Manganese (Mn), iron (Fe), zinc (Zn), and copper (Cu) are essential transitions metals that are required in trace amounts, however chronic exposure to high concentrations can cause severe and irreversible neurotoxicity. Since prolonged exposure to Mn leads to manganism, a disorder exhibiting a diverse array of neurological impairments progressing to a debilitating and irreversible extrapyramidal condition symptomatically similar to Parkinson’s disease, we measured the concentration of Mn as well as Fe, Zn and Cu in three region of the brain (globus pallidus, striatum and inferior colliculus) and three regions in the cochlea (stria vascularis, basilar membrane and modiolus) under normal conditions or after 30 or 60 days of oral administration of Mn (10 mg/ml ad libitum). Under normal conditions, Mn, Zn and Fe were typically higher in the cochlea than in the three brain regions whereas Cu was equal to or lower. Oral treatment with Mn for 30 or 60 days resulted in 20–75 % increases in Mn concentrations in both cochlea and brain samples, but had little effect on Cu and Fe levels. In contrast, Zn levels decreased (20–80 %) with Mn exposure. Our results show for the first time how prolonged oral Mn-ingestion affects the concentration of Mn, Cu, Zn and Fe, in the three regions of the cochlea, the inferior colliculus in auditory midbrain and the striatum and globus pallidus, two regions implicated in Parkinson’s disorder. The Mn-induced changes in the concentration of Mn, Cu, Zn and Fe may provide new insights relevant to the neurotoxicity of Mn and the transport and accumulation of these metals in cochlea and brain.
Manganese ICP-MS Trace analysis Cochlea Iron Copper Zinc
This is a preview of subscription content, log in to check access.
Research supported by National Institute for Occupational Safety and Health (NIOSH) award #R010HH010311-01. We acknowledge the National Science Foundation Major Research Instrumentation Program CHE0959565 for the ICP-MS. We are grateful to the Colón lab for the use of the microbalance.
Compliance with ethical standards
Conflict of Interest
The authors state that they have no conflicts of interest that affect the objectivity of this publication.
Aschner M (1997) Manganese neurotoxicity and oxidative damage. In: Connor JR (ed) Metals and oxidative damage in neurological disorders. Plenum, New York, pp 77–93CrossRefGoogle Scholar
Bouchard M, Mergler D, Baldwin ME, Panisset M (2008) Manganese cumulative exposure and symptoms: a follow-up study of alloy workers. Neurotoxicology 29:577–583CrossRefPubMedGoogle Scholar
Canonne-Hergaux F, Gruenheid S, Ponka P, Gros P (1999) Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 93:4406–4417PubMedGoogle Scholar
da Silva CJ, da Rocha AJ, Jeronymo S et al (2007) A preliminary study revealing a new association in patients undergoing maintenance hemodialysis: manganism symptoms and T1 hyperintense changes in the basal ganglia. Am J Neuroradiol 28:1474–1479CrossRefPubMedGoogle Scholar
Davidsson L, Cederblad A, Lonnerdal B, Sandstrom B (1989) Manganese retention in man: a method for estimating manganese absorption in man. Am J Clin Nutr 49:170–179PubMedGoogle Scholar
Ding D, Roth J, Salvi R (2014) Cellular localization and developmental changes of Zip8, Zip14 and transferrin receptor 1 in the inner ear of rats. Biometals 27:731–744CrossRefPubMedGoogle Scholar
Erikson KA, Shihabi ZK, Aschner JL, Aschner M (2002) Manganese accumulates in iron-deficient rat brain regions in a heterogeneous fashion and is associated with neurochemical alterations. Biol Trace Elem Res 87:143–156CrossRefPubMedGoogle Scholar
Eybalin M, Norenberg MD, Renard N (1996) Glutamine synthetase and glutamate metabolism in the guinea pig cochlea. Hear Res 101:93–101CrossRefPubMedGoogle Scholar
Garcia SJ, Gellein K, Syversen T, Aschner M (2006) A manganese-enhanced diet alters brain metals and transporters in the developing rat. Toxicol Sci 92:516–525CrossRefPubMedGoogle Scholar
Johnson PE, Lykken GI, Korynta ED (1991) Absorption and biological half-life in humans of intrinsic and extrinsic 54Mn tracers from foods of plant origin. J Nutr 121:711–717PubMedGoogle Scholar
Joly A, Lambert J, Gagnon C, Kennedy G, Mergler D, Adam-Poupart A (2011) Reduced atmospheric manganese in Montreal following removal of methylcyclopentadienyl manganese tricarbonyl (MMT). Water Air Soil Pollut 219:263–270CrossRefGoogle Scholar
Josephs KA, Ahlskog JE, Klos KJ, Kumar N, Fealey RD, Trenerry MR, Cowl CT (2005) Neurologic manifestations in welders with pallidal MRI T1 hyperintensity. Neurology 64:2033–2039CrossRefPubMedGoogle Scholar
Lin C, Zhang Z, Wang T, Chen C, James Kang Y (2015) Copper uptake by DMT1: a compensatory mechanism for CTR1 deficiency in human umbilical vein endothelial cells. Metallomics 7:1285–1289CrossRefPubMedGoogle Scholar
Mena I, Horiuchi K, Burke K, Cotzias GC (1969) Chronic manganese poisoning. Individual susceptibility and absorption of iron. Neurology 19:1000–1006CrossRefPubMedGoogle Scholar
Mergler D, Baldwin M (1997) Early manifestations of manganese neurotoxicity in humans: an update. Environ Res 73:92–100CrossRefPubMedGoogle Scholar
Moreno T, Pandolfi M, Querol X, Lavin J, Alastuey A, Viana M, Gibbons Q (2011) Manganese in the urban atmosphere: identifying anomalous concentrations and sources. Environ Sci Pollut Res 18:173–183CrossRefGoogle Scholar
Olanow CW, Good PF, Shinotoh H et al (1996) Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study. Neurology 46:492–498CrossRefPubMedGoogle Scholar
Pal PK, Samii A, Calne DB (1999) Manganese neurotoxicity: a review of clinical features, imaging and pathology. Neurotoxicology 20:227–238PubMedGoogle Scholar
Quadri M, Federico A, Zhao T et al (2012) Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet 90:467–477PubMedCentralCrossRefPubMedGoogle Scholar
Reaney SH, Bench G, Smith DR (2006) Brain accumulation and toxicity of Mn(II) and Mn(III) exposures. Toxicol Sci 93:114–124CrossRefPubMedGoogle Scholar
Sarkar P, Fischman D, Goldwasser E, Moscona A (1972) Isolation and characterization of glutamine synthetasefrom chicken neural retina. J Biol Chem 247:7743–7749PubMedGoogle Scholar
Schroeder HA, Balassa JJ, Tipton IH (1966) Essential trace metals in man: manganese. A study in homeostasis. J Chron Dis 19:545–571CrossRefPubMedGoogle Scholar
Stamelou M, Tuschl K, Chong WK, Burroughs AK, Mills PB, Bhatia KP, Clayton PT (2012) Dystonia with brain manganese accumulation resulting from SLC30A10 mutations: a new treatable disorder. Movement Disord 27:1317–1322PubMedCentralCrossRefPubMedGoogle Scholar
Wedler F, Denman R (1984) Glutamine synthetase: the major Mn(II) enzyme in mammalian brain. Curr Top Cell Regul 24:153–169CrossRefPubMedGoogle Scholar
Wegst-Uhrich SR, Mullin EJ, Ding D, Manohar S, Salvi R, Aga DS, Roth J (2015) Endogenous concentrations of biologically relevant metals in rat brain and cochlea determined by inductively coupled plasma mass spectrometry. Biometals 28:187–196CrossRefPubMedGoogle Scholar
Zheng G, Chen J, Zheng W (2012) Relative contribution of CTR1 and DMT1 in copper transport by the blood-CSF barrier: implication in manganese-induced neurotoxicity. Toxicol Appl Pharmacol 260:285–293PubMedCentralCrossRefPubMedGoogle Scholar