title: Long-term Pulmonary Responses to Quadweekly Intermittent Intratracheal Spray Instillations of Magnetite (Fe3O4) Nanoparticles for 52 Weeks in Fischer 344 Rats.
abstract: Information about potential risks of iron nanomaterials is still limited, while a wide variety of applications are expected. We recently reported acute phase responses of male and female Fischer 344 rats after a single intratracheal spray instillation of Fe3O4 nanoparticles (magnetite), clearly showing dose-dependent pulmonary inflammatory changes (Tada et al., J Toxicol Pathol 25, 233-239, 2012). The present study assessed long-term responses of male and female Fischer 344 rats to multiple administrations of magnetite. Ten-week-old male and female Fischer 344 rats (n=20/group) were exposed to a total of 13 quadweekly intermittent intratracheal spray instillations of magnetite during the experimental period of 52 weeks, at doses of 0, 0.2 (low), 1.0 (medium) and 5.0 (high-dose) mg/kg body weight per administration. Absolute and relative lung weights of the high-dose group were significantly higher than those of the control group. Macroscopically, slight enlargement and scattered black patches were recognized in the lungs and the lung-associated lymph nodes of the high-dose group. Histopathologically, infiltration of macrophages phagocytosing magnetite (all dose groups) and of chronic inflammatory cells (medium- and high-dose males and high-dose females), alveolar bronchiolization and granuloma (high-dose group) were observed. In addition, alveolar hyperplasias were observed in some rats of the high-dose group, and cytoplasmic overexpression of β-catenin protein was immunohistochemically found in such lesions. The present results clearly show that instilled magnetite causes chronic inflammatory responses in the lung. These responses occur in a dose-dependent manner without apparent differences among sexes.
authors: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.
authors: Yukie
authors: Y
authors: Tada
authors: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.
authors: Norio
authors: N
authors: Yano
authors: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.
authors: Hiroshi
authors: H
authors: Takahashi
authors: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.
authors: Katsuhiro
authors: K
authors: Yuzawa
authors: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.
authors: Hiroshi
authors: H
authors: Ando
authors: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.
authors: Yoshikazu
authors: Y
authors: Kubo
authors: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.
authors: Akemichi
authors: A
authors: Nagasawa
authors: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.
authors: Akiko
authors: A
authors: Inomata
authors: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan.
authors: Akio
authors: A
authors: Ogata
authors: Department of Pharmaceutical and Environmental Sciences, Tokyo Metropolitan Institute of Public Health, 3-24-1 Hyakunin-cho, Shinjuku, Tokyo 169-0073, Japan ; Tokyo University of Agriculture, 1-1-1 Sakura-ga-Oka, Setagaya, Tokyo 156-8502, Japan.
authors: Dai
authors: D
authors: Nakae
keywords: Fe3O4; Fischer 344 rat; intratracheal spray instillation; lung; magnetite; nanoparticles