| Translocation of Inhaled Ultrafine Manganese Oxide Particles to the Central Nervous System Alison Elder,1 Robert Gelein,1 Vanessa Silva,1* Tessa Feikert,1 Lisa Opanashuk,1 Janet Carter,2 Russell Potter,3 Andrew Maynard,4 Yasuo Ito,5 Jacob Finkelstein,6 and Günter Oberdörster1 1Department of Environmental Medicine, University of Rochester, Rochester, New York, USA; 2Procter and Gamble Co., Cincinnati, Ohio, USA; 3Owens Corning, Granville, Ohio, USA; 4Woodrow Wilson International Center for Scholars, Washington, DC, USA; 5Department of Physics, Northern Illinois University, DeKalb, Illinois, USA; 6Department of Pediatrics, University of Rochester, Rochester, New York, USA Abstract
Background: Studies in monkeys with intranasally instilled gold ultrafine particles (UFPs ; < 100 nm) and in rats with inhaled carbon UFPs suggested that solid UFPs deposited in the nose travel along the olfactory nerve to the olfactory bulb. Methods: To determine if olfactory translocation occurs for other solid metal UFPs and assess potential health effects, we exposed groups of rats to manganese (Mn) oxide UFPs (30 nm ; ~ 500 µg/m3) with either both nostrils patent or the right nostril occluded. We analyzed Mn in lung, liver, olfactory bulb, and other brain regions, and we performed gene and protein analyses. Results: After 12 days of exposure with both nostrils patent, Mn concentrations in the olfactory bulb increased 3.5-fold, whereas lung Mn concentrations doubled ; there were also increases in striatum, frontal cortex, and cerebellum. Lung lavage analysis showed no indications of lung inflammation, whereas increases in olfactory bulb tumor necrosis factor- mRNA (~ 8-fold) and protein (~ 30-fold) were found after 11 days of exposure and, to a lesser degree, in other brain regions with increased Mn levels. Macrophage inflammatory protein-2, glial fibrillary acidic protein, and neuronal cell adhesion molecule mRNA were also increased in olfactory bulb. With the right nostril occluded for a 2-day exposure, Mn accumulated only in the left olfactory bulb. Solubilization of the Mn oxide UFPs was < 1.5% per day. Conclusions: We conclude that the olfactory neuronal pathway is efficient for translocating inhaled Mn oxide as solid UFPs to the central nervous system and that this can result in inflammatory changes. We suggest that despite differences between human and rodent olfactory systems, this pathway is relevant in humans. Key words: brain, central nervous system, CNS, inhalation, intranasal instillation, manganese, metals, nose, olfactory bulb, respiratory tract. Environ Health Perspect 114: 1172–1178 (2006) . doi:10.1289/ehp.9030 available via http://dx.doi.org/ [Online 20 April 2006]
Address correspondence to A. Elder, Department of Environmental Medicine, University of Rochester, 575 Elmwood Ave., Box 850, Rochester, NY 14642 USA. Telephone: (585) 275-2324. Fax: (585) 256-2631. E-mail: Alison_Elder@urmc.rochester.edu *Current address: Procter and Gamble Co., Cincinnati, Ohio. Supplemental Material is available online at http://www.ehponline.org/docs/2006/9030/suppl.pdf We thank P. Wade-Mercer and N. Corson for their excellent technical assistance. This work was supported by the U.S. Environmental Protection Agency (EPA ; PM Center R827354) , National Institute of Environmental Health Sciences (training grant ESO527873 to T.F. ; ESO1247) , Department of Defense (MURI FA9550-04-1-0430) , and Department of Energy (W-31-109-ENG-38) . A.M.'s research was performed while at the National Institute for Occupational Safety and Health. The views expressed by the authors are their own and do not necessarily reflect those of the U.S. EPA. The authors declare they have no competing financial interests. Received 20 January 2006 ; accepted 20 April 2006.
Correction In "Materials and Methods" in the original manuscript published online, the authors incorrectly stated that animals were housed in wire-bottom cages ; this has been corrected here.
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