Iron-Responsive Olfactory Uptake of Manganese Improves Motor Function Deficits Associated with Iron Deficiency

Jonghan Kim,Marianne Wessling-Resnick,Timothy J Maher,Yuan Li,Masaya Takahashi,Mark Böhlke,Khristy J Thompson,Peter D Buckett,Veronique Sgambato-Faure

doi:10.1371/journal.pone.0033533

Jonghan Kim, Marianne Wessling-Resnick + Show 7 more

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https://doi.org/10.1371/journal.pone.0033533

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Abstract

Iron-responsive manganese uptake is increased in iron-deficient rats, suggesting that toxicity related to manganese exposure could be modified by iron status. To explore possible interactions, the distribution of intranasally-instilled manganese in control and iron-deficient rat brain was characterized by quantitative image analysis using T1-weighted magnetic resonance imaging (MRI). Manganese accumulation in the brain of iron-deficient rats was doubled after intranasal administration of MnCl2 for 1- or 3-week. Enhanced manganese level was observed in specific brain regions of iron-deficient rats, including the striatum, hippocampus, and prefrontal cortex. Iron-deficient rats spent reduced time on a standard accelerating rotarod bar before falling and with lower peak speed compared to controls; unexpectedly, these measures of motor function significantly improved in iron-deficient rats intranasally-instilled with MnCl2. Although tissue dopamine concentrations were similar in the striatum, dopamine transporter (DAT) and dopamine receptor D1 (D1R) levels were reduced and dopamine receptor D2 (D2R) levels were increased in manganese-instilled rats, suggesting that manganese-induced changes in post-synaptic dopaminergic signaling contribute to the compensatory effect. Enhanced olfactory manganese uptake during iron deficiency appears to be a programmed “rescue response” with beneficial influence on motor impairment due to low iron status.

Highlights

Divalent metal transporter-1 (DMT1) mediates uptake of manganese across the olfactory epithelium into the brain [1]
The most relevant route for occupational and environmental manganese exposure health effects is through inhalation [15]
Characterization of the influence of iron status on olfactory and pulmonary manganese transport has demonstrated that respiratory manganese uptake reflects iron stores [1,16,17] and that DMT1 is involved in absorption across the olfactory epithelium into the brain [1]

Summary

Introduction

Divalent metal transporter-1 (DMT1) mediates uptake of manganese across the olfactory epithelium into the brain [1]. It is the major transporter for iron absorption in the duodenum [2,3]. The transporter’s expression becomes upregulated in both olfactory and intestinal epithelia [1,2,4]. Upregulation of DMT1 in iron-deficient rats is associated with increased olfactory manganese uptake [1]. The physiological significance of iron-responsive manganese transport to the brain has not been explored. Manganese toxicity is known to cause motor deficits, and locura manganica or ‘‘manganese madness’’ is associated with bradykinesia, rigidity, tremor and dystonia [12]

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