title: Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice.
abstract: Titanium dioxide (TiO(2)) nanoparticles are manufactured worldwide in large quantities for use in a wide range of applications including pigment and cosmetic manufacturing. Although TiO(2) is chemically inert, TiO(2) nanoparticles can cause negative health effects, such as respiratory tract cancer in rats. However, the mechanisms involved in TiO(2)-induced genotoxicity and carcinogenicity have not been clearly defined and are poorly studied in vivo. The present study investigates TiO(2) nanoparticles-induced genotoxicity, oxidative DNA damage, and inflammation in a mice model. We treated wild-type mice with TiO(2) nanoparticles in drinking water and determined the extent of DNA damage using the comet assay, the micronuclei assay, and the gamma-H2AX immunostaining assay and by measuring 8-hydroxy-2'-deoxyguanosine levels and, as a genetic instability endpoint, DNA deletions. We also determined mRNA levels of inflammatory cytokines in the peripheral blood. Our results show that TiO(2) nanoparticles induced 8-hydroxy-2'-deoxyguanosine, gamma-H2AX foci, micronuclei, and DNA deletions. The formation of gamma-H2AX foci, indicative of DNA double-strand breaks, was the most sensitive parameter. Inflammation was also present as characterized by a moderate inflammatory response. Together, these results describe the first comprehensive study of TiO(2) nanoparticles-induced genotoxicity in vivo in mice possibly caused by a secondary genotoxic mechanism associated with inflammation and/or oxidative stress. Given the growing use of TiO(2) nanoparticles, these findings raise concern about potential health hazards associated with TiO(2) nanoparticles exposure.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Human Nutrition, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Trouiller
authors.forename: Ramune
authors.initials: R
authors.lastname: Reliene
authors.forename: Aya
authors.initials: A
authors.lastname: Westbrook
authors.forename: Parrisa
authors.initials: P
authors.lastname: Solaimani
authors.forename: Robert H
authors.initials: RH
authors.lastname: Schiestl
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects; D020552:Comet Assay; D016207:Cytokines / Q000097:blood; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D006657:Histones / Q000187:drug effects; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D053758:Nanoparticles / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis; D014025:Titanium / Q000633:toxicity*
chemical_list: D001672:Biocompatible Materials; D016207:Cytokines; D006657:Histones; D012333:RNA, Messenger; D014025:Titanium; C009495:titanium dioxide; C475961:gamma-H2AX protein, mouse