title: Study of TiO2 P25 Nanoparticles Genotoxicity on Lung, Blood, and Liver Cells in Lung Overload and Non-Overload Conditions After Repeated Respiratory Exposure in Rats.
abstract: Inhaled titanium dioxide (TiO2) nanoparticles (NPs) can have negative health effects, and have been shown to cause respiratory tract cancer in rats. Inflammation has been linked to oxidative stress, and both have been described as possible mechanisms for genotoxicity of NPs, but rarely examined side-by-side in animal studies. In the present study, a wide range of complementary endpoints have been performed to study TiO2 P25 NP-induced genotoxicity in lung overload and non-overload conditions. Additionally, lung burden, inflammation, cytotoxicity and oxidative stress have also been evaluated in order to link genotoxicity with these responses. To assess quick and delayed responses after recovery, endpoints were evaluated at two time points: 2 h and 35 days after three repeated instillations. This study confirmed the previously described lung overload threshold at approximately 200-300 cm2 of lung burden for total particle surface area lung deposition or 4.2 µl/kg for volume-based cumulative lung exposure dose, above which lung clearance is impaired and inflammation is induced. Our results went on to show that these overload doses induced delayed genotoxicity in lung, associated with persistent inflammation only at the highest dose. The lowest tested doses had no toxicity or genotoxicity effects in the lung. In blood, no lymphocyte DNA damage, erythrocytes chromosomal damage or gene mutation could be detected. Our data also demonstrated that only overload doses induced liver DNA lesions irrespective of the recovery time. Tested doses of TiO2 P25 NPs did not induce glutathione changes in lung, blood or liver at both recovery times.
authors.affiliation: Experimental Toxicology Unit, INERIS (Institut National de l'Environnement industriel et des RISques), Verneuil-en-Halatte 60550, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: Relier
authors.affiliation: Experimental Toxicology Unit, INERIS (Institut National de l'Environnement industriel et des RISques), Verneuil-en-Halatte 60550, France.|Now at Cancer Angiogenesis and Micro-environnement laboratory, Insert 1029 Unity, 33615 PESSAC.
authors.forename: Marielle
authors.initials: M
authors.lastname: Dubreuil
authors.affiliation: Research Centre for the Physics of Matter and Radiation (PMR), Namur Nanosafety Centre (NNC), NARILIS, University of Namur, Namur B-5000, Belgium.|Now at Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey 64849, México.
authors.forename: Omar
authors.initials: O
authors.lastname: Lozano Garcìa
authors.affiliation: Territorial and Production Systems Sustainability Department, Laboratory of Biosafety and Risk Assessment, ENEA CR Casaccia, Rome 00123, Italy.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cordelli
authors.affiliation: Research Centre for the Physics of Matter and Radiation (PMR), Namur Nanosafety Centre (NNC), NARILIS, University of Namur, Namur B-5000, Belgium.
authors.forename: Jorge
authors.initials: J
authors.lastname: Mejia
authors.affiliation: Territorial and Production Systems Sustainability Department, Laboratory of Biosafety and Risk Assessment, ENEA CR Casaccia, Rome 00123, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Eleuteri
authors.affiliation: Experimental Toxicology Unit, INERIS (Institut National de l'Environnement industriel et des RISques), Verneuil-en-Halatte 60550, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Robidel
authors.affiliation: Experimental Toxicology Unit, INERIS (Institut National de l'Environnement industriel et des RISques), Verneuil-en-Halatte 60550, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Loret
authors.affiliation: Territorial and Production Systems Sustainability Department, Laboratory of Biosafety and Risk Assessment, ENEA CR Casaccia, Rome 00123, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pacchierotti
authors.affiliation: Research Centre for the Physics of Matter and Radiation (PMR), Namur Nanosafety Centre (NNC), NARILIS, University of Namur, Namur B-5000, Belgium.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lucas
authors.affiliation: Experimental Toxicology Unit, INERIS (Institut National de l'Environnement industriel et des RISques), Verneuil-en-Halatte 60550, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Lacroix
authors.affiliation: Experimental Toxicology Unit, INERIS (Institut National de l'Environnement industriel et des RISques), Verneuil-en-Halatte 60550, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Trouiller
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000473:pathology; D019570:Inhalation Exposure; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D010316:Particle Size; D017207:Rats, Sprague-Dawley; D013499:Surface Properties; D014018:Tissue Distribution; D014025:Titanium / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D009153:Mutagens; C009495:titanium dioxide; D014025:Titanium
keywords: DNA damage; glutathione.; inflammation; nanomaterials; rodents; titanium dioxide