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

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.

• Publication year

  2012

• Venue

  PLoS ONE

• Publication date

  2012-03-30

• Fields of study

  Medicine, Environmental Science

• Identifiers
  DOI 10.1371/journal.pone.0033533PMID 22479410PMCID 3316579
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2011cited by this paper
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  2011cited by this paper
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  2010cited by this paper
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• Preweaning manganese exposure causes hyperactivity, disinhibition, and spatial learning and memory deficits associated with altered dopamine receptor and transporter levels

  2010cited by this paper
• New insights into the protective effect of manganese against oxidative stress

  2009cited by this paper
• Pharmacokinetic Modeling of Manganese in the Rat IV: Assessing Factors that Contribute to Brain Accumulation During Inhalation Exposure

  2008cited by this paper
• Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre‐synaptic mechanism(s): implications to manganese‐induced parkinsonism

  2008cited by this paper
• Measuring brain manganese and iron accumulation in rats following 14 weeks of low-dose manganese treatment using atomic absorption spectroscopy and magnetic resonance imaging.

  2008cited by this paper
• Manganese accumulates in iron-deficient rat brain regions in a heterogeneous fashion and is associated with neurochemical alterations

  2007cited by this paper
• Inhibition of DAT function attenuates manganese accumulation in the globus pallidus.

  2007cited by this paper
• Acute manganese administration alters dopamine transporter levels in the non-human primate striatum.

  2006cited by this paper
• The influence of high iron diet on rat lung manganese absorption.

  2006cited by this paper
• Pharmacokinetics of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading in iron-deficient rats.

  2005cited by this paper
• Effects of Manganese on Extracellular Levels of Dopamine in Rat Striatum: An Analysis In vivo by Brain Microdialysis

  2005cited by this paper
• Manganese Dosimetry: Species Differences and Implications for Neurotoxicity

  2005cited by this paper
• In vivo basal and amphetamine-induced striatal dopamine and metabolite levels are similar in the spontaneously hypertensive, Wistar-Kyoto and Sprague-Dawley male rats.

  2003cited by this paper
• Isolation and purification of tyrosine hydroxylase from callus cultures of Portulaca grandiflora.

  2001cited by this paper
• Oxalic acid stabilizes dopamine, serotonin, and their metabolites in automated liquid chromatography with electrochemical detection.

  2001cited by this paper
• Direct olfactory transport of inhaled manganese ((54)MnCl(2)) to the rat brain: toxicokinetic investigations in a unilateral nasal occlusion model.

  2000cited by this paper
• Iron deficiency alters dopamine transporter functioning in rat striatum.

  2000influential reference
• Central nervous system toxicity of manganese. II: Cocaine or reserpine inhibit manganese concentration in the rat brain.

  1999cited by this paper
• Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron.

  1999cited by this paper
• Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport.

  1998cited by this paper
• Manganese transport in the neural circuit of rat CNS.

  1998cited by this paper
• In vivo dopamine metabolism is altered in iron-deficient anemic rats.

  1997cited by this paper
• Cloning and characterization of a mammalian proton-coupled metal-ion transporter

  1997cited by this paper
• Uptake of manganese and cadmium from the nasal mucosa into the central nervous system via olfactory pathways in rats.

  1996cited by this paper
• Abnormal rat brain monoamine metabolism in iron deficiency anemia

  1995influential reference
• Biological half-lives of zinc and manganese in rat brain.

  1995cited by this paper
• Altered monamine metabolism in caudate-putamen of iron-deficient rats.

  1994cited by this paper
• Severe or marginal iron deficiency affects spontaneous physical activity in rats.

  1994cited by this paper
• Simultaneous measurement of monoamines, metabolites and amino acids in brain tissue and microdialysis perfusates.

  1993cited by this paper
• Effect of manganese on biogenic amine metabolism in regions of the rat brain.

  1991cited by this paper
• Putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behavior.

  1989cited by this paper
• Behavioral effects of chronic manganese administration in rats: locomotor activity studies.

  1986cited by this paper
• Behavioral effects of chronic manganese administration in rats: locomotor activity studies.

  1986cited by this paper
• Chronic manganese intake induces changes in the motor activity of rats.

  1984cited by this paper
• Dopamine and norepinephrine turnover in various regions of the rat brain after chronic manganese chloride administration.

  1982cited by this paper
• Manganese in health and disease.

  1958cited by this paper
• The FASEB Journal • Research Communication Olfactory uptake of manganese requires DMT1 and is enhanced by anemia

  year unknowncited by this paper

• Chronic Manganese Neuro-Toxicity in a Patient With Cirrhosis and the Role of Iron-Deficiency Anaemia

  2024cites this paper
• In-feed organic and inorganic manganese supplementation on broiler performance and physiological responses

  2021cites this paper
• Alcohol exposure increases manganese accumulation in the brain and exacerbates manganese-induced neurotoxicity in mice

  2021cites this paper
• Effects of Dietary Iron Concentration on Manganese Utilization in Broilers Fed with Manganese-Lysine Chelate-Supplemented Diet

  2020cites this paper
• Metal bashing: iron deficiency and manganese overexposure impact on peripheral nerves

  2019cites this paper
• Uptake of Manganese from the Manganese-Lysine Complex in Primary Chicken Intestinal Epithelial Cells

  2019cites this paper
• Manganese transport and toxicity in polarized WIF-B hepatocytes.

  2018cites this paper
• Valproic acid attenuates manganese‐induced reduction in expression of GLT‐1 and GLAST with concomitant changes in murine dopaminergic neurotoxicity

  2018cites this paper
• Influence of iron metabolism on manganese transport and toxicity.

  2017cites this paper
• Uptake of manganese from manganese–lysine complex in the primary rat intestinal epithelial cells

  2017cites this paper
• Valproate and sodium butyrate attenuate manganese‐decreased locomotor activity and astrocytic glutamate transporters expression in mice

  2017cites this paper
• Manganese Provision in Parenteral Nutrition: An Update.

  2017cites this paper
• Iron mitigates DMT1-mediated manganese cytotoxicity via the ASK1-JNK signaling axis: Implications of iron supplementation for manganese toxicity

  2016cites this paper
• Dietary iron concentration influences serum concentrations of manganese in rats consuming organic or inorganic sources of manganese.

  2016cites this paper
• Mechanisms of divalent metal toxicity in affective disorders.

  2016cites this paper
• Pica for Uncooked Basmati Rice in Two Women with Iron Deficiency and a Review of Ryzophagia

  2016cites this paper
• Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure.

  2016cites this paper
• Review about the manganese speciation project related to neurodegeneration: An analytical chemistry approach to increase the knowledge about manganese related parkinsonian symptoms.

  2016cites this paper
• Short-term manganese inhalation decreases brain dopamine transporter levels without disrupting motor skills in rats.

  2016cites this paper
• Behavioral and Biochemical Alterations in Sheep with Trace Elements Deficiency: A Trial for Treatment

  2016cites this paper
• Biomedical and Pharmaceutical Applications

  2016cites this paper
• An explanation of the pathophysiology of adverse neurodevelopmental outcomes in iron deficiency

  2015cites this paper
• Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis.

  2015cites this paper
• Effect of Hfe Deficiency on Memory Capacity and Motor Coordination after Manganese Exposure by Drinking Water in Mice

  2015cites this paper
• Effect of Dietary Iron Loading on Recognition Memory in Growing Rats

  2015cites this paper
• Loss of Hfe Function Reverses Impaired Recognition Memory Caused by Olfactory Manganese Exposure in Mice

  2015cites this paper
• Pathophysiology of the Belgrade rat

  2014cites this paper
• Effect of olfactory manganese dose on motor coordination in iron-deficient rats

  2014influential citation
• Exposure to manganese, fetal growth, and neurodevelopment in children living in agricultural communities in Costa Rica and California

  2014cites this paper
• Intranasal exposure to uranium results in direct transfer to the brain along olfactory nerve bundles

  2014cites this paper
• Iron depletion increases manganese uptake and potentiates apoptosis through ER stress.

  2013cites this paper
• Intranasal administration of oxytocin: Behavioral and clinical effects, a review

  2013cites this paper
• Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water

  2013cites this paper
• The Effects of 900 Megahertz Electromagnetic Field Applied in the Prenatal Period on Spinal Cord Morphology and Motor Behavior in Female Rat Pups

  2013cites this paper
• Absorption of Manganese and Iron in a Mouse Model of Hemochromatosis

  2013cites this paper
• Nramp: from sequence to structure and mechanism of divalent metal import.

  2012cites this paper
• The Journal of Toxicological Sciences

  2010cites this paper