Translocation of inhaled ultrafine manganese oxide particles to the central nervous system

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; approximately 500 microg/m(superscript)3(/superscript)) 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 (approximately 8-fold) and protein (approximately 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.

Figure 1

Mn and Fe contents in lung and brain tissues after 6 and 12 days of inhalation exposure to ultrafine Mn oxide aerosols. (A) Mn content in lung and brain tissues in controls (n = 5) and after 6 (n = 3) and 12 (n = 3) days of exposure. (B) Fe content in lung and brain tissues in controls (n = 5) and after 12 days of exposure (n = 3). Values are mean ± SE. *p < 0.05 versus filtered air-exposed controls.

Figure 2

Gene and protein expression changes, by brain region, from pooled samples after 11 days of inhalation exposure to ultrafine Mn oxide aerosols. (A) Gene expression changes represented as relative intensities (fold increase over normalized control, dashed line). (B) TNF-α protein expression changes (relative intensities, fold increase over normalized control). Abbreviations: MIP-2, macrophage inflammatory protein-2; MnSOD, manganese superoxide dismutase; NCAM, neuronal cell adhesion molecule.

Figure 3

Accumulation of Mn in right and left olfactory bulb after inhalation exposure to ultrafine Mn oxide aerosols with the right naris occluded. Exposure duration and postexposure time are shown on the x-axis. Tissues were obtained from the same rats as in Figure 2S in Supplemental Material available online (http://www.ehponline.org/docs/2006/9030/suppl.pdf). Values are mean ± SE. *p < 0.05 versus 0 hr.

Figure 4

Approximate identification of component oxides by comparing measured EELS edge structure of gas-phase–generated Mn oxide to reference oxide spectra.

Figure 5

Translocation of instilled Mn to olfactory bulb in separate experiments. (A) Percentage of instilled Mn retained in olfactory bulb (shaded bars) and retained in olfactory mucosa (solid bars) 24 hr after instillation of either MnCl₂ or Mn oxide into left naris, n = 3/group. (B) Background corrected amount of Mn in olfactory bulb (shaded bars) and on olfactory mucosa (solid bars) at 30 min and 24 hr after instillation of Mn oxide into the left naris, n = 3/group. (C) Amount of Mn in left (shaded bars) and right (solid bars) olfactory bulb tissue from untreated control rats (n = 5) and 24 hr after instillation of Mn oxide into the left naris (n = 6 rats). Values are means ± SE. *p < 0.05 versus untreated controls.