Zinc Oxide
keywords: DNA damage; Glutathione biosynthesis; Heme oxygenase; Macrophages; Methyglyoxal; Mitochondria; Nanoparticles; Phagocytosis; Proteomics; Zinc oxide; Zirconium dioxide