title: Comparative proteomic analysis of the molecular responses of mouse macrophages to titanium dioxide and copper oxide nanoparticles unravels some toxic mechanisms for copper oxide nanoparticles in macrophages.
abstract: Titanium dioxide and copper oxide nanoparticles are more and more widely used because of their catalytic properties, of their light absorbing properties (titanium dioxide) or of their biocidal properties (copper oxide), increasing the risk of adverse health effects. In this frame, the responses of mouse macrophages were studied. Both proteomic and targeted analyses were performed to investigate several parameters, such as phagocytic capacity, cytokine release, copper release, and response at sub toxic doses. Besides titanium dioxide and copper oxide nanoparticles, copper ions were used as controls. We also showed that the overall copper release in the cell does not explain per se the toxicity observed with copper oxide nanoparticles. In addition, both copper ion and copper oxide nanoparticles, but not titanium oxide, induced DNA strands breaks in macrophages. As to functional responses, the phagocytic capacity was not hampered by any of the treatments at non-toxic doses, while copper ion decreased the lipopolysaccharide-induced cytokine and nitric oxide productions. The proteomic analyses highlighted very few changes induced by titanium dioxide nanoparticles, but an induction of heme oxygenase, an increase of glutathione synthesis and a decrease of tetrahydrobiopterin in response to copper oxide nanoparticles. Subsequent targeted analyses demonstrated that the increase in glutathione biosynthesis and the induction of heme oxygenase (e.g. by lovastatin/monacolin K) are critical for macrophages to survive a copper challenge, and that the intermediates of the catecholamine pathway induce a strong cross toxicity with copper oxide nanoparticles and copper ions.
authors.affiliation: Laboratory of Chemistry and Biology of Metals, Univ. Grenoble Alpes, Grenoble, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Triboulet
authors.affiliation: Laboratory of Chemistry and Biology of Metals, CEA/ iRTSV, Grenoble, France; Laboratory of Chemistry and Biology of Metals, CNRS UMR5249, Grenoble, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Aude-Garcia
authors.affiliation: Service de Chimie Inorganique et Biologique, Univ. Grenoble Alpes & CEA, Grenoble, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Armand
authors.affiliation: Laboratory of Chemistry and Biology of Metals, CEA/ iRTSV, Grenoble, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Collin-Faure
authors.affiliation: Laboratory of Chemistry and Biology of Metals, CEA/ iRTSV, Grenoble, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Chevallet
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg & CNRS UMR 7178, Institut Pluridisciplinaire Hubert Curien, Strasbourg, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Diemer
authors.affiliation: Laboratoire Francis Perrin (Unité de recherche Associée 2453), Commissariat à l'Energie Atomique, CEA-Saclay 91191 Gif/Yvette, France.
authors.forename: Adèle
authors.initials: A
authors.lastname: Gerdil
authors.affiliation: Etablissement Français du Sang-Alsace, Unité MIxte de recherche S949 Institut National de la Santé Et de la Recherche Médicale (INSERM)-Université de Strasbourg, Strasbourg, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Proamer
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg & CNRS UMR 7178, Institut Pluridisciplinaire Hubert Curien, Strasbourg, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Strub
authors.affiliation: Laboratoire Francis Perrin (Unité de recherche Associée 2453), Commissariat à l'Energie Atomique, CEA-Saclay 91191 Gif/Yvette, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Habert
authors.affiliation: Laboratoire Francis Perrin (Unité de recherche Associée 2453), Commissariat à l'Energie Atomique, CEA-Saclay 91191 Gif/Yvette, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Herlin
authors.affiliation: Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), Université de Strasbourg & CNRS UMR 7178, Institut Pluridisciplinaire Hubert Curien, Strasbourg, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Van Dorsselaer
authors.affiliation: Service de Chimie Inorganique et Biologique, Univ. Grenoble Alpes & CEA, Grenoble, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Carrière
authors.affiliation: Laboratory of Chemistry and Biology of Metals, CNRS UMR5249, Grenoble, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Rabilloud
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000633:toxicity*; D016207:Cytokines / Q000096:biosynthesis; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000494:pharmacology; D015180:Electrophoresis, Gel, Two-Dimensional; D004790:Enzyme Induction / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D053768:Metal Nanoparticles / Q000633:toxicity*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D010587:Phagocytosis / Q000187:drug effects; D040901:Proteomics / Q000379:methods*; D014025:Titanium / Q000633:toxicity*
chemical_list: D016207:Cytokines; C009495:titanium dioxide; D009569:Nitric Oxide; D004295:Dihydroxyphenylalanine; D003300:Copper; D014025:Titanium; D006419:Heme Oxygenase (Decyclizing); D005978:Glutathione; C000520:cuprous oxide