Translocation of Inhaled Ultrafine Manganese Oxide Particles to the Central Nervous System
Elder, Alison, Gelein, Robert, Silva, Vanessa, Feikert, Tessa, Opanashuk, Lisa, Carter, Janet, Potter, Russell, Maynard, Andrew, Ito, Yasuo, Finkelstein, Jacob, Oberdorster, Gunter, Environmental Health Perspectives
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 [micro]g/[m.sup.3]) 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-[alpha] 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]
An important step in assessing the toxicology of particles is to determine their fate after inhalation. Of particular interest to us are airborne ultrafine particles (UFPs; < 100 nm), which are abundant in ambient urban air and are of the same size as engineered nanoparticles. Translocation to extrapulmonary sites after respiratory tract deposition represents an important mechanism for these particles to cause direct effects in secondary target organs (Oberdorster et al. 2005). The extent to which this process occurs depends on several factors including particle solubility, particle or aggregate size, the site of deposition, and the integrity of the epithelial lining. UFPs deposit efficiently in all regions of the respiratory tract, depending on their size; specifically, as particle size decreases toward the smallest UFPs, nasopharyngeal deposition increases (International Committee on Radiological Protection 1994).
Studies in rats have shown translocation of soluble manganese compounds from the nose along olfactory neuronal pathways to the olfactory bulb (Dorman et al. 2004; Henriksson and Tjalve 2000; Tjalve et al. 1996; Tjalve and Henriksson 1999) after inhalation or intranasal instillation exposures. Likewise, the few studies that have examined the fate of UFPs deposited on the nasal mucosa identified translocation along the neuronal olfactory route as a pathway to the olfactory bulb of the central nervous system (CNS). These include early studies in nonhuman primates, which demonstrated the translocation of solid nanosized particles (30 nm poliovirus; 50 nm silver-coated gold colloids) along the axons of olfactory nerves into the olfactory bulb (Bodian and Howe 1941a, 1941b; DeLorenzo 1970). We have also shown that inhaled elemental carbon particles ([.sup.13.C]; 35 nm, count median diameter) accumulate in rat olfactory bulb after whole-body inhalation (Oberdorster et al. …