Abstract
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.
Similar content being viewed by others
REFERENCES
Centers for Disease Control 1991. Preventing Lead Poisoning in Young Children, Centers for Disease Control, Atlanta.
Cory-Slechta, D.A. 1997. Relationships between Pb-induced changes in neurotransmitter system function and behavioral toxicity. Neurotoxicology. 18:673-688.
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.
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.
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.
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.
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.
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.
Lanphear, B.P. and Roghmann, K.J. 1997. Pathways of lead exposure in urban children. Environmental Res. 74:67-73.
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.
Faust, D. and Brown, J. 1987. Moderately elevated blood lead levels: Effects on neuropsychologic functioning in children. Pediatrics. 80:623-629.
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.
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.
Rice, D.C. 1996. Behavioral effects of lead: Commonalities between experimental and epidemiologic data. Environ Health Perspectives. 104:337-351.
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.
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.
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.
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.
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.
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.
Bliss, T.V.P. and Collingridge, G.L. 1993. A synaptic model of memory: Long-term potentiation in the hippocampus. Nature. 361:31-39.
Miller, G.D., Massaro, T.F., and Massaro, E.J. 1990. Interactions between lead and essential elements: A review. Neurotoxicology. 11:99-120.
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.
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.
Simons, T.J.B. 1995. The affinity of human erythrocyte porphobilinogen synthase for Zn2+ and Pb2+. Eur J Biochem. 234:178-183.
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.
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.
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.
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.
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.
Pounds, J.G. 1984. Effect of lead intoxication on calcium homeostasis and calcium-mediated cell function: A review. Neurotoxicology. 5:295-331.
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.
Cooper, G.P., Suszkiw, J.B., and Manalis, R.S. 1984. Heavy metals: Efects on synaptic transmission. Neurotoxicology. 5:247-266.
Fullmer, C.S. 1992. Intestinal interactions of lead and calcium. Neurotoxicology. 13:799-808.
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.
Cheung, W.Y. 1984. Calmodulin: Its potential role in cell proliferation and heavy metal toxicity. Fed. Proc. 43:2995-2999.
Habermann, E., Crowell, K., and Janicki, P. 1983. Lead and other metals can substitute for Ca2+ in calmodulin. Arch. Toxicol. 54:61-70.
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.
Goldstein, G.W. and Ar, D. 1983. Lead activates calmodulin sensitive processes. Life Sci. 33:1001-1006.
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.
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.
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.
Markovac, J. and Goldstein, G.W. 1988. Picomolar concentrations of lead stimulate brain protein kinase C. Nature. 334:71-73.
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.
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.
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.
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.
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.
Herschman, H.R. 1991. Primary response genes induced by growth factors and tumor promoters. Annu. Rev. Biochem. 60:281-319.
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.
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.
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.
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.
Smith, J.B., Dwyer, S.D., and Smith, L. 1989. Cadmium evokes inositol polyphosphate formation and calcium mobilization. J. Biol. Chem. 264:7115-7118.
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.
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.
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.
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.
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.
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.
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.
Hofmann, F., Biel, M., and Flockerzi, V. 1994. Molecular basis for Ca2+ channel diversity. Annu. Rev. Neurosci. 17:399-418.
Huang, K.-P. and Huang, F.L. 1993. How is protein kinase C activated in CNS. Neurochem. Int. 22:417-433.
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.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bressler, J., Kim, Ka., Chakraborti, T. et al. Molecular Mechanisms of Lead Neurotoxicity. Neurochem Res 24, 595–600 (1999). https://doi.org/10.1023/A:1022596115897
Issue Date:
DOI: https://doi.org/10.1023/A:1022596115897