Skip to main content
SpringerLink
Log in

Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water

  • Inorganic Compounds
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e., mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) levels, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post-Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Ageta H, Murayama A, Migishima R, Kida S, Tsuchida K, Yokoyama M, Inokuchi K (2008) Activin in the brain modulates anxiety-related behavior and adult neurogenesis. PLoS ONE 3(4):e1869. doi:10.1371/journal.pone.0001869

    PubMed Central  PubMed  Google Scholar 

  • Anderson JG, Fordahl SC, Cooney PT, Weaver TL, Colyer CL, Erikson KM (2008) Manganese exposure alters extracellular GABA, GABA receptor and transporter protein and mRNA levels in the developing rat brain. Neurotoxicology 29(6):1044–1053. doi:10.1016/j.neuro.2008.08.002

    CAS  PubMed Central  PubMed  Google Scholar 

  • Antonini JM, Sriram K, Benkovic SA, Roberts JR, Stone S, Chen BT, Schwegler-Berry D, Jefferson AM, Billig BK, Felton CM, Hammer MA, Ma F, Frazer DG, O’Callaghan JP, Miller DB (2009) Mild steel welding fume causes manganese accumulation and subtle neuroinflammatory changes but not overt neuronal damage in discrete brain regions of rats after short-term inhalation exposure. Neurotoxicology 30(6):915–925. doi:10.1016/j.neuro.2009.09.006

    CAS  PubMed  Google Scholar 

  • Aschner M (2000) Manganese: brain transport and emerging research needs. Environ Health Perspect 108(Suppl 3):429–432. doi:10.1289/ehp.00108s3429

    CAS  PubMed Central  PubMed  Google Scholar 

  • Aschner M, Erikson KM, Dorman DC (2005) Manganese dosimetry: species differences and implications for neurotoxicity. Crit Rev Toxicol 35(1):1–32. doi:10.1080/10408440590905920

    CAS  PubMed  Google Scholar 

  • Aschner M, Erikson KM, Herrero Hernandez E, Tjalkens R (2009) Manganese and its role in Parkinson’s disease: from transport to neuropathology. Neuromol Med 11(4):252–266. doi:10.1007/s12017-009-8083-0

    CAS  Google Scholar 

  • Avila DS, Colle D, Gubert P, Palma AS, Puntel G, Manarin F, Noremberg S, Nascimento PC, Aschner M, Rocha JB, Soares FA (2010) A possible neuroprotective action of a vinylic telluride against Mn-induced neurotoxicity. Toxicol Sci 115(1):194–201. doi:10.1093/toxsci/kfq036

    CAS  PubMed  Google Scholar 

  • Bagga P, Patel AB (2012) Regional cerebral metabolism in mouse under chronic manganese exposure: implications for Manganism. Neurochem Int 60(2):177–185. doi:10.1016/j.neuint.2011.10.016

    CAS  PubMed  Google Scholar 

  • Belmaker RH, Agam G (2008) Major depressive disorder. N Engl J Med 358(1):55–68. doi:10.1056/NEJMra073096

    CAS  PubMed  Google Scholar 

  • Blecharz-Klin K, Piechal A, Joniec-Maciejak I, Pyrzanowska J, Widy-Tyszkiewicz E (2012) Effect of intranasal manganese administration on neurotransmission and spatial learning in rats. Toxicol Appl Pharmacol 265(1):1–9. doi:10.1016/j.taap.2012.09.015

    CAS  PubMed  Google Scholar 

  • Bock NA, Paiva FF, Nascimento GC, Newman JD, Silva AC (2008) Cerebrospinal fluid to brain transport of manganese in a non-human primate revealed by MRI. Brain Res 1198:160–170. doi:10.1016/j.brainres.2007.12.065

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bonilla E, Prasad AL (1984) Effects of chronic manganese intake on the levels of biogenic amines in rat brain regions. Neurobehav Toxicol Teratol 6(5):341–344

    CAS  PubMed  Google Scholar 

  • Bouchard M, Laforest F, Vandelac L, Bellinger D, Mergler D (2007) Hair manganese and hyperactive behaviors: pilot study of school-age children exposed through tap water. Environ Health Perspect 115(1):122–127. doi:10.1289/ehp.9504

    CAS  PubMed Central  PubMed  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(1):138–143. doi:10.1289/ehp.1002321

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bowler RM, Gysens S, Diamond E, Booty A, Hartney C, Roels HA (2003) Neuropsychological sequelae of exposure to welding fumes in a group of occupationally exposed men. Int J Hyg Environ Health 206(6):517–529. doi:10.1078/1438-4639-00249

    PubMed  Google Scholar 

  • Bowler RM, Gysens S, Diamond E, Nakagawa S, Drezgic M, Roels HA (2006) Manganese exposure: neuropsychological and neurological symptoms and effects in welders. Neurotoxicology 27(3):315–326. doi:10.1016/j.neuro.2005.10.007

    CAS  PubMed  Google Scholar 

  • Burton NC, Schneider JS, Syversen T, Guilarte TR (2009) Effects of chronic manganese exposure on glutamatergic and GABAergic neurotransmitter markers in the nonhuman primate brain. Toxicol Sci 111(1):131–139. doi:10.1093/toxsci/kfp124

    CAS  PubMed  Google Scholar 

  • Calabresi P, Ammassari-Teule M, Gubellini P, Sancesario G, Morello M, Centonze D, Marfia GA, Saulle E, Passino E, Picconi B, Bernardi G (2001) A synaptic mechanism underlying the behavioral abnormalities induced by manganese intoxication. Neurobiol Dis 8(3):419–432. doi:10.1006/nbdi.2000.0379

    CAS  PubMed  Google Scholar 

  • Cersosimo MG, Koller WC (2006) The diagnosis of manganese-induced parkinsonism. Neurotoxicology 27(3):340–346. doi:10.1016/j.neuro.2005.10.006

    CAS  PubMed  Google Scholar 

  • Chaki H, Furuta S, Matsuda A, Yamauchi K, Yamamoto K, Kokuba Y, Fujibayashi Y (2000) Magnetic resonance image and blood manganese concentration as indices for manganese content in the brain of rats. Biol Trace Elem Res 74(3):245–257. doi:10.1385/BTER:74:3:245

    CAS  PubMed  Google Scholar 

  • Chandra SV, Shukla GS (1981) Concentrations of striatal catecholamines in rats given manganese chloride through drinking water. J Neurochem 36(2):683–687. doi:10.1111/j.1471-4159.1981.tb01642.x

    CAS  PubMed  Google Scholar 

  • Chandra SV, Shukla GS, Saxena DK (1979) Manganese-induced behavioral dysfunction and its neurochemical mechanism in growing mice. J Neurochem 33(6):1217–1221. doi:10.1111/j.1471-4159.1979.tb05267.x

    CAS  PubMed  Google Scholar 

  • Coban A, Filipov NM (2007) Dopaminergic toxicity associated with oral exposure to the herbicide atrazine in juvenile male C57BL/6 mice. J Neurochem 100(5):1177–1187. doi:10.1111/j.1471-4159.2006.04294.x

    CAS  PubMed  Google Scholar 

  • Cordova FM, Aguiar AS Jr, Peres TV, Lopes MW, Goncalves FM, Remor AP, Lopes SC, Pilati C, Latini AS, Prediger RD, Erikson KM, Aschner M, Leal RB (2012) In vivo manganese exposure modulates Erk, Akt and Darpp-32 in the striatum of developing rats, and impairs their motor function. PLoS ONE 7(3):e33057. doi:10.1371/journal.pone.0033057

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cross DJ, Minoshima S, Anzai Y, Flexman JA, Keogh BP, Kim Y, Maravilla KR (2004) Statistical mapping of functional olfactory connections of the rat brain in vivo. Neuroimage 23(4):1326–1335. doi:10.1016/j.neuroimage.2004.07.038

    PubMed  Google Scholar 

  • Deak T, Bellamy C, D’Agostino LG, Rosanoff M, McElderry NK, Bordner KA (2005) Behavioral responses during the forced swim test are not affected by anti-inflammatory agents or acute illness induced by lipopolysaccharide. Behav Brain Res 160(1):125–134. doi:10.1016/j.bbr.2004.11.024

    CAS  PubMed  Google Scholar 

  • Dodd CA, Filipov NM (2011) Manganese potentiates LPS-induced heme-oxygenase 1 in microglia but not dopaminergic cells: role in controlling microglial hydrogen peroxide and inflammatory cytokine output. Neurotoxicology 32(6):683–692. doi:10.1016/j.neuro.2011.09.002

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dodd CA, Ward DL, Klein BG (2005) Basal Ganglia accumulation and motor assessment following manganese chloride exposure in the C57BL/6 mouse. Int J Toxicol 24(6):389–397. doi:10.1080/10915810500366500

    CAS  PubMed  Google Scholar 

  • Dorman DC, Struve MF, Vitarella D, Byerly FL, Goetz J, Miller R (2000) Neurotoxicity of manganese chloride in neonatal and adult CD rats following subchronic (21-day) high-dose oral exposure. J Appl Toxicol 20(3):179–187. doi:10.1002/(SICI)1099-1263(200005/06)20:3<179:AID-JAT631>3.0.CO;2-C

    CAS  PubMed  Google Scholar 

  • Dorman DC, Struve MF, Wong BA, Dye JA, Robertson ID (2006) Correlation of brain magnetic resonance imaging changes with pallidal manganese concentrations in rhesus monkeys following subchronic manganese inhalation. Toxicol Sci 92(1):219–227. doi:10.1093/toxsci/kfj209

    CAS  PubMed  Google Scholar 

  • Erikson KM, Aschner M (2003) Manganese neurotoxicity and glutamate-GABA interaction. Neurochem Int 43(4–5):475–480. doi:10.1016/S0197-0186(03)00037-8

    CAS  PubMed  Google Scholar 

  • Erikson KM, Thompson K, Aschner J, Aschner M (2007) Manganese neurotoxicity: a focus on the neonate. Pharmacol Ther 113(2):369–377. doi:10.1016/j.pharmthera.2006.09.002

    CAS  PubMed Central  PubMed  Google Scholar 

  • Eriksson H, Lenngren S, Heilbronn E (1987) Effect of long-term administration of manganese on biogenic amine levels in discrete striatal regions of rat brain. Arch Toxicol 59(6):426–431. doi:10.1007/BF00316209

    CAS  PubMed  Google Scholar 

  • Eschenko O, Canals S, Simanova I, Beyerlein M, Murayama Y, Logothetis NK (2010) Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: implication for longitudinal studies. Neuroimage 49(3):2544–2555. doi:10.1016/j.neuroimage.2009.10.079

    CAS  PubMed  Google Scholar 

  • Filipov NM, Dodd CA (2012) Role of glial cells in manganese neurotoxicity. J Appl Toxicol 32(5):310–317. doi:10.1002/jat.1762

    CAS  PubMed  Google Scholar 

  • Filipov NM, Seegal RF, Lawrence DA (2005) Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism. Toxicol Sci 84(1):139–148. doi:10.1093/toxsci/kfi055

    CAS  PubMed  Google Scholar 

  • Finkelstein Y, Zhang N, Fitsanakis VA, Avison MJ, Gore JC, Aschner M (2008) Differential deposition of manganese in the rat brain following subchronic exposure to manganese: a T1-weighted magnetic resonance imaging study. Isr Med Assoc J 10(11):793–798

    PubMed  Google Scholar 

  • Fitsanakis VA, Zhang N, Avison MJ, Gore JC, Aschner JL, Aschner M (2006) The use of magnetic resonance imaging (MRI) in the study of manganese neurotoxicity. Neurotoxicology 27(5):798–806. doi:10.1016/j.neuro.2006.03.001

    CAS  PubMed  Google Scholar 

  • Fitsanakis VA, Zhang N, Anderson JG, Erikson KM, Avison MJ, Gore JC, Aschner M (2008) Measuring brain manganese and iron accumulation in rats following 14 weeks of low-dose manganese treatment using atomic absorption spectroscopy and magnetic resonance imaging. Toxicol Sci 103(1):116–124. doi:10.1093/toxsci/kfn019

    CAS  PubMed  Google Scholar 

  • Fordahl S, Cooney P, Qiu Y, Xie G, Jia W, Erikson KM (2012) Waterborne manganese exposure alters plasma, brain, and liver metabolites accompanied by changes in stereotypic behaviors. Neurotoxicol Teratol 34(1):27–36. doi:10.1016/j.ntt.2011.10.003

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gallez B, Baudelet C, Adline J, Geurts M, Delzenne N (1997) Accumulation of manganese in the brain of mice after intravenous injection of manganese-based contrast agents. Chem Res Toxicol 10(4):360–363. doi:10.1021/tx960194p

    CAS  PubMed  Google Scholar 

  • Guilarte TR, Chen MK, McGlothan JL, Verina T, Wong DF, Zhou Y, Alexander M, Rohde CA, Syversen T, Decamp E, Koser AJ, Fritz S, Gonczi H, Anderson DW, Schneider JS (2006a) Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates. Exp Neurol 202(2):381–390. doi:10.1016/j.expneurol.2006.06.015

    CAS  PubMed  Google Scholar 

  • Guilarte TR, McGlothan JL, Degaonkar M, Chen MK, Barker PB, Syversen T, Schneider JS (2006b) Evidence for cortical dysfunction and widespread manganese accumulation in the nonhuman primate brain following chronic manganese exposure: a 1H-MRS and MRI study. Toxicol Sci 94(2):351–358. doi:10.1093/toxsci/kfl106

    CAS  PubMed  Google Scholar 

  • Guilarte TR, Burton NC, McGlothan JL, Verina T, Zhou Y, Alexander M, Pham L, Griswold M, Wong DF, Syversen T, Schneider JS (2008) Impairment of nigrostriatal dopamine neurotransmission by manganese is mediated by pre-synaptic mechanism(s): implications to manganese-induced parkinsonism. J Neurochem 107(5):1236–1247. doi:10.1111/j.1471-4159.2008.05695.x

    CAS  PubMed Central  PubMed  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(7):1107–1112. doi:10.1289/ehp.10051

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hirata Y, Kiuchi K, Nagatsu T (2001) Manganese mimics the action of 1-methyl-4-phenylpyridinium ion, a dopaminergic neurotoxin, in rat striatal tissue slices. Neurosci Lett 311(1):53–56. doi:10.1016/S0304-3940(01)02144-9

    CAS  PubMed  Google Scholar 

  • Hogas M, Ciobica A, Hogas S, Bild V, Hritcu L (2011) The effects of the administration of two different doses of manganese on short-term spatial memory and anxiety-like behavior in rats. Arch Biol Sci 63(4):1031–1036. doi:10.2298/ABS1104031H

    Google Scholar 

  • Jiao Y, Lu L, Williams RW, Smeyne RJ (2012) Genetic dissection of strain dependent paraquat-induced neurodegeneration in the substantia nigra pars compacta. PLoS ONE 7(1):e29447. doi:10.1371/journal.pone.0029447

    CAS  PubMed Central  PubMed  Google 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(12):2033–2039. doi:10.1212/01.WNL.0000167411.93483.A1

    CAS  PubMed  Google Scholar 

  • Kim J, Li Y, Buckett PD, Bohlke M, Thompson KJ, Takahashi M, Maher TJ, Wessling-Resnick M (2012) Iron-responsive olfactory uptake of manganese improves motor function deficits associated with iron deficiency. PLoS ONE 7(3):e33533. doi:10.1371/journal.pone.0033533

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kinawy AA (2009) Impact of gasoline inhalation on some neurobehavioural characteristics of male rats. BMC Physiol 9:21. doi:10.1186/1472-6793-9-21

    PubMed Central  PubMed  Google Scholar 

  • Kondakis XG, Makris N, Leotsinidis M, Prinou M, Papapetropoulos T (1989) Possible health effects of high manganese concentration in drinking water. Arch Environ Health 44(3):175–178. doi:10.1080/00039896.1989.9935883

    CAS  PubMed  Google Scholar 

  • Kontur PJ, Fechter LD (1988) Brain regional manganese levels and monoamine metabolism in manganese-treated neonatal rats. Neurotoxicol Teratol 10(4):295–303. doi:10.1016/0892-0362(88)90031-1

    CAS  PubMed  Google Scholar 

  • Kuo YT, Herlihy AH, So PW, Bhakoo KK, Bell JD (2005) In vivo measurements of T1 relaxation times in mouse brain associated with different modes of systemic administration of manganese chloride. J Magn Reson Imaging 21(4):334–339. doi:10.1002/jmri.20285

    PubMed  Google Scholar 

  • Lai JC, Minski MJ, Chan AW, Leung TK, Lim L (1999) Manganese mineral interactions in brain. Neurotoxicology 20(2–3):433–444

    CAS  PubMed  Google Scholar 

  • Laohaudomchok W, Lin X, Herrick RF, Fang SC, Cavallari JM, Shrairman R, Landau A, Christiani DC, Weisskopf MG (2011) Neuropsychological effects of low-level manganese exposure in welders. Neurotoxicology 32(2):171–179. doi:10.1016/j.neuro.2010.12.014

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lazrishvili I, Bikashvili T, Shukakidze A, Samchkuashvili K, Shavlakadze O (2011) Effect of short-term manganese chloride intoxicatuion on anxiety and fear of young rats. Georgian Med News 11(200):102–106

    CAS  PubMed  Google Scholar 

  • Lee JH, Silva AC, Merkle H, Koretsky AP (2005) Manganese-enhanced magnetic resonance imaging of mouse brain after systemic administration of MnCl2: dose-dependent and temporal evolution of T1 contrast. Magn Reson Med 53(3):640–648. doi:10.1002/mrm.20368

    CAS  PubMed  Google Scholar 

  • Lim GP, Yang F, Chu T, Gahtan E, Ubeda O, Beech W, Overmier JB, Hsiao-Ashec K, Frautschy SA, Cole GM (2001) Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic mice. Neurobiol Aging 22(6):983–991. doi:10.1016/S0197-4580(01)00299-8

    CAS  PubMed  Google Scholar 

  • Liu X, Sullivan KA, Madl JE, Legare M, Tjalkens RB (2006) Manganese-induced neurotoxicity: the role of astroglial-derived nitric oxide in striatal interneuron degeneration. Toxicol Sci 91(2):521–531. doi:10.1093/toxsci/kfj150

    CAS  PubMed  Google Scholar 

  • Liu M, Cai T, Zhao F, Zheng G, Wang Q, Chen Y, Huang C, Luo W, Chen J (2009) Effect of microglia activation on dopaminergic neuronal injury induced by manganese, and its possible mechanism. Neurotox Res 16(1):42–49. doi:10.1007/s12640-009-9045-x

    CAS  PubMed  Google Scholar 

  • Ljung K, Vahter M (2007) Time to re-evaluate the guideline value for manganese in drinking water? Environ Health Perspect 115(11):1533–1538. doi:10.1289/ehp.10316

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lucchini RG, Martin CJ, Doney BC (2009) From manganism to manganese-induced parkinsonism: a conceptual model based on the evolution of exposure. Neuromol Med 11(4):311–321. doi:10.1007/s12017-009-8108-8

    CAS  Google Scholar 

  • Malheiros JM, Polli RS, Paiva FF, Longo BM, Mello LE, Silva AC, Tannus A, Covolan L (2012) Manganese-enhanced magnetic resonance imaging detects mossy fiber sprouting in the pilocarpine model of epilepsy. Epilepsia 53(7):1225–1232. doi:10.1111/j.1528-1167.2012.03521.x

    CAS  PubMed Central  PubMed  Google Scholar 

  • McLaughlin P, Zhou Y, Ma T, Liu J, Zhang W, Hong JS, Kovacs M, Zhang J (2006) Proteomic analysis of microglial contribution to mouse strain-dependent dopaminergic neurotoxicity. Glia 53(6):567–582. doi:10.1002/glia.20294

    PubMed  Google Scholar 

  • Messiha FS (1990) Behavioral genetic analysis of regional mouse brain biogenic amines, acidic metabolites and motor activity. Comp Biochem Physiol C 96(2):389–392. doi:10.1016/0742-8413(90)90027-7

    CAS  PubMed  Google Scholar 

  • Milatovic D, Zaja-Milatovic S, Gupta RC, Yu Y, Aschner M (2009) Oxidative damage and neurodegeneration in manganese-induced neurotoxicity. Toxicol Appl Pharmacol 240(2):219–225. doi:10.1016/j.taap.2009.07.004

    CAS  PubMed Central  PubMed  Google Scholar 

  • Miller G, Neilan M, Chia R, Gheryani N, Holt N, Charbit A, Wells S, Tucci V, Lalanne Z, Denny P, Fisher EM, Cheeseman M, Askew GN, Dear TN (2010) ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2. PLoS ONE 5(2):e9137. doi:10.1371/journal.pone.0009137

    PubMed Central  PubMed  Google Scholar 

  • Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78(1):189–225

    CAS  PubMed  Google Scholar 

  • Moreno JA, Yeomans EC, Streifel KM, Brattin BL, Taylor RJ, Tjalkens RB (2009) Age-dependent susceptibility to manganese-induced neurological dysfunction. Toxicol Sci 112(2):394–404. doi:10.1093/toxsci/kfp220

    CAS  PubMed  Google Scholar 

  • Moreno JA, Streifel KM, Sullivan KA, Hanneman WH, Tjalkens RB (2011) Manganese-induced NF-kappaB activation and nitrosative stress is decreased by estrogen in juvenile mice. Toxicol Sci 122(1):121–133. doi:10.1093/toxsci/kfr091

    CAS  PubMed  Google Scholar 

  • Mosienko V, Bert B, Beis D, Matthes S, Fink H, Bader M, Alenina N (2012) Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin. Transl Psychiatry 2:e122. doi:10.1038/tp.2012.44

    CAS  PubMed Central  PubMed  Google Scholar 

  • Olanow CW, Good PF, Shinotoh H, Hewitt KA, Vingerhoets F, Snow BJ, Beal MF, Calne DB, Perl DP (1996) Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study. Neurology 46(2):492–498. doi:10.1212/WNL.46.2.492

    CAS  PubMed  Google Scholar 

  • Pal PK, Samii A, Calne DB (1999) Manganese neurotoxicity: a review of clinical features, imaging and pathology. Neurotoxicology 20(2–3):227–238

    CAS  PubMed  Google Scholar 

  • Pappas BA, Zhang D, Davidson CM, Crowder T, Park GA, Fortin T (1997) Perinatal manganese exposure: behavioral, neurochemical, and histopathological effects in the rat. Neurotoxicol Teratol 19(1):17–25. doi:10.1016/S0892-0362(96)00185-7

    CAS  PubMed  Google Scholar 

  • Parenti M, Flauto C, Parati E, Vescovi A, Groppetti A (1986) Manganese neurotoxicity: effects of L-DOPA and pargyline treatments. Brain Res 367(1–2):8–13. doi:10.1016/0006-8993(86)91571-4

    CAS  PubMed  Google Scholar 

  • Park JD, Chung YH, Kim CY, Ha CS, Yang SO, Khang HS, Yu IK, Cheong HK, Lee JS, Song CW, Kwon IH, Han JH, Sung JH, Heo JD, Choi BS, Im R, Jeong J, Yu IJ (2007) Comparison of high MRI T1 signals with manganese concentration in brains of cynomolgus monkeys after 8 months of stainless steel welding-fume exposure. Inhal Toxicol 19(11):965–971. doi:10.1080/08958370701516108

    CAS  PubMed  Google Scholar 

  • Perl DP, Olanow CW (2007) The neuropathology of manganese-induced Parkinsonism. J Neuropathol Exp Neurol 66(8):675–682. doi:10.1097/nen.0b013e31812503cf

    CAS  PubMed  Google Scholar 

  • Perona MT, Waters S, Hall FS, Sora I, Lesch KP, Murphy DL, Caron M, Uhl GR (2008) Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions. Behav Pharmacol 19(5–6):566–574. doi:10.1097/FBP.0b013e32830cd80f

    CAS  PubMed Central  PubMed  Google Scholar 

  • Petit-Demouliere B, Chenu F, Bourin M (2005) Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology 177(3):245–255. doi:10.1007/s00213-004-2048-7

    CAS  PubMed  Google Scholar 

  • Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463(1–3):3–33. doi:10.1016/S0014-2999(03)01272-X

    CAS  PubMed  Google Scholar 

  • Rajput AH, Rozdilsky B, Rajput A (1991) Accuracy of clinical diagnosis in parkinsonism–a prospective study. Can J Neurol Sci 18(3):275–278

    CAS  PubMed  Google Scholar 

  • Royl G, Balkaya M, Lehmann S, Lehnardt S, Stohlmann K, Lindauer U, Endres M, Dirnagl U, Meisel A (2009) Effects of the PDE5-inhibitor vardenafil in a mouse stroke model. Brain Res 1265:148–157. doi:10.1016/j.brainres.2009.01.061

    CAS  PubMed  Google Scholar 

  • Salehi F, Krewski D, Mergler D, Normandin L, Kennedy G, Philippe S, Zayed J (2003) Bioaccumulation and locomotor effects of manganese phosphate/sulfate mixture in Sprague-Dawley rats following subchronic (90 days) inhalation exposure. Toxicol Appl Pharmacol 191(3):264–271. doi:10.1016/S0041-008X(03)00238-2

    CAS  PubMed  Google Scholar 

  • Santos D, Milatovic D, Andrade V, Batoreu MC, Aschner M, Marreilha dos Santos AP (2012) The inhibitory effect of manganese on acetylcholinesterase activity enhances oxidative stress and neuroinflammation in the rat brain. Toxicology 292(2–3):90–98. doi:10.1016/j.tox.2011.11.017

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schneider JS, Decamp E, Koser AJ, Fritz S, Gonczi H, Syversen T, Guilarte TR (2006) Effects of chronic manganese exposure on cognitive and motor functioning in non-human primates. Brain Res 1118(1):222–231. doi:10.1016/j.brainres.2006.08.054

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sedelis M, Hofele K, Auburger GW, Morgan S, Huston JP, Schwarting RK (2000) MPTP susceptibility in the mouse: behavioral, neurochemical, and histological analysis of gender and strain differences. Behav Genet 30(3):171–182. doi:10.1023/A:1001958023096

    CAS  PubMed  Google Scholar 

  • Selikhova M, Fedoryshyn L, Matviyenko Y, Komnatska I, Kyrylchuk M, Krolicki L, Friedman A, Taylor A, Jager HR, Lees A, Sanotsky Y (2008) Parkinsonism and dystonia caused by the illicit use of ephedrone–a longitudinal study. Mov Disord 23(15):2224–2231. doi:10.1002/mds.22290

    PubMed  Google Scholar 

  • Sen S, Flynn MR, Du G, Troster AI, An H, Huang X (2011) Manganese accumulation in the olfactory bulbs and other brain regions of “asymptomatic” welders. Toxicol Sci 121(1):160–167. doi:10.1093/toxsci/kfr033

    CAS  PubMed  Google Scholar 

  • Shinotoh H, Snow BJ, Hewitt KA, Pate BD, Doudet D, Nugent R, Perl DP, Olanow W, Calne DB (1995) MRI and PET studies of manganese-intoxicated monkeys. Neurology 45(6):1199–1204

    CAS  PubMed  Google Scholar 

  • Shukla GS, Chandra SV (1981) Striatal dopamine turnover and L-dopa treatment after short-term exposure of rats to manganese. Arch Toxicol 47(3):191–196

    CAS  PubMed  Google Scholar 

  • Sotnikova TD, Beaulieu JM, Barak LS, Wetsel WC, Caron MG, Gainetdinov RR (2005) Dopamine-independent locomotor actions of amphetamines in a novel acute mouse model of Parkinson disease. PLoS Biol 3(8):e271. doi:10.1371/journal.pbio.0030271

    PubMed Central  PubMed  Google Scholar 

  • Staropoli JF, Haliw L, Biswas S, Garrett L, Holter SM, Becker L, Skosyrski S, Da Silva-Buttkus P, Calzada-Wack J, Neff F, Rathkolb B, Rozman J, Schrewe A, Adler T, Puk O, Sun M, Favor J, Racz I, Bekeredjian R, Busch DH, Graw J, Klingenspor M, Klopstock T, Wolf E, Wurst W, Zimmer A, Lopez E, Harati H, Hill E, Krause DS, Guide J, Dragileva E, Gale E, Wheeler VC, Boustany RM, Brown DE, Breton S, Ruether K, Gailus-Durner V, Fuchs H, de Angelis MH, Cotman SL (2012) Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system. PLoS ONE 7(6):e38310. doi:10.1371/journal.pone.0038310

    CAS  PubMed Central  PubMed  Google Scholar 

  • St-Pierre A, Normandin L, Carrier G, Kennedy G, Butterworth R, Zayed J (2001) Bioaccumulation and locomotor effect of manganese dust in rats. Inhal Toxicol 13(7):623–632. doi:10.1080/08958370117066

    CAS  PubMed  Google Scholar 

  • Struve MF, McManus BE, Wong BA, Dorman DC (2007) Basal ganglia neurotransmitter concentrations in rhesus monkeys following subchronic manganese sulfate inhalation. Am J Ind Med 50(10):772–778. doi:10.1002/ajim.20489

    CAS  PubMed  Google Scholar 

  • Subhash MN, Padmashree TS (1991) Effect of manganese on biogenic amine metabolism in regions of the rat brain. Food Chem Toxicol 29(8):579–582. doi:10.1016/0278-6915(91)90051-8

    CAS  PubMed  Google Scholar 

  • Takeda A (2003) Manganese action in brain function. Brain Res Brain Res Rev 41(1):79–87. doi:10.1016/S0165-0173(02)00234-5

    CAS  PubMed  Google Scholar 

  • Takeuchi H, Iba M, Inoue H, Higuchi M, Takao K, Tsukita K, Karatsu Y, Iwamoto Y, Miyakawa T, Suhara T, Trojanowski JQ, Lee VM, Takahashi R (2011) P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating. PLoS ONE 6(6):e21050. doi:10.1371/journal.pone.0021050

    CAS  PubMed Central  PubMed  Google Scholar 

  • Talavera EJ, Arcaya JL, Giraldoth D, Suarez J, Bonilla E (1999) Decrease in spontaneous motor activity and in brain lipid peroxidation in manganese and melatonin treated mice. Neurochem Res 24(5):705–708. doi:10.1023/A:1021064711866

    CAS  PubMed  Google Scholar 

  • Tomas-Camardiel M, Herrera AJ, Venero JL, Cruz Sanchez-Hidalgo M, Cano J, Machado A (2002) Differential regulation of glutamic acid decarboxylase mRNA and tyrosine hydroxylase mRNA expression in the aged manganese-treated rats. Brain Res Mol Brain Res 103(1–2):116–129. doi:10.1016/S0169-328X(02)00192-4

    CAS  PubMed  Google Scholar 

  • Torrente M, Colomina MT, Domingo JL (2002) Effects of prenatal exposure to manganese on postnatal development and behavior in mice: influence of maternal restraint. Neurotoxicol Teratol 24(2):219–225. doi:10.1016/S0892-0362(02)00188-5

    CAS  PubMed  Google Scholar 

  • Tran TT, Chowanadisai W, Lonnerdal B, Le L, Parker M, Chicz-Demet A, Crinella FM (2002) Effects of neonatal dietary manganese exposure on brain dopamine levels and neurocognitive functions. Neurotoxicology 23(4–5):645–651. doi:10.1016/S0161-813X(02)00068-2

    CAS  PubMed  Google Scholar 

  • Uchino A, Noguchi T, Nomiyama K, Takase Y, Nakazono T, Nojiri J, Kudo S (2007) Manganese accumulation in the brain: MR imaging. Neuroradiology 49(9):715–720. doi:10.1007/s00234-007-0243-z

    CAS  PubMed  Google Scholar 

  • Umezawa M, Kogishi K, Tojo H, Yoshimura S, Seriu N, Ohta A, Takeda T, Hosokawa M (1999) High-linoleate and high-alpha-linolenate diets affect learning ability and natural behavior in SAMR1 mice. J Nutr 129(2):431–437

    CAS  PubMed  Google Scholar 

  • Verina T, Kiihl SF, Schneider JS, Guilarte TR (2011) Manganese exposure induces microglia activation and dystrophy in the substantia nigra of non-human primates. Neurotoxicology 32(2):215–226. doi:10.1016/j.neuro.2010.11.003

    CAS  PubMed Central  PubMed  Google Scholar 

  • Vezer T, Kurunczi A, Naray M, Papp A, Nagymajtenyi L (2007) Behavioral effects of subchronic inorganic manganese exposure in rats. Am J Ind Med 50(11):841–852. doi:10.1002/ajim.20485

    CAS  PubMed  Google Scholar 

  • Vieregge P, Heinzow B, Korf G, Teichert HM, Schleifenbaum P, Mosinger HU (1995) Long term exposure to manganese in rural well water has no neurological effects. Can J Neurol Sci 22(4):286–289

    CAS  PubMed  Google Scholar 

  • Wasserman GA, Liu X, Parvez F, Ahsan H, Levy D, Factor-Litvak P, Kline J, van Geen A, Slavkovich V, LoIacono NJ, Cheng Z, Zheng Y, Graziano JH (2006) Water manganese exposure and children’s intellectual function in Araihazar, Bangladesh. Environ Health Perspect 114(1):124–129. doi:10.1289/ehp.8030

    CAS  PubMed Central  PubMed  Google Scholar 

  • Witholt R, Gwiazda RH, Smith DR (2000) The neurobehavioral effects of subchronic manganese exposure in the presence and absence of pre-parkinsonism. Neurotoxicol Teratol 22(6):851–861. doi:10.1016/S0892-0362(00)00108-2

    CAS  PubMed  Google Scholar 

  • Woolf A, Wright R, Amarasiriwardena C, Bellinger D (2002) A child with chronic manganese exposure from drinking water. Environ Health Perspect 110(6):613–616. doi:10.1289/ehp.02110613

    PubMed Central  PubMed  Google Scholar 

  • Wurtman RJ, Wurtman JJ (1995) Brain serotonin, carbohydrate-craving, obesity and depression. Obes Res 3(Suppl 4):477S–480S

    PubMed  Google Scholar 

  • Zhang S, Fu J, Zhou Z (2004) In vitro effect of manganese chloride exposure on reactive oxygen species generation and respiratory chain complexes activities of mitochondria isolated from rat brain. Toxicol In Vitro 18(1):71–77. doi:10.1016/j.tiv.2003.09.002

    PubMed  Google Scholar 

  • Zhang P, Hatter A, Liu B (2007) Manganese chloride stimulates rat microglia to release hydrogen peroxide. Toxicol Lett 173(2):88–100. doi:10.1016/j.toxlet.2007.06.013

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao F, Cai T, Liu M, Zheng G, Luo W, Chen J (2009) Manganese induces dopaminergic neurodegeneration via microglial activation in a rat model of manganism. Toxicol Sci 107(1):156–164. doi:10.1093/toxsci/kfn213

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This project was supported by a grant from the National Institute of Environmental Health Sciences (R01ES016965), awarded to Nikolay M. Filipov.

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Author notes

  1. Celia A. Dodd

    Present address: Department of Biology, Fort Valley State University, Fort Valley, GA, 31030, USA

Authors and Affiliations

  1. Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602, USA

    Saritha Krishna, Celia A. Dodd & Nikolay M. Filipov

  2. Bio-Imaging Research Center, University of Georgia, Athens, GA, 30602-3013, USA

    Shahryar K. Hekmatyar

Authors
  1. Saritha Krishna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Celia A. Dodd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shahryar K. Hekmatyar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nikolay M. Filipov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nikolay M. Filipov.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 7053 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Krishna, S., Dodd, C.A., Hekmatyar, S.K. et al. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water. Arch Toxicol 88, 47–64 (2014). https://doi.org/10.1007/s00204-013-1088-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-013-1088-3

Keywords

Search

Navigation