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Titanium Dioxide Nanoparticles Induce DNA Damage and Genetic Instability In vivo in Mice

Departments of ¹ Pathology and Laboratory Medicine, ² Radiation Oncology, and ³ Medicine, Center for Human Nutrition, David Geffen School of Medicine; ⁴ Interdepartmental Program in Molecular Toxicology; ⁵ Department of Environmental Health Sciences, School of Public Health, University of California-Los Angeles, Los Angeles, California

Requests for reprints: Robert H. Schiestl, Department of Pathology, University of California-Los Angeles School of Medicine, 650 Charles E. Young Drive South, Los Angeles, CA 90095. Phone: 310-267-2087; Fax: 310-267-2578; E-mail: rschiestl{at}mednet.ucla.edu.

Titanium dioxide (TiO₂) nanoparticles are manufactured worldwide in large quantities for use in a wide range of applications including pigment and cosmetic manufacturing. Although TiO₂ is chemically inert, TiO₂ nanoparticles can cause negative health effects, such as respiratory tract cancer in rats. However, the mechanisms involved in TiO₂-induced genotoxicity and carcinogenicity have not been clearly defined and are poorly studied in vivo. The present study investigates TiO₂ nanoparticles–induced genotoxicity, oxidative DNA damage, and inflammation in a mice model. We treated wild-type mice with TiO₂ nanoparticles in drinking water and determined the extent of DNA damage using the comet assay, the micronuclei assay, and the -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 TiO₂ nanoparticles induced 8-hydroxy-2'-deoxyguanosine, -H2AX foci, micronuclei, and DNA deletions. The formation of -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 TiO₂ 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 TiO₂ nanoparticles, these findings raise concern about potential health hazards associated with TiO₂ nanoparticles exposure. [Cancer Res 2009;69(22):8784–9]

Key Words: TiO₂ • nanoparticles • mice • genetic instability • DNA damage • inflammation