Online citations, reference lists, and bibliographies.
← Back to Search

Homeostatic And Toxic Mechanisms Regulating Manganese Uptake, Retention, And Elimination.

J. Roth
Published 2006 · Biology, Medicine

Cite This
Download PDF
Analyze on Scholarcy
Share
This review attempts to summarize and clarify our basic knowledge as to the various factors that potentially influence the risks imposed from chronic exposure to high atmospheric levels of manganese (Mn). The studies describe the interrelationship of the different systems in the body that regulate Mn homeostasis by characterizing specific, biological components involved in its systemic and cellular uptake and its elimination from the body. A syndrome known as manganism occurs when individuals are exposed chronically to high levels of Mn, consisting of reduced response speed, intellectual deficits, mood changes, and compulsive behaviors in the initial stages of the disorder to more prominent and irreversible extrapyramidal dysfunction resembling Parkinson's disease upon protracted exposure. Mn intoxication is most often associated with occupations in which abnormally high atmospheric concentrations prevail, such as in welding and mining. There are three potentially important routes by which Mn in inspired air can gain access the body to: 1) direct uptake into the CNS via uptake into the olfactory or trigeminal presynaptic nerve endings located in the nasal mucosa and the subsequent retrograde axonal transport directly into the CNS; 2) transport across the pulmonary epithelial lining and its subsequent deposition into lymph or blood; and/or 3) mucocilliary elevator clearance from the lung and the subsequent ingestion of the metal in the gastrointestinal tract. Each of these processes and their overall contribution to the uptake of Mn in the body is discussed in this review as well as a description of the various mechanisms that have been proposed for the transport of Mn across the bloodbrain barrier which include both a transferrin-dependent and a transferrin-independent process that may involve store-operated Ca channels.
This paper references
10.1038/NG0897-383
Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene
M. Fleming (1997)
10.1002/HEP.510240523
Increased blood manganese in cirrhotic patients: Relationship to pallidal magnetic resonance signal hyperintensity and neurological symptoms
L. Spahr (1996)
10.1111/j.1460-9568.2004.03636.x
Death of dopaminergic neurones in the rat substantia nigra can be induced by damage to globus pallidus
A. K. Wright (2004)
Effects from environmental Mn exposures: a review of the evidence from non-occupational exposure studies.
H. K. Hudnell (1999)
10.1038/41343
Cloning and characterization of a mammalian proton-coupled metal-ion transporter
Hiromi Gunshin (1997)
10.1124/JPET.104.078469
Protein Kinase Cδ Is a Key Downstream Mediator of Manganese-Induced Apoptosis in Dopaminergic Neuronal Cells
C. Latchoumycandane (2005)
10.1055/S-2003-42211
Temporal parenteral nutrition in children causing t1 shortening in the anterior pituitary gland and globus pallidus.
H. Suzuki (2003)
10.1111/j.1651-2227.2001.tb01356.x
Manganese intake and cholestatic jaundice in neonates receiving parenteral nutrition: a randomized controlled study
T. Fok (2001)
Uptake of metals in the brain via olfactory pathways.
H. Tjälve (1999)
10.1002/ANA.410360611
Manganese intoxication and chronic liver failure
R. Hauser (1994)
10.1152/AJPGI.2000.278.6.G930
Gene expression of divalent metal transporter 1 and transferrin receptor in duodenum of Belgrade rats.
P. Oates (2000)
10.1136/gut.46.2.270
Localisation of divalent metal transporter 1 (DMT1) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in iron overload
D. Trinder (2000)
Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease.
J. Gorell (1999)
10.1212/WNL.43.8.1479
Progression after chronic manganese exposure
C. Huang (1993)
10.1002/jnr.1256
Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat
J. Burdo (2001)
10.1007/s00383-002-0929-6
Whole-blood manganese levels and brain manganese accumulation in children receiving long-term home parenteral nutrition
Y. Iinuma (2002)
10.1093/JN/121.5.711
Absorption and biological half-life in humans of intrinsic and extrinsic 54Mn tracers from foods of plant origin.
P. Johnson (1991)
10.1212/WNL.19.10.1000
Chronic manganese poisoning
I. Mena (1969)
10.1152/AJPLUNG.00114.2002
Iron increases expression of iron-export protein MTP1 in lung cells.
F. Yang (2002)
Protein transport in cerebral endothelium. In vitro transcytosis of transferrin.
L. Fenart (2003)
10.1016/J.NEURO.2003.10.001
Manganese distribution in the brain and neurobehavioral changes following inhalation exposure of rats to three chemical forms of manganese.
L. Normandin (2004)
10.1152/AJPGI.00346.2001
Effect of iron status on DMT1 expression in duodenal enterocytes from beta2-microglobulin knockout mice.
T. Moos (2002)
10.1038/sj.cdd.4400508
Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by Bcl-2
N. Schrantz (1999)
10.1006/exnr.1993.1042
Manganese Injection into the Rat Striatum Produces Excitotoxic Lesions by Impairing Energy Metabolism
E. Brouillet (1993)
Protein kinase Cdelta ( PKC { delta } ) is a key downstream mediator of manganeseinduced apoptosis in dopaminergic neuronal cells
BE LEHNERT (2005)
10.1054/CLNU.2000.0120
Factors associated to hypermanganesemia in patients receiving home parenteral nutrition.
J. Reimund (2000)
Manganese and calcium transport in mitochondria: implications for manganese toxicity.
C. Gavin (1999)
10.1006/TAAP.1999.8874
Pharmacokinetics of inhaled manganese phosphate in male Sprague-Dawley rats following subacute (14-day) exposure.
D. Vitarella (2000)
10.1023/A:1026602100160
Calcium Sequestering Ability of Mitochondria Modulates Influx of Calcium through Glutamate Receptor Channel
S. S. Kannurpatti (2004)
Chronic Parkinsonism Associated With Cirrhosis
P. Burkhard (2003)
10.1016/S0378-4274(00)00209-5
Pattern of deposition of stainless steel welding fume particles inhaled into the respiratory systems of Sprague-Dawley rats exposed to a novel welding fume generating system.
I. Yu (2000)
10.1023/A:1025005232421
Transcytosis of GCSF-Transferrin Across Rat Alveolar Epithelial Cell Monolayers
A. Widera (2004)
10.1007/s00441-002-0663-3
Phenotype-dependent synthesis of transferrin receptor in rat alveolar epithelial cell monolayers
A. Widera (2003)
10.1016/0034-5687(89)90139-4
The topography of particle deposition in the human lung.
P. Pityn (1989)
10.1164/AJRCCM.159.1.9801033
Iron uptake promotes hyperoxic injury to alveolar macrophages.
L. Wesselius (1999)
10.1080/15287390490266909
Pulmonary Responses to Welding Fumes: Role of Metal Constituents
J. Antonini (2004)
10.1016/0041-008X(92)90360-5
Mn2+ sequestration by mitochondria and inhibition of oxidative phosphorylation.
C. Gavin (1992)
10.1016/J.TAAP.2004.06.001
Changes in the brain mitochondrial proteome of male Sprague-Dawley rats treated with manganese chloride.
Surong Zhang (2005)
10.1097/01.WCB.0000095800.98378.03
Regulation of the Profile of Iron-Management Proteins in Brain Microvasculature
J. Burdo (2004)
10.1016/S0006-2952(03)00145-X
Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese.
J. Roth (2003)
10.1016/J.JNUTBIO.2003.12.006
Globus pallidus: a target brain region for divalent metal accumulation associated with dietary iron deficiency.
K. Erikson (2004)
10.1006/ENRS.1997.3710
Early manifestations of manganese neurotoxicity in humans: an update.
D. Mergler (1997)
10.3346/JKMS.1998.13.4.437
Manganese induced parkinsonism: a case report.
J. W. Kim (1998)
10.1152/PHYSREV.1981.61.2.249
Teratogenic aspects of manganese, zinc, and copper nutrition.
L. Hurley (1981)
10.1093/AJCN/49.1.170
Manganese retention in man: a method for estimating manganese absorption in man.
L. Davidsson (1989)
10.1023/A:1021064711866
Decrease in Spontaneous Motor Activity and in Brain Lipid Peroxidation in Manganese and Melatonin Treated Mice
E. Talavera (2004)
10.1016/S0161-813X(02)00012-8
Manganese causes differential regulation of glutamate transporter (GLAST) taurine transporter and metallothionein in cultured rat astrocytes.
K. Erikson (2002)
10.1212/WNL.46.2.492
Manganese intoxication in the rhesus monkey
C. W. Olanow (1996)
MOSS OR, DORMAN DC
D VITARELLA (2000)
10.1016/0304-4165(76)90218-X
Manganese metabolism in cows and goats.
R. Gibbons (1976)
10.1152/AJPLUNG.00253.2001
Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial cells.
Xinchao Wang (2002)
10.1002/ajim.4700110308
Epidemiological survey among workers exposed to manganese: effects on lung, central nervous system, and some biological indices.
H. Roels (1987)
10.1002/(SICI)1097-4547(20000215)59:4<542::AID-JNR10>3.0.CO;2-B
Influence of transferrin on manganese uptake in rat brain
A. Takeda (2000)
10.1016/S0161-813X(01)00077-8
Mechanisms of manganese-induced rat pheochromocytoma (PC12) cell death and cell differentiation.
J. Roth (2002)
10.1080/08958370490439597
Translocation of Inhaled Ultrafine Particles to the Brain
G. Oberdörster (2004)
10.1002/mds.20381
[18F]FDOPA PET and clinical features in parkinsonism due to manganism
B. Racette (2005)
Manganese toxicokinetics at the blood-brain barrier.
R. Yokel (2004)
10.1080/00984100290071630
OLFACTORY TRANSPORT: A DIRECT ROUTE OF DELIVERY OF INHALED MANGANESE PHOSPHATE TO THE RAT BRAIN
D. Dorman (2002)
10.1016/0304-3940(96)12645-8
Manganese and 1-methyl-4-(2′-ethylphenyl)-1,2,3,6-tetrahydropyridine induce apoptosis in PC12 cells
M. S. Desole (1996)
10.1016/S0140-6736(95)92164-8
Manganese and chronic hepatic encephalopathy
D. Krieger (1995)
10.1073/PNAS.95.3.1148
Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport.
M. Fleming (1998)
10.1079/BJN19790034
Trace nutrients. 2. Manganese in British food.
R. Wenlock (1979)
10.1016/0378-4274(80)90095-8
Neuromelanin in manganese-exposed primates.
S. K. Gupta (1980)
10.1016/S0306-4522(97)00660-X
Manganese: A transition metal protects nigrostriatal neurons from oxidative stress in the iron-induced animal model of Parkinsonism
I. Sziráki (1998)
10.1385/BTER:93:1-3:113
Oxidative stress is induced in the rat brain following repeated inhalation exposure to manganese sulfate
Allison W. Dobson (2007)
10.1016/S0387-7604(98)00074-6
Tremor and seizures associated with chronic manganese intoxication
H. Komaki (1999)
10.1016/S0304-3940(01)02341-2
Manganese induces endoplasmic reticulum (ER) stress and activates multiple caspases in nigral dopaminergic neuronal cells, SN4741
H. Chun (2001)
10.1016/j.brainres.2003.10.066
Expression of the iron transporter ferroportin in synaptic vesicles and the blood–brain barrier
L. J. Wu (2004)
10.1021/BI048768+
Transport of divalent transition-metal ions is lost in small-intestinal tissue of b/b Belgrade rats.
Martin Knöpfel (2005)
10.1023/A:1021994126329
Manganese Decreases Glutamate Uptake in Cultured Astrocytes
A. Hazell (2004)
10.1046/j.1471-4159.1998.71041607.x
Activation of JNK Pathway and Induction of Apoptosis by Manganese in PC12 Cells
Y. Hirata (1998)
10.1046/j.1471-4159.2003.02142.x
The significance of the mutated divalent metal transporter (DMT1) on iron transport into the Belgrade rat brain
T. Moos (2004)
Implications for atypical antioxidative properties of manganese in iron-induced brain lipid peroxidation and copper-dependent low density lipoprotein conjugation.
I. Sziráki (1999)
10.1080/009841099157205
Effect of welding fume solubility on lung macrophage viability and function in vitro.
J. Antonini (1999)
10.1093/AJCN/38.6.936
Tea and coffee as sources of some minerals in the New Zealand diet.
M. F. Gillies (1983)
10.1152/AJPLEGACY.1966.211.1.211
Role of liver in regulating distribution and excretion of manganese.
P. Papavasiliou (1966)
10.1006/exnr.2002.7894
Oxidative Stress Involves in Astrocytic Alterations Induced by Manganese
C. Chen (2002)
10.1080/15298668391405490
Retention and clearance of stainless steel shieldgas welding fumes in rat lungs.
P. Kalliomäki (1983)
10.1136/oem.43.9.592
Dissolution of stainless steel welding fumes in the rat lung: an x ray microanalytical study.
S. Anttila (1986)
Trace nutrients
RW WENLOCK (1979)
10.1016/0006-8993(95)01056-2
Novel protective effect of manganese against ferrous citrate-induced lipid peroxidation and nigrostriatal neurodegeneration in vivo
I. Sziráki (1995)
10.1002/mds.10325
Secondary progressive chronic manganism associated with markedly decreased striatal D2 receptor density
K. Kessler (2003)
10.1016/S0161-813X(02)00013-X
The relationship of particle size to olfactory nerve uptake of a non-soluble form of manganese into brain.
L. Fechter (2002)
DOLAN KG, GARRICK MD, PIANTADOSI CA (2002) Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial
X WANG (2002)
10.1097/01.WCB.0000135592.28823.47
Targeting Anti—Transferrin Receptor Antibody (OX26) and OX26-Conjugated Liposomes to Brain Capillary Endothelial Cells Using In Situ Perfusion
Sara Gosk (2004)
10.1080/08958370490439687
Nasal Toxicity of Manganese Sulfate and Manganese Phosphate in Young Male Rats Following Subchronic (13-Week) Inhalation Exposure
D. Dorman (2004)
10.1016/0021-9681(66)90094-4
Essential trace metals in man: manganese. A study in homeostasis.
H. Schroeder (1966)
10.1002/(SICI)1096-9861(19980810)397:4<437::AID-CNE1>3.0.CO;2-2
Morphological organization of the globus pallidus‐subthalamic nucleus system studied in organotypic cultures
D. Plenz (1998)
Manganese neurotoxicity: a review of clinical features, imaging and pathology.
P. Pal (1999)
10.1002/1097-4547(20000715)61:2<162::AID-JNR7>3.0.CO;2-G
Manganese‐induced rat pheochromocytoma (PC12) cell death is independent of caspase activation
J. Roth (2000)
10.1016/S0163-7258(00)00098-X
Distribution and roles of metabotropic glutamate receptors in the basal ganglia motor circuit: implications for treatment of Parkinson's disease and related disorders.
S. Rouse (2000)
10.1016/J.BCP.2004.08.035
Activation of protein kinase C delta by proteolytic cleavage contributes to manganese-induced apoptosis in dopaminergic cells: protective role of Bcl-2.
M. Kitazawa (2005)
10.1385/BTER:87:1-3:143
Manganese accumulates in iron-deficient rat brain regions in a heterogeneous fashion and is associated with neurochemical alterations
K. Erikson (2007)
10.1016/J.NEURO.2004.06.005
Trigeminal uptake and clearance of inhaled manganese chloride in rats and mice.
J. Lewis (2005)
10.1289/EHP.9297153
Phagolysosomal pH and dissolution of cobalt oxide particles by alveolar macrophages.
M. Lundborg (1992)
10.1289/EHP.9297121
Intracellular particle dissolution in alveolar macrophages.
W. Kreyling (1992)
10.1038/sj.mn.7800213
Identification of a Novel Route of Iron Transcytosis across the Mammalian Blood‐Brain Barrier
Iku Moroo (2003)
10.1016/S0197-0186(96)00146-5
Role of oxidative stress in the manganese and 1-methyl-4-(2′-ethylphenyl)-1,2,3,6-tetrahydropyridine-induced apoptosis in PC12 cells
M. S. Desole (1997)
10.1016/S0041-008X(03)00251-5
Brain barrier systems: a new frontier in metal neurotoxicological research.
W. Zheng (2003)
10.3109/01902149509031744
Phagolysosomal morphology and dissolution of cobalt oxide particles by human and rabbit alveolar macrophages.
M. Lundborg (1995)
10.1212/WNL.57.5.936
Welding-related parkinsonism: Clinical features, treatment, and pathophysiology
G. Pezzoli (2001)
10.1016/0926-6917(95)90058-6
Vulnerability of mitochondrial complex I in PC12 cells exposed to manganese.
P. Galvani (1995)
Nutritional aspects of manganese from experimental studies.
C. Keen (1999)
Nutrition versus toxicology of manganese in humans: evaluation of potential biomarkers.
J. L. Greger (1999)
10.1182/BLOOD.V93.12.4406.412K21_4406_4417
Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron.
F. Canonne-Hergaux (1999)
10.1289/EHP.929717
Pulmonary and thoracic macrophage subpopulations and clearance of particles from the lung.
B. Lehnert (1992)
10.1074/jbc.M112313200
Cloning and Functional Expression of Human Short TRP7, a Candidate Protein for Store-operated Ca2+ Influx*
A. Riccio (2002)
10.1016/S0005-2736(97)00039-4
Manganese transport through human erythrocyte membranes. An EPR study.
C. M. Lucaciu (1997)
10.1016/J.TOXLET.2003.11.004
Cytotoxicity of chromium and manganese to lung epithelial cells in vitro.
L. Pascal (2004)
10.1017/S0317167100038786
Blood manganese correlates with brain magnetic resonance imaging changes in patients with liver disease.
R. Hauser (1996)
10.1016/J.NEURO.2004.09.004
Manganese distribution across the blood-brain barrier. IV. Evidence for brain influx through store-operated calcium channels.
Janelle S. Crossgrove (2005)
10.1212/WNL.47.3.788
Late motor deficits of Chilean manganese miners
F. Hochberg (1996)
10.1289/EHP.929759
Overview of pulmonary alveolar macrophage renewal in normal rats and during different pathological processes.
P. Fritsch (1992)
10.1289/EHP.9297115
Intraphagolysosomal pH in canine and rat alveolar macrophages: flow cytometric measurements.
P. Heilmann (1992)
10.1002/mds.10089
Dopamine transporter density is decreased in parkinsonian patients with a history of manganese exposure: What does it mean?
Y. Kim (2002)



This paper is referenced by
10.1021/es200374c
In vitro assessment of the pulmonary toxicity and gastric availability of lead-rich particles from a lead recycling plant.
G. Uzu (2011)
10.1134/S1990747816040036
Effects of manganese on potassium outflow from erythrocytes and on respiration of rat liver mitochondria
M. Goncharenko (2017)
10.1016/j.neuro.2016.05.014
Effect of manganese and manganese plus noise on auditory function and cochlear structures.
V. P. K. Muthaiah (2016)
10.1093/toxsci/kfp198
Evaluating placental transfer and tissue concentrations of manganese in the pregnant rat and fetuses after inhalation exposures with a PBPK model.
Miyoung Yoon (2009)
10.1201/9781420059984
Transport and biological impact of manganese
K. Erikson (2010)
10.1007/978-1-4419-9663-3_28
Manganese Speciation Related to Neurotoxicity in Humans
Bernhard Michalke (2012)
10.1016/J.ICA.2007.09.008
Manganese neurotoxicity: A bioinorganic chemist’s perspective
L. Quintanar (2008)
10.14393/UFU.DI.2018.1130
Potencial do uso de biossurfactantes no tratamento de água contaminada com metais tóxicos pelo método de extração de fases
Larysse Caixeta Caixeta Ferreira (2017)
10.1021/tx200465e
Metabolomic characterization of laborers exposed to welding fumes.
Kuo-ching Wang (2012)
Exposure to manganese, fetal growth, and neurodevelopment in children living in agricultural communities in Costa Rica and California
Ana M Mora (2014)
10.1007/978-3-319-19018-1_16
Advances in Manganese Pollution and Its Bioremediation
Aradhana Das (2015)
10.1016/j.neuro.2013.11.007
Nicotinamide adenine dinucleotide prevents neuroaxonal degeneration induced by manganese in cochlear organotypic cultures.
L. Wang (2014)
10.17077/ETD.JXTADT3U
Mechanisitic studies of the toxicities of the aryl hydrocarbon receptor agonist PCB126
B. Wang (2011)
10.1371/journal.pone.0030572
Human Tumor Cell Proliferation Evaluated Using Manganese-Enhanced MRI
R. Braun (2012)
10.1016/j.etap.2015.06.016
Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis.
Q. Ye (2015)
10.1016/j.envres.2018.07.007
Airborne manganese exposure and neurobehavior in school‐aged children living near a ferro‐manganese alloy plant
J. L. Rodrigues (2018)
10.1007/s12017-009-8101-2
Manganese Flux Across the Blood–Brain Barrier
R. Yokel (2009)
Ultrastructural study of the hypothalamus in mice chronically treated with manganese
Virginia Villalobos (2010)
Cellular Imaging of Human Embryonic Stem Cells using a New Positive-Contrast Magnetic Resonance Contrast Agent
Andrei Venter (2017)
Biokemijske funkcije i toksičnost mangana te njegove koncentracije u tkivima morskih sisavaca
Maja Đokić (2017)
10.35841/FISHERIES-RESEARCH.3.2.10-14
Ecological and health risk from heavy metal exposure to fish.
Olawusi-Peters Oo (2019)
10.1016/j.neuro.2012.10.009
Genetic risk for Parkinson's disease correlates with alterations in neuronal manganese sensitivity between two human subjects.
A. A. Aboud (2012)
10.1016/j.neuro.2011.01.003
α-Synuclein, leucine-rich repeat kinase-2, and manganese in the pathogenesis of Parkinson disease.
Jason P. Covy (2011)
10.1586/14737175.7.12.1693
Molecular pathways and genetic aspects of Parkinson’s disease: from bench to bedside
M. Di Napoli (2007)
10.17077/ETD.4MUY9XNY
Protein reactivity of 3,4-dihydroxyphenylacetaldehyde, an endogenous, potential neurotoxin relevant to Parkinson's disease
J. N. Rees (2009)
10.1016/j.exger.2014.08.002
Protein molecular forms of insulin-like growth factor binding protein-2 change with aging
M. Šunderić (2014)
10.1172/JCI90896
Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity
Wen Lin (2017)
10.1002/9781119951438.EIBC2139
Manganese in Neurodegeneration
D. Ávila (2013)
10.1002/anie.201002853
Discrimination between hard metals with soft ligand donor atoms: an on-fluorescence probe for manganese(II).
J. Liang (2010)
10.1093/toxsci/kfn231
Ceruloplasmin alters the tissue disposition and neurotoxicity of manganese, but not its loading onto transferrin.
T. Jursa (2009)
10.2478/v10102-010-0001-7
Protective effects of manganese(II) chloride on hyaluronan degradation by oxidative system ascorbate plus cupric chloride
K. Valachová (2010)
10.1007/s00204-017-1932-y
Are multitasking abilities impaired in welders exposed to manganese? Translating cognitive neuroscience to neurotoxicology
C. van Thriel (2017)
See more
Semantic Scholar Logo Some data provided by SemanticScholar