Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts

Dale W. Porter, Nianqiang Wu, Ann F. Hubbs, Robert R. Mercer, Kathleen Funk, Fanke Meng, Jiangtian Li, Michael G. Wolfarth, Lori Battelli, Sherri Friend, Michael Andrew, Raymond Hamilton, Krishnan Sriram, Feng Yang, Vincent Castranova, Andrij Holian

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63 Scopus citations


Three anatase titanium dioxide (TiO. 2) nanoparticles (NPs) were prepared; nanospheres (NSs), short nanobelts (NB1), and long nanobelts (NB2). These NPs were used to investigate the effect of NP shape and length on lung toxicity. Mice were exposed (0-30 μg per mouse) by pharyngeal aspiration and pulmonary toxicity was assessed over a 112-day time course. Whole lung lavage data indicated that NB1- and NB2-exposed mice, but not NS-exposed mice, had significant dose- and time-dependent pulmonary inflammation and damage. Histopathological analyses at 112 days postexposure determined no interstitial fibrosis in any NS-exposed mice, an increased incidence in 30 μg NB1-exposed mice, and significant interstitial fibrosis in 30 μg NB2-exposed mice. At 112 days postexposure, lung burden of NS was decreased by 96.4% and NB2 by 80.5% from initial deposition levels. At 112 days postexposure, enhanced dark field microscopy determined that alveolar macro- phages were the dominant deposition site, but a fraction of NB1 and NB2 was observed in the alveolar interstitial spaces. For the 30 μg exposure groups at 112 days postexposure, confocal micro- scopy and immunofluorescent staining demonstrated that retained NB2 but not NS were present in the interstitium subjacent to the terminal bronchiole near the normal location of the smallest lymphatic capillaries in the lung. These lymphatic capillaries play a critical role in particle clearance, and the accumulation of NB2, but not NS, suggests possible impaired lymphatic clearance by the high aspect ratio particles. In summary, our data indicate that TiO. 2 NP shape alters pulmonary responses, with severity of responses being ranked as NS < NB1 < NB2.

Original languageEnglish
Pages (from-to)179-193
Number of pages15
JournalToxicological Sciences
Issue number1
StatePublished - Jan 2013


  • Pulmonary clearance
  • Pulmonary fibrosis
  • Pulmonary inflammation
  • Titanium dioxide nanobelts
  • Titanium dioxide nanospheres


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