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Neurotoxicity of Metal Mixtures

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Neurotoxicity of Metals

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 18))

Abstract

Metals are the oldest toxins known to humans. Metals differ from other toxic substances in that they are neither created nor destroyed by humans (Casarett and Doull’s, Toxicology: the basic science of poisons, 8th edn. McGraw-Hill, London, 2013). Metals are of great importance in our daily life and their frequent use makes their omnipresence and a constant source of human exposure. Metals such as arsenic [As], lead [Pb], mercury [Hg], aluminum [Al] and cadmium [Cd] do not have any specific role in an organism and can be toxic even at low levels. The Substance Priority List of Agency for Toxic Substances and Disease Registry (ATSDR) ranked substances based on a combination of their frequency, toxicity, and potential for human exposure. In this list, As, Pb, Hg, and Cd occupy the first, second, third, and seventh positions, respectively (ATSDR, Priority list of hazardous substances. U.S. Department of Health and Human Services, Public Health Service, Atlanta, 2016). Besides existing individually, these metals are also (or mainly) found as mixtures in various parts of the ecosystem (Cobbina SJ, Chen Y, Zhou Z, Wub X, Feng W, Wang W, Mao G, Xu H, Zhang Z, Wua X, Yang L, Chemosphere 132:79–86, 2015). Interactions among components of a mixture may change toxicokinetics and toxicodynamics (Spurgeon DJ, Jones OAH, Dorne J-L, Svendsen C, Swain S, Stürzenbaum SR, Sci Total Environ 408:3725–3734, 2010) and may result in greater (synergistic) toxicity (Lister LJ, Svendsen C, Wright J, Hooper HL, Spurgeon DJ, Environ Int 37:663–670, 2011). This is particularly worrisome when the components of the mixture individually attack the same organs. On the other hand, metals such as manganese [Mn], iron [Fe], copper [Cu], and zinc [Zn] are essential metals, and their presence in the body below or above homeostatic levels can also lead to disease states (Annangi B, Bonassi S, Marcos R, Hernández A, Mutat Res 770(Pt A):140–161, 2016). Pb, As, Cd, and Hg can induce Fe, Cu, and Zn dyshomeostasis, potentially triggering neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Additionally, changes in heme synthesis have been associated with neurodegeneration, supported by evidence that a decline in heme levels might explain the age-associated loss of Fe homeostasis (Atamna H, Killile DK, Killile NB, Ames BN, Proc Natl Acad Sci U S A 99(23):14807–14812, 2002).

The sources, disposition, transport to the brain, mechanisms of toxicity, and effects in the central nervous system (CNS) and in the hematopoietic system of each one of these metals will be described. More detailed information on Pb, Mn, Al, Hg, Cu, and Zn is available in other chapters. A major focus of the chapter will be on Pb toxicity and its interaction with other metals.

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References

  • Abboud P, Wilkinson KJ. Role of metal mixtures (Ca, Cu and Pb) on Cd bioaccumulation and phytochelatin production by Chlamydomonas reinhardtii. Environ Pollut. 2013;179:33–8.

    Article  CAS  PubMed  Google Scholar 

  • Abdulla M, Svensson S, Haeger-Aronsen B. Antagonistic effects of zinc and aluminum on lead inhibition of delta-aminolevulinic acid dehydratase.Arch. Environ Health. 1979;34(6):464–9.

    Article  CAS  Google Scholar 

  • Abreo K, Glass J, Sella M. Aluminum inhibits hemoglobin synthesis but enhances iron uptake in friend erythroleukemia cells. Kidney Int. 1990;37:677–81.

    Article  CAS  PubMed  Google Scholar 

  • Ademuyiwa A, Agarwal R, Chandra R, Behari JR. Effects of sub-chronic low-level lead exposure on the homeostasis of copper and zinc in rat tissues. J Trace Elem Med Biol. 2010;24:207–11.

    Article  CAS  PubMed  Google Scholar 

  • Adhikari A, Penatti CAA, Resende RR, Ulrich H, Britto LRG, Bechara EJH. 5-Aminolevulinate and 4, 5-dioxovalerate ions decrease GABAA receptor density in neuronal cells, synaptosomes and rat brain. Brain Res. 2006;1093:95–104.

    Article  CAS  PubMed  Google Scholar 

  • Adriano DC. Trace elements in terrestrial environments. New York: Eds. Springer; 2001. 867p.

    Book  Google Scholar 

  • Agency for Toxic Substances and Disease Registry. Supplementary guidance for conducting health risk assessment of chemical mixtures, Risk Assessment Forum U.S. Atlanta: U.S. Department of Health and Human Services, Public Health Service; 2000.

    Google Scholar 

  • Agency for Toxic Substances and Disease Registry. Priority list of hazardous substances. Atlanta: U.S. Department of Health and Human Services, Public Health Service. 2016. https://www.atsdr.cdc.gov/spl/, 5th September 2016, 5 pm.

  • Agency for Toxic Substances and Disease Registry (ATSDR). Interaction profile for: lead, manganese, zinc and copper. Atlanta: U.S. Department of Health and Human Services, Public Health Service; 2004.

    Google Scholar 

  • Agency for Toxic Substances and Disease Registry (ATSDR). Arsenic CAS# 7440–38-2. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service; 2007.

    Google Scholar 

  • Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for Cadmium. Atlanta: U.S. Department of Health and Human Services, Public Health Service; 2012.

    Google Scholar 

  • Ali MM, Alia ML, Islam S, Rahman Z. Preliminary assessment of heavy metals in water and sediment of Karnaphuli River. Bangladesh Environ Earth Sci. 2016;73:1837–48.

    Google Scholar 

  • Al-Saleh I, Nester M, Abduljabbar M, Al-Rouqi R, Eltabache C, Al-Rajudi T, Elkhati R. Mercury (Hg) exposure and its effects on Saudi breastfed infant’s neurodevelopment. Int J Hyg Environ Health. 2016;219:129–41.

    Article  CAS  PubMed  Google Scholar 

  • Anderson D. Factors contributing to biomarker responses in exposed workers. Mutat Res. 1999;428:197–202.

    Article  CAS  PubMed  Google Scholar 

  • Andrade V, Mateus ML, Batoréu MC, Aschner M, Marreilha dos Santos AP. Changes in rat urinary porphyrin profiles predict the magnitude of the neurotoxic effects induced by a mixture of lead, arsenic and manganese. Neurotoxicology. 2014a;45:168–77.

    Article  CAS  PubMed  Google Scholar 

  • Andrade V, Mateus ML, Santos D, Aschner M, Batoréu MC, Marreilha dos Santos AP. Arsenic and manganese alter lead deposition in the rat. Biol Trace Elem Res. 2014b;158(3):384–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Angelovicová L, Fazekasová D. Contamination of the soil and water environment by heavy metals in the former mining area of Rudňany (Slovakia). Soil Water Res. 2014;9(1):18–24.

    Google Scholar 

  • Annangi B, Bonassi S, Marcos R, Hernández A. Biomonitoring of humans exposed to arsenic, chromium, nickel, vanadium, and complex mixtures of metals by using the micronucleus test in lymphocytes. Mutat Res. 2016;770(Pt A):140–61.

    Article  CAS  PubMed  Google Scholar 

  • Antonio MT, López N and Leret ML. Pb and Cd poisoning during development alters cerebellar and striatal function in rats. Toxicology. 2002; 176: 59–66.

    Google Scholar 

  • Appel MJ, Kuper CF, Woutersen RA. Disposition, accumulation and toxicity of iron fed as iron (II) sulfate or as sodium iron EDTA in rats. Food Chem Toxicol. 2001;39:261–9.

    Article  CAS  PubMed  Google Scholar 

  • Atamna H, Killile DK, Killile NB, Ames BN. Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. Proc Natl Acad Sci U S A. 2002;99(23):14807–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP, Tanzi R, Bush AI. Characterization of copper interactions with Alzheimer amyloid b peptides: identification of an Attomolar-affinity copper binding site on amyloid b1-42. J Neurochem. 2000;43(2):560–8.

    Google Scholar 

  • Ballatori N. Transport of toxic metals by molecular mimicry. Environ Health Perspect. 2002;110(5):689–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banks WA, Kastin AJ. The aluminum-induced increase in blood-brain barrier permeability to delta-sleep-inducing peptide occurs throughout the brain and is independent of phosphorus and acetylcholinesterase levels. Psychopharmacology. 1985;86(1–2):84–9.

    Article  CAS  PubMed  Google Scholar 

  • Basha R, Wei W, Brydie M, Razmiafshari M, Zawia NH. Lead-induced developmental perturbations in hippocampal Sp1 DNA-binding are prevented by zinc supplementation: in vivo evidence for Pb and Zn competition. Int J Devl Neuroscience. 2003;21:1–12.

    Article  CAS  Google Scholar 

  • Bazzoni GB, Bollini AN, Hernandez GN, Contini MC, Chiarotto MM, Rasia ML. In vivo effect of aluminium upon the physical properties of the erythrocyte membrane. J Inorg Biochem. 2005;99:822–7.

    Article  CAS  PubMed  Google Scholar 

  • Becaria A, Campbell A, Bondy SC. Aluminum and copper interact in the promotion of oxidative but not in? Ammatory events: implications for Alzheimer’s disease. J Alzheimers Dis. 2003;5:31–8.

    Article  CAS  PubMed  Google Scholar 

  • Bleiberg J, Wallen M, Brodkin R, Applebaum IL. Industrially acquired porphyria. Arch Dermatol. 1967;80:793–7.

    Google Scholar 

  • Bondier JR, Michel G, Propper A. Harmful effects of cadmium on olfactory system in mice. Inhal Toxicol. 2008;20(13):1169–77.

    Article  CAS  PubMed  Google Scholar 

  • Bowers MA, Aicher LD, Davis HA, Woods JS. Quantitative determination of porphyrins in rat and human urine and evaluation of urinary porphyrin profiles during mercury and lead exposures. J Lab Clin Med. 1992;120:272–81.

    CAS  PubMed  Google Scholar 

  • Bradberry SM. Metals (cobalt, copper, lead, mercury). Medicine. 2016;44(3):182–4.

    Article  Google Scholar 

  • Brenneman KA, Wong BA, Buccellato MA, Costa ER, Gross EA, Dorman DC. Direct olfactory transport of inhaled manganese (54MnCl2) to the rat brain: toxicokinetic investigations in a unilateral nasal occlusion model. Toxicol Appl Pharmacol. 2000;169:238–48.

    Article  CAS  PubMed  Google Scholar 

  • Buchta M, Kiesswetter E, Schaper M, Zschiesche W, Schaller KH, Kuhlmann A, Letzel S. Neurotoxicity of exposures to aluminium welding fumes in the truck trailer construction industry. Environ Toxicol Pharmacol. 2005;19:677–85.

    Article  CAS  Google Scholar 

  • Calderon J, Ortiz-Perez D, Yanez L, Díaz-Barriga F. Human exposure to metals. Pathways of exposure, biomarkers of effect, and host factors. Ecotoxicol Environ Saf. 2003;56:93–103.

    Article  CAS  PubMed  Google Scholar 

  • Carrizales L, Razoa I, Tellez-Hernandez J, Torres-Nerioa R, Torres A, Batres LE, Cubillas A-C, Díaz-Barriga F. Exposure to arsenic and lead of children living near a copper-smelter in San Luis Potosi, Mexico: Importance of soil contamination for exposure. Environ Res. 2006;101:1–10.

    Article  CAS  PubMed  Google Scholar 

  • Casarett & Doull’s. Toxicology: the basic science of poisons. 8th ed. London: McGraw-Hill; 2013.

    Google Scholar 

  • Ceccatelli S, Daréb E, Moors M. Methylmercury-induced neurotoxicity and apoptosis. Chem Biol Interact. 2010;188:301–8.

    Article  CAS  PubMed  Google Scholar 

  • Chong ZZ, Li F, Maiese K. Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol. 2005;75:207–46.

    Article  CAS  PubMed  Google Scholar 

  • Christensen JM. Human exposure to toxic metals: factors influencing interpretation of biomonitoring results. Sci Total Environ. 1995;166:89–135.

    Article  CAS  PubMed  Google Scholar 

  • Clarkson TW, Vyas JB, Ballatori N. Mechanisms of mercury disposition in the body. Am J Ind Med. 2007;50(10):757–64.

    Article  CAS  PubMed  Google Scholar 

  • Cobbina SJ, Chen Y, Zhou Z, Wub X, Feng W, Wang W, Mao G, Xu H, Zhang Z, Wua X, Yang L. Low concentration toxic metal mixture interactions: effects on essential and non-essential metals in brain, liver, and kidneys of mice on sub-chronic exposure. Chemosphere. 2015;132:79–86.

    Article  CAS  PubMed  Google Scholar 

  • Colomina MT, Roig JL, Sánchez DJ, Domingo JL. Influence of age on aluminum-induced neurobehavioral effects and morphological changes in rat brain. Neurotoxicology. 2002;23(6):775–81.

    Article  CAS  PubMed  Google Scholar 

  • Costa LG. Biochemical and molecular neurotoxicology: relevance to biomarker development, neurotoxicity testing and risk assessment. Toxicol Lett. 1998;102-103:417–21.

    Article  CAS  PubMed  Google Scholar 

  • Costa LG, Manzo L. Biochemical markers of neurotoxicity: research epidemiological applications. Toxicol Lett. 1995;77(1–3):137–44.

    Article  CAS  PubMed  Google Scholar 

  • Csavina J, Field J, Taylor MP, Gao S, Landázuri A, Betterton EA, Sáez AE. A review on the importance of metals and metalloids in atmospheric dust and aerosol from mining operations. Sci Total Environ. 2012;433:58–73.

    Article  CAS  PubMed  Google Scholar 

  • Dai M-C, Zhong Z-H, Sun Y-H, Sun Q-F, Wang Y-T, Yang G-Y, Bian L-G. Curcumin protects against iron induced neurotoxicity in primary cortical neurons by attenuating necroptosis. Neurosci Lett. 2013;536:41–6.

    Article  CAS  PubMed  Google Scholar 

  • Davies KM, Hare DJ, Cottam V, Chen N, Hilgers L, Halliday G, et al. Localization of copper and copper transporters in the human brain. Metallomics. 2013;5:43–51.

    Article  CAS  PubMed  Google Scholar 

  • Desi I, Nagymajtenyi L and Schulz H. Behavioural and neurotoxicological changes caused by cadmium treatment of rats during development. J Appl Toxicol. 1998; 18(1), 63–70, 1998.

    Google Scholar 

  • Dringen R. Metabolism and functions of glutathione in brain. Prog Neurobiol. 2000;62:649–71.

    Article  CAS  PubMed  Google Scholar 

  • Dudzik CG, Walter ED, Abrams BS, Jurica MS, Millhauser GL. Coordination of copper to the membrane-bound form of alpha-synuclein. Biochemistry. 2012;52:53–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dusek P, Roosc PM, Litwin T, Schneider SA, Flaten TP, Aaseth J. The neurotoxicity of iron, copper and manganese in Parkinson’s and Wilson’s diseases. J Trace Elem Med Biol. 2015;31:193–203.

    Article  CAS  PubMed  Google Scholar 

  • Ebert BL, Bunn HF. Regulation of the erythropoietin gene. Blood. 1999;94:1864–77.

    CAS  PubMed  Google Scholar 

  • Ekino S, Susa M, Ninomiya T, Imamura K, Kitamura T. Minamata disease revisited: an update on the acute and chronic manifestations of methyl mercury poisoning. J Neur Sci. 2007;262:131–44.

    Article  CAS  Google Scholar 

  • Emerit J, Edeas M, Bricaire F. Neurodegenerative diseases and oxidative stress. Biomed Pharmacother. 2004;58:39–46.

    Article  CAS  PubMed  Google Scholar 

  • Espinoza A, Le Blanc S, Olivares M, Pizarro F, Ruz M, Arredondo M. Iron, copper, and zinc transport: inhibition of divalent metal transporter 1 (DMT1) and human copper transporter 1 (hCTR1) by shRNA. Biol Trace Elem Res. 2012;146(2):281–6.

    Article  CAS  PubMed  Google Scholar 

  • Exley C. Aluminum and Alzheimer’s disease. J Alzheimers Dis. 2001;3(6):551–2.

    Article  PubMed  Google Scholar 

  • Fabisiak JP, Pearce LL, Borisenko GG, Tyhurina YY, Tyurin VA, Razzack J, Lazo JS, Pitt BR, Kagan VE. Bifunctional anti/prooxidant potential of metallothionein: redox signaling of copper binding and release. Antioxid Redox Signal. 1999;1:349–64.

    Article  CAS  PubMed  Google Scholar 

  • Fairbrother A, Wenste R, Sappington K, Wood W. Framework for metals risk assessment. Ecotoxicol Environ Saf. 2007;68:145–227.

    Article  CAS  PubMed  Google Scholar 

  • Feron VJ, Groten JP, Jonker D, Cassee FR, van Bladeren PJ. Toxicology of chemical mixtures: challenges for today and the future. Toxicology. 1995;105:415–27.

    Article  CAS  PubMed  Google Scholar 

  • Flora SJS. Arsenic-induced oxidative stress and its reversibility. Free Radic Biol Med. 2011;51:257–81.

    Article  CAS  PubMed  Google Scholar 

  • Flora G, Gupta D, Tiwari A. Toxicity of lead: a review with recent updates. Iternterdis Toxicol. 2012;5(2):47–58.

    CAS  Google Scholar 

  • Fowler BA, Mahaffey KR. Interactions among lead, cadmium, and arsenic in relation to porphyrin excretion patterns. Environ Health Perspect. 1978;25:87–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freitas Fonseca M, De Souza Hacon S, Grandjean P, Choi AL, Rodrigues Bastos W. Iron status as a covariate in methylmercury-associated neurotoxicity risk. Chemosphere. 2014;100:89–96.

    Article  CAS  Google Scholar 

  • Garrick MD, Singleton S, Vargas F, Kuo HC, Zhao L, Knopfel M, Davidson T, Costa M, Paradkar P, Roth JA, Garrick LM. DMT1: which metals does it transport? Biol Res. 2006;39:79–85.

    Article  CAS  PubMed  Google Scholar 

  • Ghorbel I, Maktouf S, Kallel C, Chaabouni SE, Boudawara T, Zeghal N. Disruption of erythrocyte antioxidant defense system, hematological parameters, induction of pro-inflammatory cytokines and DNA damage in liver of co-exposed rats to aluminium and acrylamide. Chem Biol Interact. 2015;236:31–40.

    Article  CAS  PubMed  Google Scholar 

  • Gianutsos G, Seltzer MD, Saymeh R, Wu M-LW, Michel RG. Brain manganese accumulation following systemic administration of different forms. Arch Toxicol. 1985;57:272–5.

    Article  CAS  PubMed  Google Scholar 

  • Gorsky JE, Dietz AA, Spencer H, Osis D. Metabolic balance of aluminum studied in six men. Clin Chem. 1979;25(10):1739–43.

    CAS  PubMed  Google Scholar 

  • Grandjean P, Herz KT. Methylmercury and brain development: imprecision and underestimation of developmental neurotoxicity in humans. Mt Sinai J Med. 2011;78(1):107–18.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gu C, Chen S, Xu X, Zheng L, Li Y, Wu K, Liu J, Qi Z, Han D, Chen G, Huo X. Lead and cadmium synergistically enhance the expression of divalent metal transporter 1 protein in central nervous system of developing rats. Neurochem Res. 2009;34:1150–6.

    Article  CAS  PubMed  Google Scholar 

  • Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482–8.

    Article  CAS  PubMed  Google Scholar 

  • Guolo M, Stella AM, Melito V, Parera V, Batle AMC. Altered 5-aminolevulinic acid metabolism leading to pseudophorphyria in hemodialysed patients. lnt J Biochem Cell Bid. 1996;28:311–7.

    Article  CAS  Google Scholar 

  • Heyer NJ, Bittner AC Jr, Echeverria D, Woods JS. A cascade analysis of the interaction of mercury and coproporphyrinogen oxidase (CPOX) polymorphism on the heme biosynthetic pathway and porphyrin production. Toxicol Lett. 2006;161:159–66.

    Article  CAS  PubMed  Google Scholar 

  • Hift RJ, Thunell S, Brun A. Drugs in porphyria: from observation to a modern algorithm-based system for the prediction of porphyrogenicity. Pharmacol Ther. 2011;132(2):158–69.

    Article  CAS  PubMed  Google Scholar 

  • Hoffmeyer RE, Singh SP, Doonan CJ, Ross ARS, Hughes RJ, Pickering IJ, George GN. Molecular mimicry in mercury toxicology. Chem Res Toxicol. 2006;19(6):753–9.

    Article  CAS  PubMed  Google Scholar 

  • Horiguchi H, Teranishi H, Niiya K, Aoshima K, Katoh T, Sakuragawa N, Kasuya M. Hypoproduction of erythropoietin contributes to anemia in chronic cadmium intoxication: clinical study on Itai-itai disease in Japan. Arch Toxicol. 1994;68(10):632–6.

    Article  CAS  PubMed  Google Scholar 

  • Horiguchi H, Aoshima K, Oguma R, Sasaki S, Miyamoto K, Hosoi Y, Katoh T, Kayama F. Latest status of cadmium accumulation and its effects on kidneys, bone, and erythropoiesis in inhabitants of the formerly cadmium-polluted Jinzu River Basin in Toyama, Japan, after restoration of rice paddies. Int Arch Occup Environ Health. 2010;83:953–70.

    Article  CAS  PubMed  Google Scholar 

  • Hsu-Kim H, Kucharzyk KH, Zhang T, Deshusses MA. Mechanisms regulating mercury bioavailability for methylating microorganisms in the aquatic environment: a critical review. Environ Sci Technol. 2013;47(6):2441–56.

    Article  CAS  PubMed  Google Scholar 

  • Huang P, Chen C, Wang H, Li G, Jing H, Han Y, Li N, Xiao Y, Yu Q, Liu Y, Wang P, Shi Z, Sun Z. Manganese effects in the liver following subacute or subchronic manganese chloride exposure in rats. Ecotoxicol Environ Saf. 2011;74:615–22.

    Article  CAS  PubMed  Google Scholar 

  • Illing AC, Shawki A, Cunningham CL, Mackenzie B. Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1. J Biol Chem. 2012;287(36):30485–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Islam E, Yang X, He Z and Mahmood Q. Assessing potential dietary toxicity of heavy metals in selected vegetables and food crops. J Zhejiang Univ Sci B. 2007; 8(1): 1–13.

    Google Scholar 

  • Jadhav S, Sarkar S, Patil R, Tripathi H. Effects of subchronic exposure via drinking water to a mixture of eight water-contaminating metals: a biochemical and histopathological study in male rats. Arch Environ Con Tox. 2007;53:667–77.

    Article  CAS  Google Scholar 

  • Järup L. Hazards of heavy metal contamination. Br Med Bull. 2003;68:167–82.

    Article  PubMed  Google Scholar 

  • Jeong KS, Park H, Hac E, Hong Y-C, Hae M, Park H, Kimf B-N, Leeg SJ, Lee KY, Kim JH, Kim Y. Evidence that cognitive deficit in children is associated not only with iron deficiency, but also with blood lead concentration: a preliminary study. J Trace Elem Med Biol. 2015;29:336–41.

    Article  CAS  PubMed  Google Scholar 

  • Jiang X, McDermott JR, Ajees AA, Rosen BP, Liu Z. Trivalent arsenicals and glucose use different translocation pathways in mammalian GLUT1. Metallomics. 2010;2(3):211–9.

    Article  CAS  PubMed  Google Scholar 

  • Jin T, Lu J and Nordberg M.Toxicokinetics and biochemistry of cadmium with special emphasis on the role of metallothionein. Neurotoxicology. 1998; 19(4-5):529-35.

    Google Scholar 

  • Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology. 2011;283(2–3):65–87.

    Article  CAS  PubMed  Google Scholar 

  • Julka D, Gill KD. Development of a possible peripheral marker for aluminum neurotoxicity. Med Sci Res. 1995;23:311–4.

    CAS  Google Scholar 

  • Kakkar P, Jaffery FN. Biological markers for metal toxicity. Environ Toxicol Pharmacol. 2005;19:335–49.

    Article  CAS  PubMed  Google Scholar 

  • Kalia K, Chandra SV, Viswanathan PN. Effect of 54Mn and lead interaction on their binding with tissue proteins: in vitro studies. Ind Health. 1984;22:207–18.

    Article  CAS  PubMed  Google Scholar 

  • Kauppinen R. Porphyrias Lancet. 2005;365:241–52.

    Article  CAS  PubMed  Google Scholar 

  • Kaur A, Joshi K, Minz RW, Gill KD. Neurofilament phosphorylation and disruption: a possible mechanism of chronic aluminium toxicity in Wistar rats. Toxicology. 2006;219(1–3):1–10.

    Article  CAS  PubMed  Google Scholar 

  • Kawahara M, Kato-Negishi M. Link between aluminum and the pathogenesis of Alzheimer’s disease: the integration of the aluminum and amyloid Cascade hypotheses. Int J Alzheimers Dis. 2011;2011:276393.

    PubMed  PubMed Central  Google Scholar 

  • Kerper LE, Ballatori N, Clarkson TW. Methylmercury transport across the blood-brain barrier by an amino acid carrier. Am J Phys. 1992;262:761–5.

    Google Scholar 

  • Kile ML, Fara JM, Ronnenberg AG, Quamruzzaman Q, Rahman M, Mostofa G, Afroz S, Christiani DC. A cross sectional study of anemia and iron deficiency as risk factors for arsenic-induced skin lesions in Bangladeshi women. BMC Public Health. 2016;16:158.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim S, Moon C, Eun S, Ryu P, Jo S. Identification of ASK1, MKK4, JNK, c-Jun, and caspase-3 as a signaling cascade involved in cadmium-induced neuronal cell apoptosis. Biochem Biophys Res Commun. 2005;328:326–34.

    Article  CAS  PubMed  Google Scholar 

  • Kim Y, Kim BN, Hong Y-C, Shin M-S, Yoo H-J, Kim J-W, Bhang S-Y, Cho S-C. Co-exposure to environmental lead and manganese affects the intelligence of school-aged children. Neurotoxicology. 2009;30:564–71.

    Article  CAS  PubMed  Google Scholar 

  • Kim JH, Lee SJ, Kim SY, Choi G, Lee JJ, Kim HJ, Kim S, Park J, Moon HB, Choi K, Kim S, Choi SR. Association of food consumption during pregnancy with mercury and lead levels in cord blood. Sci Total Environ. 2016a;29(563–564):118–24.

    Article  CAS  Google Scholar 

  • Kim Y, Oh HG, Cho YY, Kwon O-H, Park MK, Chung S. Stress hormone potentiates Zn2+-induced neurotoxicity via TRPM7 channel in dopaminergic neuron. Biochem Biophys Res Commun. 2016b;470:362–7.

    Article  CAS  PubMed  Google Scholar 

  • Klandorf H, Van Dyke K. Oxidative and nitrosative stresses: their role in health and disease in man and birds. Oxidative stress – molecular mechanisms and biological effects. (Chapter 3). Ed. Volodymyr Lushchak and Halyna M. Semchyshyn. 2012. ISBN 978-953-51-0554-1, Published: April 25, 2012 under CC BY 3.0 license.

    Google Scholar 

  • Klatzo I, Wisniewski H, Streicher E. Experimental production of neurofibrillary degeneration: 1. Light microscopic observations. J Neuropathol Exp Neurol. 1965;24:187–99.

    Article  CAS  PubMed  Google Scholar 

  • Klauder DS, Petering HG. Protective value of dietary copper and iron against some toxic effects of lead in rats. Environ Health Perspect. 1975;12:77–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kordas K, Queirolo EI, Ettinger AS, Wright RO, Stoltzfus RJ. Prevalence and predictors of exposure to multiple metals in preschool children from Montevideo. Uruguay Sci Total Environ. 2010;408:4488–94.

    Article  CAS  PubMed  Google Scholar 

  • Korolnek T, Hamza I. Like iron in the blood of the people: the requirement for heme trafficking in iron metabolism. Front Pharmacol. 2014;4;5,126.

    Google Scholar 

  • Kortenkamp and Faust. State of the art report on mixture toxicity – final report. UE Comission. 2009. http://ec.europa.eu/environment/chemicals/effects/pdf/report_mixture_toxicity.pdf, 13th June 2014, 2 p.m.

  • Kozlowski H, Janicka-Klos A, Brasun J, Gaggelli E, Valensin D, Valensin G. Copper, iron, and zinc ions homeostasis and their role in neurodegenerative disorders (metal uptake, transport, distribution and regulation). Coord Chem Rev. 2009;253:2665–85.

    Article  CAS  Google Scholar 

  • Krüger K, Straub H, Hirner AV, Hippler J, Binding N, Musshoff U. Effects of monomethylarsonic and monomethylarsonous acid on evoked synaptic potentials in hippocampal slices of adult and young rats. Toxicol Appl Pharmacol. 2009;236(1):115–23.

    Article  PubMed  CAS  Google Scholar 

  • Kumar V, Gill KD. Oxidative stress and mitochondrial dysfunction in aluminium neurotoxicity and its amelioration: a review. Neurotoxicology. 2014;41:154–66.

    Article  CAS  PubMed  Google Scholar 

  • Kumar A, Dogra S, Prakash A. Protective effect of curcumin (Curcuma longa), against aluminium toxicity: possible behavioral and biochemical alterations in rats. Behav Brain Res. 2009;205(2):384–90.

    Article  CAS  PubMed  Google Scholar 

  • Kwong WT, Friello P, Semba RD. Interactions between iron deficiency and lead poisoning: epidemiology and pathogenesis. Sci Total Environ. 2004;330:21–37.

    Article  CAS  PubMed  Google Scholar 

  • Lafuente A, Esquifino A. Cadmium effects on hypothalamic activity and pituitary hormone secretion in the male. Toxicol Lett. 1999;110(3):209–18.

    Article  CAS  PubMed  Google Scholar 

  • Landrigan P, Nordberg M, Lucchini R, Nordberg G, Grandjean P, Iregren A, Alessio L. The declaration of Brescia on prevention of the neurotoxicity of metals. Am J Ind Med. 2006;50(10):709–11.

    Article  Google Scholar 

  • Lieu PT, Heiskala M, Peterson PA, Yang Y. The roles of iron in health and disease. Mol Asp Med. 2001;22:1–87.

    Article  CAS  Google Scholar 

  • Lin C-Y, Hsiao W-C, Huang C-J, Kao C-F, Hsua G-S-W. Heme oxygenase-1 induction by the ROS-JNK pathway plays a role in aluminum-induced anemia. J Inorg Biochem. 2013;128:221–8.

    Article  CAS  PubMed  Google Scholar 

  • Lister LJ, Svendsen C, Wright J, Hooper HL, Spurgeon DJ. Modelling the joint effects of a metal and a pesticide on reproduction and toxicokinetics in Lumbricid earthworms. Environ Int. 2011;37:663–70.

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Klaassen CD. Absorption and distribution of cadmium in Metallothionein-I transgenic mice. Fund Appl Toxicol. 1996;29:294–300.

    Article  CAS  Google Scholar 

  • Liu Z, Sanchez MA, Jiang X, Boles E, Landfear SM, Rosen BP. Mammalian glucose permease GLUT1 facilitates transport of arsenic trioxide and methylarsonous acid. Biochem Biophys Res Commun. 2006;351(2):424–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lohren H, Pieper I, Blagojevic L, Bornhorst J, Galla H-J, Schwerdtle T. Neurotoxicity of organic and inorganic mercury species – effects on and transfer across the blood-cerebrospinal fluid barrier, cytotoxic effects in target cells. Perspect Sci. 2015;3:21–2.

    Article  Google Scholar 

  • López Alonso M, Prieto Montaña F, Miranda M, Castillo C, Hernández J, Benedito JL. Cadmium and lead accumulation in cattle in NW Spain. Vet Hum Toxicol. 2003;45(3):128–30.

    PubMed  Google Scholar 

  • Lopez E, Arce C, Oset-Gasque MJ, Canadas S, González MP. Cadmium induces reactive oxygen species generation and lipid peroxidation in cortical neurons in culture. Free Rad Biol Med. 2006;40:940–51.

    Article  CAS  PubMed  Google Scholar 

  • Lorincz MT. Neurologic Wilson’s disease. Ann N Y Acad Sci. 2010;1184:173–87.

    Article  CAS  PubMed  Google Scholar 

  • Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR. Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci. 1998;158(1):47–52.

    Article  CAS  PubMed  Google Scholar 

  • Lu J, Zheng Y-L, Wu D-M, Sun D-X, Shan Q, Fan S-H. Trace amounts of copper induce neurotoxicity in the cholesterol-fed mice through apoptosis. FEBS Lett. 2006;580:6730–40.

    Article  CAS  PubMed  Google Scholar 

  • Lucchini R, Zimmerman N. Lifetime cumulative exposure as a threat for neurodegeneration: need for prevention strategies on a global scale. Neurotoxicology. 2009;30(6):1144–8.

    Article  PubMed  Google Scholar 

  • Mahaffey KR, Fowler BA. Effects of concurrent Administration of Lead, cadmium, and arsenic in the rat. Environ Health Perspect. 1977;19:165–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahaffey KR, Capar SG, Gladen BC, Fowler BA. Concurrent exposure to lead, cadmium, and arsenic. Effects on toxicity and tissue metal concentrations in the rat. J Lab Clin Med. 1981;98(4):463–81.

    CAS  PubMed  Google Scholar 

  • Maines MD. Regional distribution of the enzymes of haem biosynthesis and the inhibition of 5-aminolaevulinate synthase by manganese in the rat brain. Biochem J. 1980;190:315–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Markiewicz-Górka I, Januszewska L, Michalak A, Prokopowicz A, Januszewska E, Pawlas N, Pawlas K. Effects of chronic exposure to lead, cadmium, and manganese mixtures on oxidative stress in rat liver and heart. Arh Hig Rada Toksikol. 2015;66(1):51–62.

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Finley EJ, Chakraborty S, Fretham SJB, Aschner M. Cellular transport and homeostasis of essential and nonessential metals. Metallomics. 2012;4(7):593–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCord MC, Aizenman E. The role of intracellular zinc release in aging, oxidative stress, and Alzheimer’s disease. Front Aging Neurosci. 2014;6:77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mejía JJ, Diáz-Barriga F, Calderón J, Ríos C, Jiménez-Capdeville ME. Effects of lead-arsenic combined exposure on central Monoaminergic systems. Neurotoxicol Teratol. 1997;19(6):489–97.

    Article  PubMed  Google Scholar 

  • Méndez-Armenta M, Ríos C. Cadmium neurotoxicity. Environ Toxicol Pharmacol. 2007;23(3):350–8.

    Article  PubMed  CAS  Google Scholar 

  • Méndez-Armenta M, Villeda-Hernández J, Barroso-Moguel R, Nava-Ruiz C, Jiménez-Capdeville ME, Rios C. Brain regional lipid peroxidation and metallothionein levels of developing rats exposed to cadmium and dexamethasone. Toxicol Lett. 2003;144(2):151–7.

    Article  PubMed  CAS  Google Scholar 

  • Migliore L, Coppedè F. Environmental-induced oxidative stress in neurodegenerative disorders and aging. Mut Res. 2009;674:73–84.

    Article  CAS  Google Scholar 

  • Miu AC, Andreescu CE, Vasiu R, Olteanu AI. A behavioral and histological study of the effects of long-term exposure of adult rats to aluminum. Int J Neurosci. 2003;113(9):1197–211.

    Article  PubMed  Google Scholar 

  • Molina RM, Phattanarudee S, Kim J, Thompson K, Wessling-Resnick M, Maher TJ, Brain JD. Ingestion of Mn and Pb by rats during and after pregnancy alters iron metabolism and behavior in offspring. Neurotoxicology. 2011;32(4):413–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monroe RK, Halvorsen SW. Cadmium blocks receptor-mediated Jak/STAT signaling in neurons by oxidative stress. Free Radic Biol Med. 2006;41(3):493–502.

    Article  CAS  PubMed  Google Scholar 

  • Mutti A. Biological monitoring in occupational and environmental toxicology. Toxicol Lett. 1999;108:77–89.

    Article  CAS  PubMed  Google Scholar 

  • Nasiadek M, Chmielnicka J, Subdys J. Analysis of urinary Porphyrins in rats exposed to aluminum and iron. Ecotoxicol Environ Saf. 2001;48(1):11–7.

    Article  CAS  PubMed  Google Scholar 

  • Naujokas MF, Anderson B, Ahsan H, Aposhian HV, Graziano JH, Thompson C, Suk WA. The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environ Health Perspect. 2013;121(3):295–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nazir R, Shaheen N, Shah MH. Indoor/outdoor relationship of trace metals in the atmospheric particulate matter of an industrial area. Atmos Res. 2011;101:765–72.

    Article  CAS  Google Scholar 

  • Neal AP, Guilarte TR. Mechanisms of heavy metal neurotoxicity: lead and manganese. Toxicol Res (Camb). 2013;(2):99–114.

    Google Scholar 

  • Nehru B, Anand P. Oxidative damage following chronic aluminium exposure in adult and pup rat brains. J Trace Elem Med Biol. 2005;19(2–3):203–8.

    Article  CAS  PubMed  Google Scholar 

  • Nordberg M, Nordberg GF. Metallothioneins: historical development and overview. Met Ions Life Sci. 2009;5:1–29.

    CAS  Google Scholar 

  • Notarachille G, Arnesano F, Calò V, Meleleo D. Heavy metals toxicity: effect of cadmium ions on amyloid beta protein 1-42. Possible implications for Alzheimer’s disease. Biometals. 2014;27(2):371–88.

    Article  CAS  PubMed  Google Scholar 

  • Nriagu J. Zinc toxicity in humans. School of Public Health, University of Michigan, Elsevier B.V. 2007.

    Google Scholar 

  • O’Neil P. Heavy metals in soils. In: Alloway BJ, editor. Arsenic. London: Blackie Academic and Professional Arsenic; 1995. p. 105–21.

    Google Scholar 

  • Obiri S, Yeboah PO, Osae S, Adu-Kumi S. Levels of arsenic, mercury, cadmium, copper, lead, zinc and manganese in serum and whole blood of resident adults from mining and non-mining communities in Ghana. Environ Sci Pollut Res Int. 2016;23(16):16589–97.

    Article  CAS  PubMed  Google Scholar 

  • Oteiza PI, Keen CL, Han B, Golub MS. Aluminum accumulation and neurotoxicity in Swiss-Webster mice after long-term dietary exposure to aluminum and citrate. Metabolism. 1993;42(10):1296–300.

    Article  CAS  PubMed  Google Scholar 

  • Park JD, Zheng W. Human exposure and health effects of inorganic and elemental mercury. J Prev Med Public Health. 2012;45(6):344–52.

    Article  PubMed  PubMed Central  Google Scholar 

  • Patrick L. Lead toxicity, a review of the literature. Part I: exposure, evaluation, and treatment. Altern Med Rev. 2006;11(1):2–22.

    PubMed  Google Scholar 

  • Peakall D, Burger J. Methodologies for assessing exposure to metals: speciation, bioavailability of metals, and ecological host factors. Ecotoxicol Environ Saf. 2003;56(1):110–21.

    Article  CAS  PubMed  Google Scholar 

  • Piao F, Cheng F, Chen H, Li G, Sun X, Liu S, Yamauchi T, Yokoyama K. Effects of Zn administration on Pb toxicities in rats. Ind Health. 2007;45:546–51.

    Article  CAS  PubMed  Google Scholar 

  • Pirpamer L, Hofer E, Gesierich B, De Guio F, Freudenberger P, Seiler S, Duering M, Jouvent E, Duchesnay E, Dichgans M, Ropele S, Schmidt R. Determinants of iron accumulation in the normal aging brain. Neurobiol Aging. 2016;43:149–55.

    Article  CAS  PubMed  Google Scholar 

  • Pohl HR, Hansen H, Chou C-HSJ. Public health guidance values for chemical mixtures: current practice and future directions. Regul Toxicol Pharmacol. 1997;26:322–9.

    Article  CAS  PubMed  Google Scholar 

  • Pohl HR, Roney N, Abadin HG. Metal ions affecting the neurological system. Met Ions Life Sci. 2011;8:247–62.

    CAS  PubMed  Google Scholar 

  • Prüss-Ustün A, Wolf J, Corvalán C, Bos R, Neira M. Preventing disease through healthy environments. A global assessment of the burden of disease from environmental risks. Geneva: World Health Organization (WHO); 2016.

    Google Scholar 

  • Qato MK, Maines MD. Regulation of heme and drug metabolism activities in the brain by manganese. Biochem Biophys Res Commun. 1985;128(1):18–24.

    Article  CAS  PubMed  Google Scholar 

  • Quintanar L. Manganese neurotoxicity: a bioinorganic chemist’s perspective. Inorg Chim Acta. 2008;361:875–84.

    Article  CAS  Google Scholar 

  • Quintanilla-Vega B, Hernandez A, Mendoza-Figueroa T. Reduction in porphyrin excretion as a sensitive indicator of lead toxicity in primary cultures of adult rat hepatocytes. Toxicol In Vitro. 1996;10:675–83.

    Article  CAS  PubMed  Google Scholar 

  • Rachakonda V, Pan TH, Le WD. Biomarkers of neurodegenerative disorders: how good are they? Cell Res. 2004;14(5):349–60.

    Article  Google Scholar 

  • Ramos-Chávez LA, Rendón-López CRR, Zepeda A, Silva-Adaya D, Del Razo LM, Gonsebatt ME. Neurological effects of inorganic arsenic exposure: altered cysteine/glutamate transport, NMDA expression and spatial memory impairment. Front Cell Neurosci. 2015;9:9–21.

    Article  Google Scholar 

  • Rodríguez-Barranco M, Lacasaña M, Aguilar-Garduño C, Alguacil J, Gil F, González-Alzaga B, Rojas-García A. Association of arsenic, cadmium and manganese exposure with neurodevelopment and behavioural disorders in children: a systematic review and meta-analysis. Sci Total Environ. 2013;1(454–455):562–77.

    Article  CAS  Google Scholar 

  • Roels HA, Bowler RM, Kim Y, Claus Henn B, Mergler D, Hoet P, Gocheva VV, Bellinger DC, Wright RO, Harris MG, Chang Y, Bouchard MF, Riojas-Rodriguez H, Menezes-Filho JA, Tellez-Rojo MM. Manganese exposure and cognitive deficits: a growing concern for manganese neurotoxicity. Neurotoxicology. 2012;33:872–80.

    Article  CAS  PubMed  Google Scholar 

  • Roneya N, Colman J. Interaction profile for lead, manganese, zinc, and copper. Environ Toxicol Pharmacol. 2004;18:231–4.

    Article  CAS  Google Scholar 

  • Rosado JL, Ronquillo D, Kordas K, Rojas O, Alatorre J, Lopez P, Garcia-Vargas G, Caamaño MC, Cebrián ME, Stoltzfus RJ. Arsenic exposure and cognitive performance in Mexican schoolchildren. Environ Health Perspect. 2007;115(9):1371–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rubio-Osornio M, Montes S, Heras-Romero Y, Guevara J, Rubio C, Aguilera P, Rivera-Mancia S, Floriano-Sánchez E, Monroy-Noyola A, Ríos C. Induction of ferroxidase enzymatic activity by copper reduces MPP+−evoked neurotoxicity in rats. Neurosci Res. 2013;75:250–5.

    Article  CAS  PubMed  Google Scholar 

  • Rush T, Hjelmhaug J, Lobner D. Effects of chelators on mercury, iron, and lead neurotoxicity in cortical culture. Neurotoxicology. 2009;30:47–51.

    Article  CAS  PubMed  Google Scholar 

  • Sahin G, Varol I, Temizer A, Benli K, Demirdamar R, Duru S. Determination of aluminum levels in the kidney, liver, and brain of mice treated with aluminum hydroxide. Biol Trace Elem Res. 1994;41(1–2):129–35.

    Article  CAS  PubMed  Google Scholar 

  • Sánchez-Peña LC, Petrosyan P, Morales M, González NB, Gutiérrez-Ospina G, Del Razo LM, Gonsebatt ME. Arsenic species, AS3MT amount, and AS3MT gene expression in different brain regions of mouse exposed to arsenite. Environ Res. 2010;110(5):428–34.

    Article  PubMed  CAS  Google Scholar 

  • Santamaria AB. Manganese exposure, essentiality & toxicity. Indian J Med Res. 2008;128:484–500.

    CAS  PubMed  Google Scholar 

  • Scheiber IF, Mercer JFB, Dringen R. Metabolism and functions of copper in brain. Prog Neurobiol. 2014;116:33–57.

    Article  CAS  PubMed  Google Scholar 

  • Schneider SA. Neurodegenerations with brain iron accumulation. Parkinsonism Rel Disord. 2016;22:21–5.

    Article  Google Scholar 

  • Sensi SL, Jeng JM. Rethinking the excitotoxic ionic milieu: the emerging role of Zn(2+) in ischemic neuronal injury. Curr Mol Med. 2004;4(2):87–111.

    Article  CAS  PubMed  Google Scholar 

  • Sensi SL, Yin HZ, Weiss JH. AMPA/kainate receptor-triggered Zn2+ entry into cortical neurons induces mitochondrial Zn2+ uptake and persistent mitochondrial dysfunction. Eur J Neurosci. 2000;12:3813–8.

    Article  CAS  PubMed  Google Scholar 

  • Sethi P, Jyoti A, Hussain E, Sharma D. Curcumin attenuates aluminium-induced functional neurotoxicity in rats. Pharmacol Biochem Behav. 2009;93:31–9.

    Article  CAS  PubMed  Google Scholar 

  • Shi LZ, Zheng W. Early lead exposure increases the leakage of the blood–cerebrospinal fluid barrier, in vitro. Hum Exp Toxicol. 2007;26(3):159–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shukla GS, Hussain T, Chandra SV. Possible role of regional superoxide dismutase activity and lipid peroxide levels in cadmium neurotoxicity: in vivo and in vitro studies in growing rats. Life Sci. 1987;41(19):2215–21.

    Article  CAS  PubMed  Google Scholar 

  • Shukla GS and Chandra SV. Concurrent exposure to lead, manganese, and cadmium and their distribution to various brain regions, liver, kidney, and testis of growing rats. Archives of Environ Contam Toxicol. 1987; 16(3):303–310.

    Google Scholar 

  • Shukla A, Shukla GS, Srimal RC. Cadmium-induced alterations in blood-brain barrier permeability and its possible correlation with decreased microvessel antioxidant potential in rat. Hum Exp Toxicol. 1996;15(5):400–5.

    Article  CAS  PubMed  Google Scholar 

  • Shy CM. Epidemiological studies of neurotoxic, reproductive, and carcinogenic effects of complex mixtures. Environ Health Perspect. 1993;101(4):183–8.

    Article  PubMed  PubMed Central  Google Scholar 

  • Simmons JE. Chemical mixtures: challenge for toxicology and risk assessment. Toxicology. 1995;105:11–9.

    Google Scholar 

  • Simmons-Willis TA, Koh AS, Clarkson TW, Ballatori N. Transport of a neurotoxicant by molecular mimicry : the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. Biochem J. 2002;367:239–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sinczuk-Walczaki H, Szymczak M, Razniewska G, Matczak W, Szymczak W. Effects of occupational exposure to aluminium on nervous system: clinical and electroencephalographic findings. Int J Occup Med Environ Health. 2003;16(4):301–10.

    Google Scholar 

  • Singh T, Goel RK. Neuroprotective effect of Allium cepa L. in aluminium chloride induced neurotoxicity. Neurotoxicology. 2015;49:1–7.

    Article  CAS  PubMed  Google Scholar 

  • Skjørringe T, Burkhart A, Johnsen KB, Moos T. Divalent metal transporter 1 (DMT1) in the brain: implications for a role in iron transport at the blood-brain barrier, and neuronal and glial pathology. Front Mol Neurosci. 2015;8(19):1–13.

    Google Scholar 

  • Song H, Zheng G, Liu Y, Shen X-F, Zhao Z-H, Aschner M, Luo W-J, Chen J-Y. Cellular uptake of lead in the blood-cerebrospinal fluid barrier: novel roles of Connexin 43 hemichannel and its down-regulations via Erk phosphorylation. Toxicol Appl Pharmacol. 2016;15(297):1–11.

    Article  CAS  Google Scholar 

  • Spurgeon DJ, Jones OAH, Dorne J-L, Svendsen C, Swain S, Stürzenbaum SR. Systems toxicology approaches for understanding the joint effects of environmental chemical mixtures. Sci Total Environ. 2010;408:3725–34.

    Article  CAS  PubMed  Google Scholar 

  • Strak E, Ellinger I, Balthasar C, Scheinast M, Schatz J, Szattler T, Bleichert S, Saleh L, Knöfler M, Zeisler H, Hengstschläger M, Rosner M, Salzer H, Gundacker C. Mercury toxicokinetics of the healthy human term placenta involve amino acid transporters and ABC transporters. Toxicology. 2016;340:34–42.

    Article  CAS  Google Scholar 

  • Struys-Ponsar C, Kerkhofs A, Gauthier A, Soffié M, van den Bosch de Aguilar P. Effects of aluminum exposure on behavioral parameters in the rat. Pharmacol Biochem Behav. 1997;56(4):643–8.

    Article  CAS  PubMed  Google Scholar 

  • Szewczyk B. Zinc homeostasis and neurodegenerative disorders. Front Aging Neurosci. 2013;5:33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tallkvist J, Bowlus CL, Lonnerdal B. DMT1 gene expression and cadmium absorption in human absorptive enterocytes. Toxicol Lett. 2001;122:171–7.

    Article  CAS  PubMed  Google Scholar 

  • Tiffany-Castiglioni E, Hong S, Qian Y, Tang Y, Donnelly KC. In vitro models for assessing neurotoxicity of mixtures. Neurotoxicology. 2006;27:835–9.

    Article  CAS  PubMed  Google Scholar 

  • Tjälve H, Henriksson J. Uptake of metals in the brain via olfactory pathways. Neurotoxicology. 1999;20(2–3):181–95.

    PubMed  Google Scholar 

  • Tougu V, Tiiman A, Palumaa P. Interactions of Zn(II) and cu(II) ions with Alzheimer’s amyloid-beta peptide metal ion binding, contribution to fibrillization and toxicity. Metallomics. 2011;3:250–61.

    Article  CAS  PubMed  Google Scholar 

  • Vazquez M, Velez D, Devesa V, Puig S. Participation of divalent cation transporter DMT1 in the uptake of inorganic mercury. Toxicology. 2015;331:119–24.

    Article  CAS  PubMed  Google Scholar 

  • von Stackelberg K. Guzy E, Chu T, Henn BC. Mixtures, metals, genes and pathways: a systematic review. Working paper prepared for: methods for research synthesis: a cross-disciplinary workshop. Harvard Center for Risk Analysis. 2013.

    Google Scholar 

  • Wagner GS, Tephly TR. A possible role of copper in the regulation of heme biosynthesis through ferrochelatase. Adv Exp Med Biol. 1975;58:343–54.

    Article  CAS  PubMed  Google Scholar 

  • Walton JR. Aluminum disruption of calcium homeostasis and signal transduction resembles change that occurs in aging and Alzheimer’s disease. J Alzheimers Dis. 2012;29(2):255–73.

    CAS  PubMed  Google Scholar 

  • Waalkes MP, Harvey MJ, Klaassen CD. Relative in vitro affinity of hepatic metallothionein for metals. Toxicol Lett. 1984; 20(1):33-9.

    Google Scholar 

  • Wang G, Fowler BA. Roles of biomarkers in evaluating interactions among mixtures of lead, cadmium and arsenic. Toxicol Appl Pharmacol. 2008;233:92–9.

    Article  CAS  PubMed  Google Scholar 

  • Wang Q, Luo W, Zheng W, Liu Y, Xu H, Zheng G, Dai Z, Zhang W, Chen Y, Chen J. Iron supplement prevents lead-induced disruption of the blood–brain barrier during rat development. Toxicol Appl Pharmacol. 2007;219(1):33–41.

    Article  CAS  PubMed  Google Scholar 

  • Wang Q, Luo W, Zhang W, Liu M, Song H, Chen J. Involvement of DMT1 +IRE in the transport of lead in an in vitro BBB model. Toxicol In Vitro. 2011;25:991–8.

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Wang X, Zhang S, Qu G, Liu S. A protective role of heme-regulated eIF2a kinase in cadmium-induced toxicity in erythroid cells. Food Chem Toxicol. 2013;62:880–91.

    Article  CAS  PubMed  Google Scholar 

  • Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 2014;13(10):1045–60.

    Article  CAS  PubMed  Google Scholar 

  • Watanabe T, Hirano S. Metabolism of arsenic and its toxicological relevance. Arch Toxicol. 2013;87(6):969–79.

    Article  CAS  PubMed  Google Scholar 

  • Weidenhamer JD, Lobunski PA, Kuepouo G, Corbin RW, Gottesfeld P. Lead exposure from aluminum cookware in Cameroon. Sci Total Environ. 2014;496:339–47.

    Article  CAS  PubMed  Google Scholar 

  • Weiss B. Economic implications of manganese neurotoxicity. Neurotoxicology. 2006;27:362–8.

    Article  CAS  PubMed  Google Scholar 

  • Wenting L, Ping L, Haitao J, Meng Q, Xiaofei R. Therapeutic effect of taurine against aluminum-induced impairment on learning, memory and brain neurotransmitters in rats. Neurol Sci. 2014;35(10):1579–84.

    Article  PubMed  Google Scholar 

  • Wester RC, Maibach HI, Sedik L, Melendres J, DiZio S, Wade M. In vitro percutaneous absorption of cadmium from water and soil into human skin. Fund Appl Toxicol. 1992;19(1):1–5.

    Article  CAS  Google Scholar 

  • Whittaker MH, Wang G, Chen X-Q, Lipsky M, Smith D, Gwiazda R, Fowler BA. Exposure to Pb, Cd, and As mixtures potentiates the production of oxidative stress precursors: 30-day, 90-day, and 180-day drinking water studies in rats. Toxicol Appl Pharmacol. 2010;254(2):154–66.

    Google Scholar 

  • Wills MR, Hewitt CD, Sturgill BC, et al. Long-term oral or intravenous aluminum administration in rabbits I. Renal and hepatic changes. Ann Clin Lab Sci. 1993;23(1):1–16.

    CAS  PubMed  Google Scholar 

  • Witholt R, Gwiazda RH, Smith DR. The neurobehavioral effects of subchronic manganese exposure in the presence and absence of pre-parkinsonism. Neurotoxicol Teratol. 2000;22:851–61.

    Article  CAS  PubMed  Google Scholar 

  • Woods JS. Porphyrin metabolism as indicator of metal exposure and toxicity. In: Goyer RA, Cherian MG, editors. Handbook of experimental pharmacology. Vol. 115. Chap. 2. Toxicology of metals, biochemical aspects. Berlin: Springer; 1995. p. 19–52.

    Google Scholar 

  • Woods JS. Altered porphyrin metabolism as a biomarker of mercury exposure and toxicity. Can J Physiol Pharmacol. 1996;74:210–5.

    CAS  PubMed  Google Scholar 

  • Woods JS, Southern MR. Studies on the etiology of trace metal-induced porphyria: effect of porphyrinogenic metals on coproporphyrinogen oxidase in rat liver and kidney. Toxicol Appl Pharmacol. 1989;97:183–90.

    Article  CAS  PubMed  Google Scholar 

  • Woods JS, Eaton DL, Lukens CB. Studies on porphyrin metabolism in the kidney. Effects of trace metals and glutathione of renal uroporphyrinogen decarboxylase. Mol Pharmacol. 1984;26:336–41.

    CAS  PubMed  Google Scholar 

  • Woods JS, Bowers MA, Davis HA. Urinary porphyrin profiles as biomarkers of trace metal exposure and toxicity: studies on urinary porphyrin excretion patterns in rats during prolonged exposure to methyl mercury. Toxicol Appl Pharmacol. 1991;110:464–76.

    Article  CAS  PubMed  Google Scholar 

  • Woods JS, Martin MD, Leroux BG, DeRouen TA, Bernardo MF, Luis HS, Leitão JG, Simmonds PL, Rue TC. Urinary porphyrin excretion in normal children and adolescents. Clin Chim Acta. 2009;405:104–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wright RO, Baccarelli A. Metals and neurotoxicology. J Nutr. 2007;137(12):2809–13.

    Google Scholar 

  • Yang XF, Han QG, Liu DY, Fan GY, Ma JY, Wang ZL. Microstructure and ultrastructure alterations in the pallium of immature mice exposed to cadmium. Biol Trace Elem Res. 2016;1–7.

    Google Scholar 

  • Yasui M, Kihira T, Ota K. Calcium, magnesium and aluminum concentrations in Parkinson’s disease. Neurotoxicology. 1992;13:593–600.

    CAS  PubMed  Google Scholar 

  • Yasuno T, Okamoto H, Nagai M, Kimura S, Yamamoto T, Nagano K, Furubayashi T, Yoshikawa Y, Yasui H, Katsumi H, Sakane T, Yamamoto A. The disposition and intestinal absorption of zinc in rats. Eur J Pharm Sci. 2011;44:410–5.

    Article  CAS  PubMed  Google Scholar 

  • Yen Le TT, Vijver MG, Kinraide TB, Peijnenburg SWJGM, Hendriks AJ. Modelling metal interactions and metal toxicity to lettuce Lactuca sativa following mixture exposure (Cu2+-Zn2+ and Cu2+-Ag+). Environ Pollut. 2013;176:185–92.

    Article  CAS  Google Scholar 

  • Yokel RA. Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration. J Alzheimers Dis. 2006;10:223–53.

    Article  PubMed  Google Scholar 

  • Zheng W. Toxicology of choroid plexus: special reference to metal-induced neurotoxicities. Microsc Res Tech. 2001;52(1):89–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng W, Monnot AD. Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases. Pharmacol Ther. 2012;133(2):177–88.

    Article  CAS  PubMed  Google Scholar 

  • Zheng W, Perry DF, Nelson DL, Aposhian HV. Protection of cerebrospinal fluid against toxic metals by the choroid plexus. FASEB J. 1991;5:2188–93.

    CAS  PubMed  Google Scholar 

  • Zheng W, Aschner M, Ghersi-Egeac J-F. Brain barrier systems: a new frontier in metal neurotoxicological research. Toxicol Appl Pharmacol. 2003;192:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng G, Zhang J, Xuc Y, Shen X, Song H, Jing J, Luo W, Zheng W, Chen J. Involvement of CTR1 and ATP7A in lead (Pb)-induced copper (Cu)accumulation in choroidal epithelial cells. Toxicol Lett. 2014;225:110–8.

    Article  CAS  PubMed  Google Scholar 

  • Zhi D, Tao AIJ, Fang HJ, Sun RB, Shi Y, Wang LL, Wang Q. Influence of iron supplementation on DMT1 (IRE)-induced transport of lead by brain barrier systems in vivo. Biomed Environ Sci. 2015;28(9):651–9.

    Google Scholar 

  • Zhou F, Chen Y, Fan G, Feng C, Dub G, Zhu G, Li Y, Jiao H, Guan L, Wang Z. Lead-induced iron overload and attenuated effects of ferroportin 1 overexpression in PC12 cells. Toxicol In Vitro. 2014;28:1339–48.

    Article  CAS  PubMed  Google Scholar 

  • Zhu L, Ji X-J, Wang H-D, Pan H, Chen M, Lu T-J. Zinc neurotoxicity to hippocampal neurons in vitro induces ubiquitin conjugation that requires p38 activation. Brain Res. 2012;1438:1–7.

    Article  CAS  PubMed  Google Scholar 

  • Zhu G, Fan G, Feng C, Li Y, Chen Y, Zhou F, Du G, Jiao H, Liu Z, Xiao X, Lin F, Yand J. The effect of lead exposure on brain iron homeostasis and the expression of DMT1/FP1 in the brain in developing and aged rats. Toxicol Lett. 2013;216:108–23.

    Article  CAS  PubMed  Google Scholar 

  • Zhu H, Jia Y, Cao H, Meng F, Liu X. Biochemical and histopathological effects of subchronic oral exposure of rats to a mixture of five toxic elements. Food Chem Toxicol. 2014;71:166–75.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal

    V. M. Andrade & A. P. Marreilha dos Santos

  2. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA

    M. Aschner

Authors
  1. V. M. Andrade
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  2. M. Aschner
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  3. A. P. Marreilha dos Santos
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Correspondence to A. P. Marreilha dos Santos .

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Editors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA

    Michael Aschner

  2. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA

    Lucio G. Costa

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Andrade, V.M., Aschner, M., Marreilha dos Santos, A.P. (2017). Neurotoxicity of Metal Mixtures. In: Aschner, M., Costa, L. (eds) Neurotoxicity of Metals. Advances in Neurobiology, vol 18. Springer, Cham. https://doi.org/10.1007/978-3-319-60189-2_12

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