Selected biochemical mechanisms of lead neurotoxicity

Mikołaj Chlubek, Irena Baranowska-Bosiacka


Elevated levels of lead ions (Pb2+) in the bloodstream present a fatal risk to all age demographics. Furthermore, a wealth of research underscores that chronic exposure to even low, non-symptomatic doses can trigger developmental disorders in children. Various studies have illustrated the competitive nature of Pb2+ with divalent metals from the metabolic pool, notably calcium ions (Ca2+). By exploiting transport pathways and binding sites on specific proteins, Pb2+ can infiltrate nearly every organ, including the brain. The N-methyl-D-aspartate receptor (NMDAR) is recognized as one of the key molecular targets for Pb2+. Mitochondria are also the subject of many studies investigating the toxicity of lead. Maintaining the health of the fragile developing nervous system during prenatal and neonatal stages necessitates diligent monitoring and reassessment of what constitutes safe lead ion concentrations in the bloodstream.


divalent metals; lead; mitochondria; neurotoxicity; neurodegenerative disorders; NMDAR; oxidative stress; synaptic conduction

Full Text:



The restriction of the use of certain hazardous substances in electrical and electronic equipment (amendment) regulations 2009. Environmental Protection. Statutory Instruments 2009, No. 581. (14.04.2023).

Directive 98/70/EC of the European Parliament and of the Council of 13 October 1998 relating to the quality of petrol and diesel fuels and amending Council Directive 93/12/EEC. Official Journal of the European Communities 1998;L 350(41):58-67.

Blackowicz MJ, Hryhorczuk DO, Rankin KM, Lewis DA, Haider D, Lanphear BP, et al. The impact of low-level lead toxicity on school performance among Hispanic subgroups in the Chicago Public Schools. Int J Environ Res Public Health 2016;13(8):774. doi: 10.3390/ijerph13080774.

Cecil KM, Brubaker CJ, Adler CM, Dietrich KN, Altaye M, Egelhoff JC, et al. Decreased brain volume in adults with childhood lead exposure. PLoS Med 2008;5(5):e112. doi: 10.1371/journal.pmed.0050112.

Stansfield KH, Pilsner JR, Lu Q, Wright RO, Guilarte TR. Dysregulation of BDNF-TrkB signaling in developing hippocampal neurons by Pb(2+): implications for an environmental basis of neurodevelopmental disorders. Toxicol Sci 2012;127(1):277-95. doi: 10.1093/toxsci/kfs090.

Liu J, Liu X, Wang W, McCauley L, Pinto-Martin J, Wang Y, et al. Blood lead concentrations and children’s behavioral and emotional problems: a cohort study. JAMA Pediatr 2014;168(8):737-45. doi: 10.1001/jamapediatrics.2014.332.

CDC. Blood Lead Reference Value. 2022. (14.04.2023).

Wells AC, Venn JB, Heard MJ. Deposition in the lung and uptake to blood of motor exhaust labelled with 203Pb. Inhaled Part 1975;4 Pt 1:175-89.

Bailey MR, Roy M. Human respiratory tract model for radiological protection. A report of a Task Group of the International Commission on Radiological Protection. Ann ICRP 1994;24(1-3):1-482. Erratum in: Ann ICRP 1995;25(3-4):iii. Ann ICRP 2002;32(1-2):307-9.

Heard MJ, Wells AC, Newton D, Chamberlain AC. Human uptake and metabolism of tetra ethyl and tetra methyl lead vapour labelled with 203Pb. In: International Conference on Management and Control of Heavy Metals in the Environment. London: CEP Consultants; 1979. p. 103-8.

Mushak P. Gastro-intestinal absorption of lead in children and adults: overview of biological and biophysico-chemical aspects. Chem Spec Bioavailab 1991;3(3-4):87-104. doi: 10.1080/09542299.1991.11083160.

Bronner F, Pansu D, Stein WD. An analysis of intestinal calcium transport across the rat intestine. Am J Physiol 1986;250(5 Pt 1):G561-9. doi: 10.1152/ajpgi.1986.250.5.G561.

Teichmann R, Stremmel W. Iron uptake by human upper small intestine microvillous membrane vesicles. Indication for a facilitated transport mechanism mediated by a membrane iron-binding protein. J Clin Invest 1990;86(6):2145-53. doi: 10.1172/JCI114953.

Watson WS, Morrison J, Bethel MI, Baldwin NM, Lyon DT, Dobson H, et al. Food iron and lead absorption in humans. Am J Clin Nutr 1986;44(2):248-56. doi: 10.1093/ajcn/44.2.248.

Marcus AH, Schwartz J. Dose-response curves for erythrocyte protoporphyrin vs blood lead: effects of iron status. Environ Res 1987;44(2):221-7. doi: 10.1016/s0013-9351(87)80230-x.

Elias SM, Hashim Z, Marjan ZM, Abdullah AS, Hashim JH. Relationship between blood lead concentration and nutritional status among Malay primary school children in Kuala Lumpur, Malaysia. Asia Pac J Public Health 2007;19(3):29-37. doi: 10.1177/101053950701900306.

Maddaloni M, Lolacono N, Manton W, Blum C, Drexler J, Graziano J. Bioavailability of soilborne lead in adults, by stable isotope dilution. Environ Health Perspect 1998;106 Suppl 6(Suppl 6):1589-94. doi: 10.1289/ehp.98106s61589.

Ziegler EE, Edwards BB, Jensen RL, Mahaffey KR, Fomon SJ. Absorption and retention of lead by infants. Pediatr Res 1978;12(1):29-34. doi: 10.1203/00006450-197801000-00008.

Sun CC, Wong TT, Hwang YH, Chao KY, Jee SH, Wang JD. Percutaneous absorption of inorganic lead compounds. AIHA J (Fairfax, Va) 2002;63(5):641-6. doi: 10.1080/15428110208984751.

Laug EP, Kunze FM. The penetration of lead through the skin. J Ind Hyg Toxicol 1948;30(4):256-9.

Bergdahl IA, Sheveleva M, Schütz A, Artamonova VG, Skerfving S. Plasma and blood lead in humans: capacity-limited binding to delta-aminolevulinic acid dehydratase and other lead-binding components. Toxicol Sci 1998;46(2):247-53. doi: 10.1006/toxs.1998.2535.

Schütz A, Bergdahl IA, Ekholm A, Skerfving S. Measurement by ICP-MS of lead in plasma and whole blood of lead workers and controls. Occup Environ Med 1996;53(11):736-40. doi: 10.1136/oem.53.11.736.

Bannon DI, Olivi L, Bressler J. The role of anion exchange in the uptake of Pb by human erythrocytes and Madin–Darby canine kidney cells. Toxicology 2000;147(2):101-7. doi: 10.1016/s0300-483x(00)00187-6.

Calderón-Salinas JV, Quintanar-Escorcia MA, González-Martínez MT, Hernández-Luna CE. Lead and calcium transport in human erythrocyte. Hum Exp Toxicol 1999;18(5):327-32. doi: 10.1191/096032799678840138.

Bergdahl IA, Grubb A, Schütz A, Desnick RJ, Wetmur JG, Sassa S, et al. Lead binding to delta-aminolevulinic acid dehydratase (ALAD) in human erythrocytes. Pharmacol Toxicol 1997;81(4):153-8. doi: 10.1111/j.1600-0773.1997.tb02061.x.

Simons TJ. Active transport of lead by the calcium pump in human red cell ghosts. J Physiol 1988;405:105-13. doi: 10.1113/jphysiol.1988.sp017323.

Barry PS. A comparison of concentrations of lead in human tissues. Br J Ind Med 1975;32(2):119-39. doi: 10.1136/oem.32.2.119.

Behinaein S, Chettle DR, Egden LM, McNeill FE, Norman G, Richard N, et al. The estimation of the rates of lead exchange between body compartments of smelter employees. Environ Sci Process Impacts 2014;16(7):1705-15. doi: 10.1039/c4em00032c.

Hernandez-Avila M, Gonzalez-Cossio T, Palazuelos E, Romieu I, Aro A, Fishbein E, et al. Dietary and environmental determinants of blood and bone lead levels in lactating postpartum women living in Mexico City. Environ Health Perspect 1996;104(10):1076-82. doi: 10.1289/ehp.961041076.

Gross SB, Pfitzer EA, Yeager DW, Kehoe RA. Lead in human tissues. Toxicol Appl Pharmacol 1975;32(3):638-51. doi: 10.1016/0041-008x(75)90127-1.

Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood–brain barrier. Neurobiol Dis 2010;37(1):13-25. doi: 10.1016/j.nbd.2009.07.030.

Tomsig JL, Suszkiw JB. Permeation of Pb2+ through calcium channels: fura-2 measurements of voltage- and dihydropyridine-sensitive Pb2+ entry in isolated bovine chromaffin cells. Biochim Biophys Acta 1991;1069(2):197-200. doi: 10.1016/0005-2736(91)90124-q.

Kerper LE, Hinkle PM. Lead uptake in brain capillary endothelial cells: activation by calcium store depletion. Toxicol Appl Pharmacol 1997;146(1):127-33. doi: 10.1006/taap.1997.8234.

Luo W, Ruan D, Yan C, Yin S, Chen J. Effects of chronic lead exposure on functions of nervous system in Chinese children and developmental rats. Neurotoxicology 2012;33(4):862-71. doi: 10.1016/j.neuro.2012.03.008.

Deane R, Bradbury MW. Transport of lead-203 at the blood–brain barrier during short cerebrovascular perfusion with saline in the rat. J Neurochem 1990;54(3):905-14. doi: 10.1111/j.1471-4159.1990.tb02337.x.

Struzyńska L, Walski M, Gadamski R, Dabrowska-Bouta B, Rafałowska U. Lead-induced abnormalities in blood-brain barrier permeability in experimental chronic toxicity. Mol Chem Neuropathol 1997;31(3):207-24. doi: 10.1007/BF02815125.

Bradbury MW, Deane R. Permeability of the blood–brain barrier to lead. Neurotoxicology 1993;14(2-3):131-6.

Guilarte TR, McGlothan JL, Nihei MK. Hippocampal expression of N-methyl-D-aspartate receptor (NMDAR1) subunit splice variant mRNA is altered by developmental exposure to Pb(2+). Brain Res Mol Brain Res 2000;76(2):299-305. doi: 10.1016/s0169-328x(00)00010-3.

Zhang XY, Liu AP, Ruan DY, Liu J. Effect of developmental lead exposure on the expression of specific NMDA receptor subunit mRNAs in the hippocampus of neonatal rats by digoxigenin-labeled in situ hybridization histochemistry. Neurotoxicol Teratol 2002;24(2):149-60. doi: 10.1016/s0892-0362(01)00210-0.

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. doi: 10.1177/0960327107070560.

Zheng W, Lu YM, Lu GY, Zhao Q, Cheung O, Blaner WS. Transthyretin, thyroxine, and retinol-binding protein in human cerebrospinal fluid: effect of lead exposure. Toxicol Sci 2001;61(1):107-14. doi: 10.1093/toxsci/61.1.107.

Tiffany-Castiglion E, Qian Y. Astroglia as metal depots: molecular mechanisms for metal accumulation, storage and release. Neurotoxicology 2001;22(5):577-92. doi: 10.1016/s0161-813x(01)00050-x.

Struzyńska L. The protective role of astroglia in the early period of experimental lead toxicity in the rat. Acta Neurobiol Exp (Wars) 2000;60(2):167-73.

Legare ME, Barhoumi R, Hebert E, Bratton GR, Burghardt RC, Tiffany--Castiglioni E. Analysis of Pb2+ entry into cultured astroglia. Toxicol Sci 1998;46(1):90-100. doi: 10.1006/toxs.1998.2492.

Lindahl LS, Bird L, Legare ME, Mikeska G, Bratton GR, Tiffany-Castiglioni E. Differential ability of astroglia and neuronal cells to accumulate lead: dependence on cell type and on degree of differentiation. Toxicol Sci 1999;50(2):236-43. doi: 10.1093/toxsci/50.2.236.

Selvín-Testa A, Lopez-Costa JJ, Nessi de Aviñon AC, Pecci Saavedra J. Astroglial alterations in rat hippocampus during chronic lead exposure. Glia 1991;4(4):384-92. doi: 10.1002/glia.440040406.

Tiffany-Castiglioni E. Cell culture models for lead toxicity in neuronal and glial cells. Neurotoxicology 1993;14(4):513-36.

Ma T, Wu X, Cai Q, Wang Y, Xiao L, Tian Y, et al. Lead poisoning disturbs oligodendrocytes differentiation involved in decreased expression of NCX3 inducing intracellular calcium overload. Int J Mol Sci 2015;16(8):19096-110. doi: 10.3390/ijms160819096.

Deng W, McKinnon RD, Poretz RD. Lead exposure delays the differentiation of oligodendroglial progenitors in vitro. Toxicol Appl Pharmacol 2001;174(3):235-44. doi: 10.1006/taap.2001.9219.

Mazzolini M, Traverso S, Marchetti C. Multiple pathways of Pb(2+) permeation in rat cerebellar granule neurones. J Neurochem 2001;79(2):407-16. doi: 10.1046/j.1471-4159.2001.00557.x.

Atchison WD. Effects of toxic environmental contaminants on voltage--gated calcium channel function: from past to present. J Bioenerg Biomembr 2003;35(6):507-32. doi: 10.1023/b:jobb.0000008023.11211.13.

Kern M, Wisniewski M, Cabell L, Audesirk G. Inorganic lead and calcium interact positively in activation of calmodulin. Neurotoxicology 2000;21(3):353-63.

Kirberger M, Yang JJ. Structural differences between Pb2+- and Ca2+-binding sites in proteins: implications with respect to toxicity. J Inorg Biochem 2008;102(10):1901-9. doi: 10.1016/j.jinorgbio.2008.06.014.

Li S, Liu XL, Zhou XL, Jiang SJ, Yuan H. Expression of calmodulin-related genes in lead-exposed mice. Interdiscip Toxicol 2015;8(4):155-8. doi: 10.1515/intox-2015-0024.

Tomsig JL, Suszkiw JB. Multisite interactions between Pb2+ and protein kinase C and its role in norepinephrine release from bovine adrenal chromaffin cells. J Neurochem 1995;64(6):2667-73. doi: 10.1046/j.1471-4159.1995.64062667.x.

Ordemann JM, Austin RN. Lead neurotoxicity: exploring the potential impact of lead substitution in zinc-finger proteins on mental health. Metallomics 2016;8(6):579-88. doi: 10.1039/c5mt00300h.

Zawia NH, Crumpton T, Brydie M, Reddy GR, Razmiafshari M. Disruption of the zinc finger domain: a common target that underlies many of the effects of lead. Neurotoxicology 2000;21(6):1069-80.

Basha MR, 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 Dev Neurosci 2003;21(1):1-12. doi: 10.1016/s0736-5748(02)00137-5.

Reddy GR, Zawia NH. Lead exposure alters Egr-1 DNA-binding in the neonatal rat brain. Int J Dev Neurosci 2000;18(8):791-5. doi: 10.1016/s0736-5748(00)00048-4.

Ahamed M, Siddiqui MK. Low level lead exposure and oxidative stress: current opinions. Clin Chim Acta 2007;383(1-2):57-64. doi: 10.1016/j.cca.2007.04.024.

Guilarte TR, Miceli RC, Jett DA. Biochemical evidence of an interaction of lead at the zinc allosteric sites of the NMDA receptor complex: effects of neuronal development. Neurotoxicology 1995;16(1):63-71.

Gilbert ME, Lasley SM. Developmental lead (Pb) exposure reduces the ability of the NMDA antagonist MK-801 to suppress long-term potentiation (LTP) in the rat dentate gyrus, in vivo. Neurotoxicol Teratol 2007;29(3):385-93. doi: 10.1016/

Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizuno N, Nakanishi S. Molecular cloning and characterization of the rat NMDA receptor. Nature 1991;354(6348):31-7. doi: 10.1038/354031a0.

Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993;361(6407):31-9. doi: 10.1038/361031a0.

Baranowska-Bosiacka I, Gutowska I, Rybicka M, Nowacki P, Chlubek D. Neurotoxicity of lead. Hypothetical molecular mechanisms of synaptic function disorders. Neurol Neurochir Pol 2012;46(6):569-78. doi: 10.5114/ninp.2012.31607.

Morris RG, Anderson E, Lynch GS, Baudry M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 1986;319(6056):774-6. doi: 10.1038/319774a0.

Jansen M, Dannhardt G. Antagonists and agonists at the glycine site of the NMDA receptor for therapeutic interventions. Eur J Med Chem 2003;38(7--8):661-70. doi: 10.1016/s0223-5234(03)00113-2.

Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 2001;11(3):327-35. doi: 10.1016/s0959-4388(00)00215-4.

Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 1994;12(3):529-40. doi: 10.1016/0896-6273(94)90210-0.

Boyce S, Wyatt A, Webb JK, O’Donnell R, Mason G, Rigby M, et al. Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn. Neuropharmacology 1999;38(5):611-23. doi: 10.1016/s0028-3908(98)00218-4.

Walz C, Jüngling K, Lessmann V, Gottmann K. Presynaptic plasticity in an immature neocortical network requires NMDA receptor activation and BDNF release. J Neurophysiol 2006;96(6):3512-6. doi: 10.1152/jn.00018.2006.

Madara JC, Levine ES. Presynaptic and postsynaptic NMDA receptors mediate distinct effects of brain-derived neurotrophic factor on synaptic transmission. J Neurophysiol 2008;100(6):3175-84. doi: 10.1152/jn.90880.2008.

Fumagalli F, Racagni G, Riva MA. The expanding role of BDNF: a therapeutic target for Alzheimer’s disease? Pharmacogenomics J 2006;6(1):8-15. doi: 10.1038/sj.tpj.6500337.

Alkondon M, Costa AC, Radhakrishnan V, Aronstam RS, Albuquerque EX. Selective blockade of NMDA-activated channel currents may be implicated in learning deficits caused by lead. FEBS Lett 1990;261(1):124-30. doi: 10.1016/0014-5793(90)80652-y.

Byers RK, Lord EE. Late effects of lead poisoning on mental development. Am J Dis Child 1943;66(5):471-94. doi: 10.1001/archpedi.1943.02010230003001.

Chen Q, He S, Hu XL, Yu J, Zhou Y, Zheng J, et al. Differential roles of NR2A- and NR2B-containing NMDA receptors in activity-dependent brain-derived neurotrophic factor gene regulation and limbic epileptogenesis. J Neurosci 2007;27(3):542-52. doi: 10.1523/JNEUROSCI.3607-06.2007.

Neal AP, Stansfield KH, Worley PF, Thompson RE, Guilarte TR. Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: potential role of NMDA receptor-dependent BDNF signaling. Toxicol Sci 2010;116(1):249-63. doi: 10.1093/toxsci/kfq111.

Bouton CM, Frelin LP, Forde CE, Arnold Godwin H, Pevsner J. Synaptotagmin I is a molecular target for lead. J Neurochem 2001;76(6):1724-35. doi: 10.1046/j.1471-4159.2001.00168.x.

Meyer JN, Leung MC, Rooney JP, Sendoel A, Hengartner MO, Kisby GE, et al. Mitochondria as a target of environmental toxicants. Toxicol Sci 2013;134(1):1-17. doi: 10.1093/toxsci/kft102.

Baranowska-Bosiacka I, Gutowska I, Marchetti C, Rutkowska M, Marchlewicz M, Kolasa A, et al. Altered energy status of primary cerebellar granule neuronal cultures from rats exposed to lead in the pre- and neonatal period. Toxicology 2011;280(1-2):24-32. doi: 10.1016/j.tox.2010.11.004.

Nam E, Han J, Suh JM, Yi Y, Lim MH. Link of impaired metal ion homeostasis to mitochondrial dysfunction in neurons. Curr Opin Chem Biol 2018;43:8-14. doi: 10.1016/j.cbpa.2017.09.009.

Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem 1992;59(5):1609-23. doi: 10.1111/j.1471-4159.1992.tb10990.x. Erratum in: J Neurochem 2012;120(5):850.

Jia Q, Du G, Li Y, Wang Z, Xie J, Gu J, et al. Pb2+ modulates ryanodine receptors from the endoplasmic reticulum in rat brain. Toxicol Appl Pharmacol 2018;338:103-11. doi: 10.1016/j.taap.2017.11.013.

Kumar V, Tripathi VK, Jahan S, Agrawal M, Pandey A, Khanna VK, et al. Lead intoxication synergies of the ethanol-induced toxic responses in neuronal cells – PC12. Mol Neurobiol 2015;52(3):1504-20. doi: 10.1007/s12035-014-8928-x.

Virgolini MB, Aschner M. Molecular mechanisms of lead neurotoxicity. Adv Neurotoxicol 2021;5:159-213. doi: 10.1016/bs.ant.2020.11.002.

Gurer-Orhan H, Sabir HU, Ozgüneş H. Correlation between clinical indicators of lead poisoning and oxidative stress parameters in controls and lead-exposed workers. Toxicology 2004;195(2-3):147-54. doi: 10.1016/j.tox.2003.09.009.

Cairo G, Bernuzzi F, Recalcati S. A precious metal: iron, an essential nutrient for all cells. Genes Nutr 2006;1(1):25-39. doi: 10.1007/BF02829934.

Kirberger M, Wong HC, Jiang J, Yang JJ. Metal toxicity and opportunistic binding of Pb(2+) in proteins. J Inorg Biochem 2013;125:40-9. doi: 10.1016/j.jinorgbio.2013.04.002.

Zhu G, Fan G, Feng C, Li Y, Chen Y, Zhou F, et al. 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(2-3):108-23. doi: 10.1016/j.toxlet.2012.11.024.


Copyright (c) 2023 Mikołaj Chlubek

License URL: