title: Titanium oxide nanoparticle instillation induces inflammation and inhibits lung development in mice.
abstract: Nanoparticles are used in an increasing number of biomedical, industrial, and food applications, but their safety profiles in developing organisms, including the human fetus and infant, have not been evaluated. Titanium oxide (TiO(2)) nanoparticles, which are commonly used in cosmetics, sunscreens, paints, and food, have been shown to induce emphysema and lung inflammation in adult mice. We hypothesized that exposure of newborn mice to TiO(2) would induce lung inflammation and inhibit lung development. C57BL/6 mice were exposed to TiO(2) (anatase; 8-10 nm) nanoparticles by intranasal instillation as a single dose on postnatal day 4 (P4) or as three doses on postnatal days 4, 7, and 10 (each dose = 1 μg/g body wt). Measurements of lung function (compliance and resistance), development (morphometry), inflammation (histology; multiplex analysis of bronchoalveolar lavage fluid for cytokines; PCR array and multiplex analysis of lung homogenates for cytokines) was performed on postnatal day 14. It was observed that a single dose of TiO(2) nanoparticles led to inflammatory cell influx, and multiple doses led to increased inflammation and inhibition of lung development without significant effects on lung function. Macrophages were noted to take up the TiO(2) nanoparticles, followed by polymorphonuclear infiltrate. Multiple cytokines and matrix metalloproteinase-9 were increased in lung homogenates, and VEGF was reduced. These results suggest that exposure of the developing lung to nanoparticles may lead to ineffective clearance by macrophages and persistent inflammation with resulting effects on lung development and may possibly impact the risk of respiratory disorders in later life.
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, 176F Suite 9380, 619 South 20 St., Birmingham, AL 35233, USA. ambal@uab.edu
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.forename: Andrei
authors.initials: A
authors.lastname: Stanishevsky
authors.forename: Arlene
authors.initials: A
authors.lastname: Bulger
authors.forename: Brian
authors.initials: B
authors.lastname: Halloran
authors.forename: Chad
authors.initials: C
authors.lastname: Steele
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Vohra
authors.forename: Sadis
authors.initials: S
authors.lastname: Matalon
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000831:Animals, Newborn; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D015536:Down-Regulation; D004705:Endocytosis; D008168:Lung / Q000187:drug effects / Q000254:growth & development / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D060885:Multiplex Polymerase Chain Reaction; D053758:Nanoparticles; D011014:Pneumonia / Q000209:etiology* / Q000276:immunology / Q000473:pathology*; D012129:Respiratory Function Tests; D014025:Titanium / Q000633:toxicity*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C009495:titanium dioxide; D014025:Titanium; D020780:Matrix Metalloproteinase 9