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Exposure, epidemiology, and mechanism of the environmental toxicant manganese

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Abstract

It has become increasingly apparent that global manganese (Mn) pollution to air and water is a significant threat to human health. Despite this recognition, research is only beginning to comprehend the detrimental effects of exposure. Mn, while essential, is particularly harmful to the central nervous system, and overexposure is symptomatic of several neurological disorders. At-risk populations have been identified, but it is still unclear whether typical exposure levels have any long-term consequences. Those at an elevated risk have diminished intellectual function, learning and memory, and mental development. While the overall mechanism of toxicity is undetermined, Mn has been found to induce oxidative stress, exacerbate mitochondrial dysfunction, dysregulate autophagy, and promote apoptosis, ultimately enhancing neurodegeneration. Extrapolation of this in vitro and in vivo data to humans is difficult. There is a definite need to correlate epidemiological studies with causative effects. It is imperative that research efforts endure, so threats are appropriately identified and exposure properly regulated.

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References

  • Aisen P, Leibman A, Zweier J (1978) Stoichiometric and site characteristics of the binding of iron to human transferrin. J Biol Chem 253:1930–1937

    CAS  Google Scholar 

  • Angeli S, Barhydt T, Jacobs R, Killilea DW, Lithgow GJ, Andersen JK (2014) Manganese disturbs metal and protein homeostasis in Caenorhabditis elegans. Metallomics 6:1816–1823

    Article  CAS  Google Scholar 

  • Aschner JL, Aschner M (2005) Nutritional aspects of manganese homeostasis. Mol Asp Med 26:353–362

    Article  CAS  Google Scholar 

  • ATSDR (2012) Toxicological profile for manganese (Draft for Public Comment). U.S. Department of Health and Human Services, Public Service

  • Bao XL, Yu RJ, Li ZS, Zhang BL (1991) Twenty-item behavioral neurological assessment for normal newborns in 12 cities of China. Chin Med J 104:742–746

    CAS  Google Scholar 

  • Behrens MI et al (2010) Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with ATP13A2 mutations. Mov Disord 25:1929–1937

    Article  Google Scholar 

  • Bouchard MF, Sauve S, Barbeau B, Legrand M, Brodeur ME, Bouffard T, Limoges E, Bellinger DC, Mergler D (2011) Intellectual impairment in school-age children exposed to manganese from drinking water. Environ Health Perspect 119:138–143

    Article  CAS  Google Scholar 

  • Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ, Beard JL, Connor JR (2001) Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res 66:1198–1207

    Article  CAS  Google Scholar 

  • Butterworth RF (2013) Parkinsonism in cirrhosis: pathogenesis and current therapeutic options. Metab Brain Dis 28:261–267

    Article  CAS  Google Scholar 

  • Carvalho CF, Menezes-Filho JA, de Matos VP, Bessa JR, Coelho-Santos J, Viana GF, Argollo N, Abreu N (2014) Elevated airborne manganese and low executive function in school-aged children in Brazil. Neurotoxicology 45:301–308

    Article  CAS  Google Scholar 

  • Chakraborty S, Martinez-Finley E, Caito S, Chen P, Aschner M (2014) CHAPTER 9 manganese, binding, transport and storage of metal ions in biological cells. R Soc Chem 260–281

  • Chen L, Ding G, Gao Y, Wang P, Shi R, Huang H, Tian Y (2014a) Manganese concentrations in maternal-infant blood and birth weight. Environ Sci Pollut Res Int 21:6170–6175

    Article  CAS  Google Scholar 

  • Chen P, Chakraborty S, Peres TV, Bowman AB, Aschner M (2014) Manganese-induced Neurotoxicity: From C. elegans to Humans. Toxicol Res

  • Chen P, Parmalee N, Aschner M (2014) Genetic factors and manganese-induced neurotoxicity. Front Genet 5

  • Chen P, Chakraborty S, Mukhopadhyay S, Lee E, Paoliello MMB, Bowman AB, Aschner M (2015) Manganese homeostasis in the nervous system. J Neurochem 134:601–610

    Article  CAS  Google Scholar 

  • Chung SE, Cheong HK, Ha EH, Kim BN, Ha M, Kim Y, Hong YC, Park H, Oh SY (2015) Maternal blood manganese and early neurodevelopment: the mothers and children’s environmental health (MOCEH) study. Environ Health Perspect 123:717–722

    Google Scholar 

  • Claus Henn B, Ettinger AS, Schwartz J, Tellez-Rojo MM, Lamadrid-Figueroa H, Hernandez-Avila M, Schnaas L, Amarasiriwardena C, Bellinger DC, Hu H, Wright RO (2010) Early postnatal blood manganese levels and children’s neurodevelopment. Epidemiology 21:433–439

    Article  Google Scholar 

  • Davis CD, Zech L, Greger JL (1993) Manganese metabolism in rats: an improved methodology for assessing gut endogenous losses. Exp Biol Med 202:103–108

    Article  CAS  Google Scholar 

  • de Bie RM, Gladstone RM, Strafella AP, Ko J-H, Lang AE (2007) Manganese-induced Parkinsonism associated with methcathinone (Ephedrone) abuse. Arch Neurol 64:886–889

    Article  Google Scholar 

  • Di Fonzo A et al (2007) ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease. Neurology 68:1557–1562

    Article  Google Scholar 

  • Donaldson J, McGregor D, LaBella F (1982) Manganese neurotoxicity: a model for free radical mediated neurodegeneration? Can J Physiol Pharmacol 60:1398–1405

    Article  CAS  Google Scholar 

  • Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1:191–200

    Article  CAS  Google Scholar 

  • Fernsebner K, Zorn J, Kanawati B, Walker A, Michalke B (2014) Manganese leads to an increase in markers of oxidative stress as well as to a shift in the ratio of Fe(ii)/(iii) in rat brain tissue. Metallomics 6:921–931

    Article  CAS  Google Scholar 

  • Fitsanakis VA, Zhang N, Avison MJ, Erikson KM, Gore JC, Aschner M (2011) Changes in dietary iron exacerbate regional brain manganese accumulation as determined by magnetic resonance imaging. Toxicol Sci Off J Soc Toxicol 120:146–153

    Article  CAS  Google Scholar 

  • Garrick MD, Singleton ST, Vargas F, Kuo H, Zhao L, KNÖPFEL M, Davidson T, Costa M, Paradkar P, Roth JA (2006) DMT1: which metals does it transport? Biol Res 39:79–85

    Article  CAS  Google Scholar 

  • Gavin CE, Gunter KK, Gunter TE (1990) Manganese and calcium efflux kinetics in brain mitochondria. Relevance to manganese toxicity. Biochem J 266:329–334

    Article  CAS  Google Scholar 

  • Gavin CE, Gunter KK, Gunter TE (1999) Manganese and calcium transport in mitochondria: implications for manganese toxicity. Neurotoxicology 20:445–453

    CAS  Google Scholar 

  • Genter MB, Kendig EL, Knutson MD (2009) Uptake of materials from the nasal cavity into the blood and brain. Ann N Y Acad Sci 1170:623–628

    Article  Google Scholar 

  • Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, Caldwell KA, Caldwell GA, Cooper AA, Rochet JC, Lindquist S (2009) Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet 41:308–315

    Article  CAS  Google Scholar 

  • Graham DG (1978) Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol 14:633–643

    CAS  Google Scholar 

  • Guan H, Wang M, Li X, Piao F, Li Q, Xu L, Kitamura F, Yokoyama K (2014) Manganese concentrations in maternal and umbilical cord blood: related to birth size and environmental factors. Eur J Pub Health 24:150–157

    Article  Google Scholar 

  • Gunier RB, Arora M, Jerrett M, Bradman A, Harley KG, Mora AM, Kogut K, Hubbard A, Austin C, Holland N, Eskenazi B (2015) Manganese in teeth and neurodevelopment in young Mexican-American children. Environ Res 142:688–695

    Article  CAS  Google Scholar 

  • Gunter TE, Gerstner B, Gunter KK, Malecki J, Gelein R, Valentine WM, Aschner M, Yule DI (2013) Manganese transport via the transferrin mechanism. NeuroToxicology 34:118–127

    Article  CAS  Google Scholar 

  • Hafeman D, Factor-Litvak P, Cheng Z, van Geen A, Ahsan H (2007) Association between manganese exposure through drinking water and infant mortality in Bangladesh. Environ Health Perspect 115:1107–1112

    Article  CAS  Google Scholar 

  • Haynes EN, Sucharew H, Kuhnell P, Alden J, Barnas M, Wright RO, Parsons PJ, Aldous KM, Praamsma ML, Beidler C, Dietrich KN (2015) Manganese exposure and neurocognitive outcomes in rural school-age children: the communities actively researching exposure study (Ohio, USA). Environ Health Perspect 123:1066–1071

    Article  Google Scholar 

  • Hirata Y, Adachi K, Kiuchi K (1998) Activation of JNK pathway and induction of apoptosis by manganese in PC12 cells. J Neurochem 71:1607–1615

    Article  CAS  Google Scholar 

  • Huang E, Ong WY, Connor JR (2004) Distribution of divalent metal transporter-1 in the monkey basal ganglia. Neuroscience 128:487–496

    Article  CAS  Google Scholar 

  • Leitch S, Feng M, Muend S, Braiterman LT, Hubbard AL, Rao R (2011) Vesicular distribution of secretory pathway Ca(2)+-ATPase isoform 1 and a role in manganese detoxification in liver-derived polarized cells. Biometals Int J Role Metal Ions Biol Biochem Med 24:159–170

    Article  CAS  Google Scholar 

  • Leyva-Illades D, Chen P, Zogzas CE, Hutchens S, Mercado JM, Swaim CD, Morrisett RA, Bowman AB, Aschner M, Mukhopadhyay S (2014) SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its intracellular trafficking and efflux activity. J Neurosci 34:14079–14095

    Article  Google Scholar 

  • Madejczyk MS, Ballatori N (2012a) The iron transporter ferroportin can also function as a manganese exporter. Biochim Biophys Acta 1818:651–657

    Article  CAS  Google Scholar 

  • Madejczyk MS, Ballatori N (2012b) The iron transporter ferroportin can also function as a manganese exporter. Biochim Biophys Acta Biomembr 1818:651–657

    Article  CAS  Google Scholar 

  • Malecki EA (2001) Manganese toxicity is associated with mitochondrial dysfunction and DNA fragmentation in rat primary striatal neurons. Brain Res Bull 55:225–228

    Article  CAS  Google Scholar 

  • Menezes-Filho JA, Novaes Cde O, Moreira JC, Sarcinelli PN, Mergler D (2011) Elevated manganese and cognitive performance in school-aged children and their mothers. Environ Res 111:156–163

    Article  CAS  Google Scholar 

  • Migheli R, Godani C, Sciola L, Delogu MR, Serra PA, Zangani D, De Natale G, Miele E, Desole MS (1999) Enhancing effect of manganese on L‐DOPA‐induced apoptosis in PC12 cells. J Neurochem 73:1155–1163

    Article  CAS  Google Scholar 

  • Moos T, Morgan E (2000) Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol 20:77–95

    Article  CAS  Google Scholar 

  • Mukhopadhyay S, Linstedt AD (2011) Identification of a gain-of-function mutation in a Golgi P-type ATPase that enhances Mn2+ efflux and protects against toxicity. Proc Natl Acad Sci U S A 108:858–863

    Article  CAS  Google Scholar 

  • Mukhopadhyay S, Bachert C, Smith DR, Linstedt AD (2010) Manganese-induced trafficking and turnover of the cis-Golgi glycoprotein GPP130. Mol Biol Cell 21:1282–1292

    Article  CAS  Google Scholar 

  • O’Neal SL, Zheng W (2015) Manganese toxicity upon overexposure: a decade in review. Curr Environ Health Rep 2:315–328

    Article  Google Scholar 

  • Oulhote Y, Mergler D, Barbeau B, Bellinger DC, Bouffard T, Brodeur ME, Saint-Amour D, Legrand M, Sauve S, Bouchard MF (2014) Neurobehavioral function in school-age children exposed to manganese in drinking water. Environ Health Perspect 122:1343–1350

    CAS  Google Scholar 

  • Quadri M, Federico A, Zhao T, Breedveld Guido J, Battisti C, Delnooz C, Severijnen L-A, Di Toro Mammarella L, Mignarri A, Monti L, Sanna A, Lu P, Punzo F, Cossu G, Willemsen R, Rasi F, Oostra Ben A, van de Warrenburg Bart P, Bonifati V (2012) Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet 90:467–477

    Article  CAS  Google Scholar 

  • Reaney S, Smith D (2005) Manganese oxidation state mediates toxicity in PC12 cells. Toxicol Appl Pharmacol 205:271–281

    Article  CAS  Google Scholar 

  • Rink SM, Ardoino G, Queirolo EI, Cicariello D, Manay N, Kordas K (2014) Associations between hair manganese levels and cognitive, language, and motor development in preschool children from Montevideo, Uruguay. Arch Environ Occup Health 69:46–54

    Article  CAS  Google Scholar 

  • Riojas-Rodriguez H, Solis-Vivanco R, Schilmann A, Montes S, Rodriguez S, Rios C, Rodriguez-Agudelo Y (2010) Intellectual function in Mexican children living in a mining area and environmentally exposed to manganese. Environ Health Perspect 118:1465–1470

    Article  CAS  Google Scholar 

  • Roth JA, Feng L, Walowitz J, Browne RW (2000) Manganese‐induced rat pheochromocytoma (PC12) cell death is independent of caspase activation. J Neurosci Res 61:162–171

    Article  CAS  Google Scholar 

  • Roth JA, Horbinski C, Higgins D, Lein P, Garrick MD (2002) Mechanisms of manganese-induced rat pheochromocytoma (PC12) cell death and cell differentiation. NeuroToxicology 23:147–157

    Article  CAS  Google Scholar 

  • Schrantz N, Blanchard DA, Mitenne F, Auffredou M-T, Vazquez A, Leca G (1999) Manganese induces apoptosis of human B cells: caspase-dependent cell death blocked by bcl-2. Cell Death Differ 6:445–453

    Article  CAS  Google Scholar 

  • Seo YA, Li Y, Wessling-Resnick M (2013) Iron depletion increases manganese uptake and potentiates apoptosis through ER stress. NeuroToxicology 38:67–73

    Article  CAS  Google Scholar 

  • Sikk K, Taba P, Haldre S, Bergquist J, Nyholm D, Askmark H, Danfors T, Sörensen J, Thurfjell L, Raininko R (2010) Clinical, neuroimaging and neurophysiological features in addicts with manganese‐ephedrone exposure. Acta Neurol Scand 121:237–243

    Article  CAS  Google Scholar 

  • Smith EA, Newland P, Bestwick KG, Ahmed N (2012) Increased whole blood manganese concentrations observed in children with iron deficiency anaemia. J Trace Elem Med Biol Organ Soc Miner Trace Elem

  • Spangler AH, Spangler JG (2009) Groundwater manganese and infant mortality rate by county in North Carolina: an ecological analysis. Ecohealth 6:596–600

    Article  Google 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. Mov Disord 27:1317–1322

    Article  CAS  Google Scholar 

  • Takser L, Mergler D, Hellier G, Sahuquillo J, Huel G (2003) Manganese, monoamine metabolite levels at birth, and child psychomotor development. Neurotoxicology 24:667–674

    Article  CAS  Google Scholar 

  • Tan J, Zhang T, Jiang L, Chi J, Hu D, Pan Q, Wang D, Zhang Z (2011) Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein. J Biol Chem 286:29654–29662

    Article  CAS  Google Scholar 

  • Ton VK, Mandal D, Vahadji C, Rao R (2002) Functional expression in yeast of the human secretory pathway Ca(2+), Mn(2+)-ATPase defective in Hailey-Hailey disease. J Biol Chem 277:6422–6427

    Article  CAS  Google Scholar 

  • Torres-Agustin R, Rodriguez-Agudelo Y, Schilmann A, Solis-Vivanco R, Montes S, Riojas-Rodriguez H, Cortez-Lugo M, Rios C (2013) Effect of environmental manganese exposure on verbal learning and memory in Mexican children. Environ Res 121:39–44

    Article  CAS  Google Scholar 

  • Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P, Aulakh R, Ribeiro RT, Barsottini OG, Zaki MS, Del Rosario ML, Dyack S, Price V, Rideout A, Gordon K, Wevers RA, Chong WK, Mills PB (2012) Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet 90:457–466

    Article  CAS  Google Scholar 

  • Tuschl K, Mills PB, Clayton PT (2013) Manganese and the brain. Int Rev Neurobiol 110:277–312

    Article  CAS  Google Scholar 

  • Williams K, Wilson MA, Bressler J (2000) Regulation and developmental expression of the divalent metal-ion transporter in the rat brain. Cell Mol Biol (Noisy-le-Grand) 46:563–571

    CAS  Google Scholar 

  • Yin Z, Jiang H, Lee ES, Ni M, Erikson KM, Milatovic D, Bowman AB, Aschner M (2010) Ferroportin is a manganese-responsive protein that decreases manganese cytotoxicity and accumulation. J Neurochem 112:1190–1198

    Article  CAS  Google Scholar 

  • Yu X, Cao L, Yu X (2013) Elevated cord serum manganese level is associated with a neonatal high ponderal index. Environ Res 121:79–83

    Article  CAS  Google Scholar 

  • Yu XD, Zhang J, Yan CH, Shen XM (2014) Prenatal exposure to manganese at environment relevant level and neonatal neurobehavioral development. Environ Res 133:232–238

    Article  CAS  Google Scholar 

  • Zhang J, Cao R, Cai T, Aschner M, Zhao F, Yao T, Chen Y, Cao Z, Luo W, Chen J (2013) The role of autophagy dysregulation in manganese-induced dopaminergic neurodegeneration. Neurotox Res 24:478–490

    Article  CAS  Google Scholar 

  • Zota AR, Ettinger AS, Bouchard M, Amarasiriwardena CJ, Schwartz J, Hu H, Wright RO (2009) Maternal blood manganese levels and infant birth weight. Epidemiology 20:367–373

    Article  Google Scholar 

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    1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

      Pan Chen, Megan Culbreth & Michael Aschner

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    Correspondence to Michael Aschner.

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    Responsible editor: Philippe Garrigues

    Pan Chen and Megan Culbreth contributed equally to this work.

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    Chen, P., Culbreth, M. & Aschner, M. Exposure, epidemiology, and mechanism of the environmental toxicant manganese. Environ Sci Pollut Res 23, 13802–13810 (2016). https://doi.org/10.1007/s11356-016-6687-0

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