Neurochemical Research

, Volume 24, Issue 4, pp 595–600 | Cite as

Molecular Mechanisms of Lead Neurotoxicity

  • Joseph Bressler
  • Kyung-ah Kim
  • Tamal Chakraborti
  • Gary Goldstein


Epidemiological studies have shown a strong relationship between the level of lead in blood and bone as assessed by performance on IQ tests and other psychometric tests. Approximately 1 out of 10 children in the United States have blood lead levels above 10μg/dl, which has been established as the level of concern. Studies on experimental animals exposed to lead after birth have shown learning deficits at similar blood lead levels. Since learning requires the remodeling of synapses in the brain, lead may specifically affect synaptic transmission. Although the molecular targets for lead are unknown, a vast amount of evidence accumulated over many years has shown that lead disrupts processes that are regulated by calcium. Our laboratory has been studying the effect of lead on protein kinase C, a family of isozymes some of which require calcium for activity. We and others have shown that picomolar concentrations of lead can replace micromolar concentrations of calcium in a protein kinase C enzyme assay. Furthermore, lead activates protein kinase C in intact cells and induces the expression of new genes by a mechanism dependent on protein kinase C. We propose that the learning deficits caused by lead are due to events regulated by protein kinase C that most likely occur at the synapse.

Lead calcium protein kinase C synapse behavior 


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  1. 1.
    Centers for Disease Control 1991. Preventing Lead Poisoning in Young Children, Centers for Disease Control, Atlanta.Google Scholar
  2. 2.
    Cory-Slechta, D.A. 1997. Relationships between Pb-induced changes in neurotransmitter system function and behavioral toxicity. Neurotoxicology. 18:673-688.Google Scholar
  3. 3.
    Lagerkvist, B.J., Ekesrydh, S., Englyst, V., Nordberg, G.F., Soderberg, H.A., and Wiklund, D.E. 1996. Increased blood lead and decreased calcium levels during pregnancy: A prospective study of Swedish women living near a smelter. Am. J. Public Health. 86:1247-1252.Google Scholar
  4. 4.
    Hernandez-Avila, M., Gonzalezcossio, T., Palazuelos, E., Romieu, I., Aro, A., Fishbein, E., Peterson, K.E., and Hu, H. 1996. Dietary and environmental determinants of blood and bone lead levels in lactating postpartum women living in Mexico City. Environmental Health Perspectives. 104:1076-1082.Google Scholar
  5. 5.
    Maldonado-Vega, M., Solorzano, J.C., Alboresmedina, A., Hernandezluna, C., and Calderonsalinas, J.V. 1996. Lead: Intestinal absorption and bone mobilization during lactation. Human & Exp. Toxicol. 15:872-877.Google Scholar
  6. 6.
    Rifai, N., Cohen, G., Wolf, M., Cohen, L., Faser, C., Savory, J., and DePalma, L. 1993. Incidence of lead poisoning in young children from inner-city, suburban, and rural communitites. Therapeutic Drug Monitoring. 15:71-74.Google Scholar
  7. 7.
    Brody, D.J., Pirkle, J.L., Kramer, R.A., Flegal, K.M., Matte, T.D., Gunter, E.W., and Paschal, D.C. 1994. Blood lead levels in the US population—Phase 1 of the third National Health and Nutrition Examination Survey (NHANES III, 1988 to 1991). JAMA. 272:277-283.Google Scholar
  8. 8.
    Alexander, L.M., Heaven, A., Delves, H.T., Moreton, J., and Trenouth, M.J. 1993. Relative exposure of children to lead from dust and drinking water. Archives of Environmental Health. 48:392-400.Google Scholar
  9. 9.
    Lanphear, B.P. and Roghmann, K.J. 1997. Pathways of lead exposure in urban children. Environmental Res. 74:67-73.Google Scholar
  10. 10.
    Needleman, H.L., Schell, A., Bellinger, D., Leviton, A., and Allred, E.N. 1990. The long-term effects of exposure to low doses of lead in childhood. An 11-year follow-up report. N. Engl. J. Med. 322:83-88.Google Scholar
  11. 11.
    Faust, D. and Brown, J. 1987. Moderately elevated blood lead levels: Effects on neuropsychologic functioning in children. Pediatrics. 80:623-629.Google Scholar
  12. 12.
    Bellinger, D.C. 1997. Epidemiologic approaches to characterizing the developmental neurotoxicity of lead. Pages 275-283, in Yasui, M., Strong, M.J., Ota, K., and Verity, M.A. (eds.), Mineral and Metal Neurotoxicology, CRC Press, Inc., New York.Google Scholar
  13. 13.
    Cory-Slechta, D.A. 1995. Relationships between lead-induced learning impairments and changes in dopaminergic, cholinergic, and glutamatergic neurotransmitter system functions. Annual Review of Pharmacol Toxicol. 35:391-415.Google Scholar
  14. 14.
    Rice, D.C. 1996. Behavioral effects of lead: Commonalities between experimental and epidemiologic data. Environ Health Perspectives. 104:337-351.Google Scholar
  15. 15.
    Purves, D. 1994. in Radicati di Brozolo, L.A., Superiore, S.N., and Pisa (eds.), Neural Activity and the Growth of the Brain, Cambridge University Press, Cambridge.Google Scholar
  16. 16.
    Kandel, E.R. 1985. Early experience, critical periods, and developmental fine tuning of brain architecture. Pages 757-769, in Kandel, E.R. and Schwartz, J.H. (eds.), Principles of Neural Science, Elsevier, New York.Google Scholar
  17. 17.
    Kandel, E.R. 1985. Synapse formation, trophic interaction between neurons and the development of behavior. Pages 743-755, in Kandel, E.R. and Schwartz, J.H. (eds.), Priciples of Neural Science, Elsevier, New York.Google Scholar
  18. 18.
    Lasley, S.M. and Gilbert, M.E. 1996. Presynaptic glutamatergic function in dentate gyrus in vivo is diminished by chronic exposure to inorganic lead. Brain Res. 736:125-134.Google Scholar
  19. 19.
    Zaiser, A.E. and Miletic, V. 1997. Prenatal and postnatal chronic exposure to low levels of inorganic lead attenuates long-term potentiation in the adult rat hippocampus in vivo. Neuroscience Letters. 239:128-130.Google Scholar
  20. 20.
    Gilbert, M.E., Mack, C.M., and Lasley, S.M. 1996. Chronic developmental lead exposure increases the threshold for long-term potentiation in rat dentate gyrus in vivo. Brain Res. 736:118-124.Google Scholar
  21. 21.
    Bliss, T.V.P. and Collingridge, G.L. 1993. A synaptic model of memory: Long-term potentiation in the hippocampus. Nature. 361:31-39.Google Scholar
  22. 22.
    Miller, G.D., Massaro, T.F., and Massaro, E.J. 1990. Interactions between lead and essential elements: A review. Neurotoxicology. 11:99-120.Google Scholar
  23. 23.
    Bebe, F.N. and Panemangalore, M. 1996. Modulation of tissue trace metal concentrations in weanling rats fed different levels of zine and exposed to oral lead and cadmium. Nutrition Res. 16:1369-1380.Google Scholar
  24. 24.
    Chisolm, J.J. Jr. 1980. Lead and other metals: A hypothesis of interaction. Pages 641-660, in Singhal, R.L. and Thomas, J.A. (eds.), Lead Toxicity, Urban Schwarzenberg, Baltimore.Google Scholar
  25. 25.
    Simons, T.J.B. 1995. The affinity of human erythrocyte porphobilinogen synthase for Zn2+ and Pb2+. Eur J Biochem. 234:178-183.Google Scholar
  26. 26.
    Choi, D.W. 1996. Zinc neurotoxicity may contribute to selective neuronal death following transient global cerebral ischemia. Cold Spring Harbor Symposia on Quantitative Biology. 61:385-387.Google Scholar
  27. 27.
    Canzoniero, L.M., Sensi, S.L., and Choi, D.W. 1997. Measurement of intracellular free zine in living neurons. Neurobiology of disease. 4:275-279.Google Scholar
  28. 28.
    Ujihara, H. and Abbuquerque, E.X. 1993. Developmental change of the inhibition by lead of NMDA-activated currents in cultured hippocampal neurons. J. Pharmacol. Exp. Ther. 263:868-875.Google Scholar
  29. 29.
    Guilarte, T.R., Miceli, R.C., and Jett, D.A. 1995. Biochemical evidence of an interaction of lead at the zinc allosteric sites of the NMDA receptor complex: Effects of neuronal development. Neurotoxicology. 16:63-72.Google Scholar
  30. 30.
    Cory-Slechta, D.A., Garcia-Osuna, M., and Greenamyre, J.T. 1997. Lead-induced changes in NMDA receptor complex binding: Correlations with learning accuracy and with sensitivity to learning impairments caused by MK-801 and NMDA administration. Behavioural Brain Res. 85:161-174.Google Scholar
  31. 31.
    Pounds, J.G. 1984. Effect of lead intoxication on calcium homeostasis and calcium-mediated cell function: A review. Neurotoxicology. 5:295-331.Google Scholar
  32. 32.
    Ziegler, E.E., Edwards, B.B., Jensen, R.L., Mahaffey, K.R., and Fomon, S.J. 1978. Absorption and retention of lead by infants. Pediat. Res. 12:29-34.Google Scholar
  33. 33.
    Cooper, G.P., Suszkiw, J.B., and Manalis, R.S. 1984. Heavy metals: Efects on synaptic transmission. Neurotoxicology. 5:247-266.Google Scholar
  34. 34.
    Fullmer, C.S. 1992. Intestinal interactions of lead and calcium. Neurotoxicology. 13:799-808.Google Scholar
  35. 35.
    Bernal, J., Lee, J.-H., Cribbs, L.L., and Perez-Reyes, E. 1997. Full reversal of Pb++ lock of L-type Ca++ channels requires treatment with heavy metal antidotes. J Pharmacol Exp Therapeutics. 282:172-180.Google Scholar
  36. 36.
    Cheung, W.Y. 1984. Calmodulin: Its potential role in cell proliferation and heavy metal toxicity. Fed. Proc. 43:2995-2999.Google Scholar
  37. 37.
    Habermann, E., Crowell, K., and Janicki, P. 1983. Lead and other metals can substitute for Ca2+ in calmodulin. Arch. Toxicol. 54:61-70.Google Scholar
  38. 38.
    Pauls, T.L., Cox, J.A., and Berchtold, M.W. 1996. The Ca2+(−) binding proteins parvalbumin and oncmodulin and their genes: New structural and functional findings. Biochimica. et Biophysica. Acta. 1306:39-54.Google Scholar
  39. 39.
    Goldstein, G.W. and Ar, D. 1983. Lead activates calmodulin sensitive processes. Life Sci. 33:1001-1006.Google Scholar
  40. 40.
    Kern, M. and Audesirk, G. 1995. Inorganic lead may inhibit neurite development in cultured rat hippocampoal neurons through hyperphosphorylation. Toxicol. Appl. Pharmacol. 134:111-123.Google Scholar
  41. 41.
    Giese, K.P., Fedorov, N.B., Flipkowski, R.K., and Silva, A.J. 1998. Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science. 279:870-873.Google Scholar
  42. 42.
    Cho, Y.H., Giese, K.P., Tanila, H., Silva, A.J., and Eichenbaum, H. 1998. Abnormal hippocampal spatial representations in alphaCaMKIIT286A and CREBalphaDelta-mice. Science. 279:867-869.Google Scholar
  43. 43.
    Markovac, J. and Goldstein, G.W. 1988. Picomolar concentrations of lead stimulate brain protein kinase C. Nature. 334:71-73.Google Scholar
  44. 44.
    Long, G.J., Rosen, J.F., and Schanne, F.A. 1994. Lead activation of protein kinase C from rat brain. Determination of free calcium, lead, and zinc by 19F NMR. J. Biol. Chem. 269:834-837.Google Scholar
  45. 45.
    Tomsig, J.L. and Suszkiw, J.B. 1995. Multisite interactions between Pb2+ and protein kinase C and its role in norepinephrine release from bovine adrenal chromaffin cells. J. Neurochem. 64:2667-2673.Google Scholar
  46. 46.
    Kazanietz, M.G. and Blumberg, P.M. 1996. Protein kinase C and signal transduction in normal and neoplastic cells. Pages 389-402, in Sirica, A.E. (ed.), Cellular and Molecular Pathogenesis, Lippincott-Raven, Philadelphia.Google Scholar
  47. 47.
    Laterra, J., Bressler, J.P., Indurti, R.R., Belloni-Olivi, L., and Goldstein, G.W. 1992. Inhibition of astroglial-induced endothelial differentiation by inorganic lead: A role for protein kinase C. Proc. Natl. Acad. Sci. USA. 89:10748-10752.Google Scholar
  48. 48.
    Belloni-Olivi, L., Annadata, M., Goldstein, G.W., and Bressler, J.P. 1996. Phosphorylation of membrane proteins in erythrocytes treated with lead. Biochem. J. 315:401-406.Google Scholar
  49. 49.
    Herschman, H.R. 1991. Primary response genes induced by growth factors and tumor promoters. Annu. Rev. Biochem. 60:281-319.Google Scholar
  50. 50.
    Sheng, M. and Greenberg, M.E. 1990. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron. 4:477-485.Google Scholar
  51. 51.
    Johansen, F.E. and Prywes, R. 1995. Serum response factor: Transcriptional regulation of genes induced by growth factors and differentiation. Biochimica. et Biophysica. Acta. 1242:1-10.Google Scholar
  52. 52.
    Schanne, F.A.X., Dowd, T.L., Gupta, R.K., and Rosen, J.F. 1989. Lead increases free Ca2+ concentration in cultured osteoblstic vone cells: Simultaneous detection of intracellular free Pb2+ by 19F NMR. Proc. Natl. Acad. Sci. USA. 86:6133-5135.Google Scholar
  53. 53.
    Dave, V., Vitarella, D., Aschner, J.L., Fletcher, P., Kimelberg, H.K., and Aschner, M. 1993. Lead increases inositol 1,4,5-trisphosphate levels but does not interfere with calcium transients in primary rat astrocytes. Brain Res. 618:9-18.Google Scholar
  54. 54.
    Smith, J.B., Dwyer, S.D., and Smith, L. 1989. Cadmium evokes inositol polyphosphate formation and calcium mobilization. J. Biol. Chem. 264:7115-7118.Google Scholar
  55. 55.
    Sheu, F.-S., McCabe, B.J., Horn, G., and Routtenberg, A. 1993. Learning selectively increases protein kinase C substrate phosphorylation in specific regions of the chick brain. Proc. Natl. Acad. Sci. USA. 90:2705-2709.Google Scholar
  56. 56.
    Ramakers, G.M.J., Degraan, P.N.E., Urban, I.J.A., Kraay, D., Tang, T., Pasinelli, P., Oestreicher, A.B., and Gispen, W.H. 1995. Temporal differences in the phosphorylation state of pre-and postsynaptic protein kinase C substrates B-50/GAP-43 and neurogranin during long term potentiation. J. Biol. Chem. 270:13892-13898.Google Scholar
  57. 57.
    Pasinelli, P., Ramakers, G.M., Urban, I.J., Hens, J.J., Oestreicher, A.B., de Graan, P.N., and Gispen, W.H. 1995. Long-term potentiation and synaptic protein phosphorylation. Behavioural Brain Res. 661:53-59.Google Scholar
  58. 58.
    Haycock, J.W. 1993. Multiple signaling pathways in bovine chromaffin cells regulate tyrosine hydroxylase phosphorylation at Ser19, Ser31, and Ser40. Neurochem. Res. 18:15-26.Google Scholar
  59. 59.
    Pitcher, J., Lohse, M.J., Codina, J., Caron, M.G., and Lefkowitz, R.J. 1992. Desensitization of the isolated β2-adrenergic receptor by β-adrenergic receptor kinase, cAMP-dependent protein kinase, and protein kinase-C occurs via distinct molecular mechanisms. Biochemistry. 31:3193-3197.Google Scholar
  60. 60.
    Patel, A.J., Hunt, A., Jacquesberg, W., Kiss, J., and Rodriguez, J. 1995. Effects of protein kinase C modulation on NMDA receptor mediated regulation of neurotransmitter enzyme and c-fos protein in cultured neurons. Neurochem. Res. 20:561-569.Google Scholar
  61. 61.
    Doerner, D., Abdel-Latif, M., Rogers, T.B., and Alger, B.E. 1990. Protein kinase C-dependent and-independent effects of phorbol esters on hippocampal calcium channel current. J. Neurosci. 10:1699-1706.Google Scholar
  62. 62.
    Hofmann, F., Biel, M., and Flockerzi, V. 1994. Molecular basis for Ca2+ channel diversity. Annu. Rev. Neurosci. 17:399-418.Google Scholar
  63. 63.
    Huang, K.-P. and Huang, F.L. 1993. How is protein kinase C activated in CNS. Neurochem. Int. 22:417-433.Google Scholar
  64. 64.
    Hundle, B., Mcmahon, T., Dadgar, J., and Messing, R.O. 1995. Overexpression of epsilon-protein kinase C enhances nerve growth factor-induced phosphorylation of mitogen-activated protein kinases and neurite outgrowth. J. Biol. Chem. 270:30134-30140.Google Scholar

Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • Joseph Bressler
    • 1
    • 2
  • Kyung-ah Kim
    • 1
    • 2
  • Tamal Chakraborti
    • 1
  • Gary Goldstein
    • 1
    • 2
    • 3
  1. 1.Depts. of NeurologyUSA
  2. 2.Environmental Health SciencesThe Johns Hopkins University School of Public Health and Hygiene and The Kennedy Krieger Research InstituteBaltimore
  3. 3.PediatricsThe Johns Hopkins University School of Public Health and Hygiene and The Kennedy Krieger Research InstituteBaltimore

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