title: Oxidative stress pathways involved in cytotoxicity and genotoxicity of titanium dioxide (TiO2) nanoparticles on cells constitutive of alveolo-capillary barrier in vitro.
abstract: The health risks of nanoparticles remain a serious concern given their prevalence from industrial and domestic use. The primary route of titanium dioxide nanoparticle exposure is inhalation. The extent to which nanoparticles contribute to cellular toxicity is known to associate induction of oxidative stress. To investigate this problem further, the effect of titanium dioxide nanoparticles was examined on cell lines representative of alveolo-capillary barrier. The present study showed that all nanoparticle-exposed cell lines displayed ROS generation. Macrophage-like THP-1 and HPMEC-ST1.6R microvascular cells were sensitive to endogenous redox changes and underwent apoptosis, but not alveolar epithelial A549 cells. Genotoxic potential of titanium dioxide nanoparticles was investigated using the activation of γH2AX, activation of DNA repair proteins and cell cycle arrest. In the sensitive cell lines, DNA damage was persistent and activation of DNA repair pathways was observed. Moreover, western blot analysis showed that specific pathways associated with cellular stress response were activated concomitantly with DNA repair or apoptosis. Nanoparticles-induced oxidative stress is finally signal transducer for further physiological effects including genotoxicity and cytotoxicity. Within activated pathways, HSP27 and SAPK/JNK proteins appeared as potential biomarkers of intracellular stress and of sensitivity to endogenous redox changes, respectively, enabling to predict cell behavior.
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité de Toxicologie Expérimentale, Parc Technologique ALATA-BP 2, F-60550 Verneuil-en-Halatte, France; Université de Technologie de Compiègne (UTC), Laboratoire BioMécanique et BioIngénierie (BMBI), UMR CNRS 7338, 60205 Compiègne, France. Electronic address: maite.hanot@free.fr.
authors.forename: Maïté
authors.initials: M
authors.lastname: Hanot-Roy
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité de Toxicologie Expérimentale, Parc Technologique ALATA-BP 2, F-60550 Verneuil-en-Halatte, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Tubeuf
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité de Toxicologie Expérimentale, Parc Technologique ALATA-BP 2, F-60550 Verneuil-en-Halatte, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Guilbert
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité d'Ecotoxicologie in vitro et in vivo, Parc Technologique ALATA-BP 2, F-60550 Verneuil-en-Halatte, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bado-Nilles
authors.affiliation: Université de Technologie de Compiègne (UTC), Laboratoire BioMécanique et BioIngénierie (BMBI), UMR CNRS 7338, 60205 Compiègne, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Vigneron
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité de Toxicologie Expérimentale, Parc Technologique ALATA-BP 2, F-60550 Verneuil-en-Halatte, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Trouiller
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité de Toxicologie Expérimentale, Parc Technologique ALATA-BP 2, F-60550 Verneuil-en-Halatte, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Braun
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité de Toxicologie Expérimentale, Parc Technologique ALATA-BP 2, F-60550 Verneuil-en-Halatte, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Lacroix
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002196:Capillaries; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D005978:Glutathione / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006657:Histones / Q000378:metabolism; D006801:Humans; D053768:Metal Nanoparticles / Q000633:toxicity*; D018832:Molecular Chaperones; D018384:Oxidative Stress / Q000187:drug effects; D011650:Pulmonary Alveoli; D017382:Reactive Oxygen Species / Q000378:metabolism; D014025:Titanium / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C468783:H2AX protein, human; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D006657:Histones; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; C009495:titanium dioxide; D014025:Titanium; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione
keywords: Cell death; DNA repair; Nanotoxicology; Oxidative stress