Translocation of Inhaled Ultrafine Manganese Oxide Particles to the CentralNervous System

TLDR

Studies in monkeys and rats have shown that solid ultrafine particles deposited in the nose can travel along the olfactory nerve to the olfactory bulb. This study aimed to determine whether inhaled manganese oxide ultrafine particles also translocate via the olfactory pathway and to evaluate potential health effects. Rats were exposed to 30‑nm manganese oxide ultrafine particles at ~500 µg/m³, with either both nostrils patent or the right nostril occluded, and Mn distribution was measured in lung, liver, olfactory bulb, and other brain regions. Exposure caused a 3.5‑fold rise in olfactory bulb Mn and marked inflammatory gene and protein upregulation (e.g., TNF‑α mRNA 8‑fold, protein 30‑fold) without lung inflammation, while Mn accumulation was confined to the bulb when the right nostril was occluded, indicating efficient olfactory translocation of solid manganese oxide particles and potential neuroinflammatory effects.

Abstract

BackgroundStudies 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.MethodsTo 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.ResultsAfter 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-α 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.ConclusionsWe 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.