• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Sep 3, 1996; 93(18): 9915–9920.
PMCID: PMC38529

Low lead levels stunt neuronal growth in a reversible manner.

Abstract

The developing brain is particularly susceptible to lead toxicity; however, the cellular effects of lead on neuronal development are not well understood. The effect of exposure to nanomolar concentrations of lead on several parameters of the developing retinotectal system of frog tadpoles was tested. Lead severely reduced the area and branchtip number of retinal ganglion cell axon arborizations within the optic tectum at submicromolar concentrations. These effects of lead on neuronal growth are more dramatic and occur at lower exposure levels than previously reported. Lead exposure did not interfere with the development of retinotectal topography. The deficient neuronal growth does not appear to be secondary to impaired synaptic transmission, because concentrations of lead that stunted neuronal growth were lower than those required to block synaptic transmission. Subsequent treatment of lead-exposed animals with the chelating agent 2,3-dimercaptosuccinic acid completely reversed the effect of lead on neuronal growth. These studies indicate that impaired neuronal growth may be responsible in part for lead-induced cognitive deficits and that chelator treatment counteracts this effect.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Fulton M, Raab G, Thomson G, Laxen D, Hunter R, Hepburn W. Influence of blood lead on the ability and attainment of children in Edinburgh. Lancet. 1987 May 30;1(8544):1221–1226. [PubMed]
  • Needleman HL, Schell A, Bellinger D, Leviton A, Allred EN. The long-term effects of exposure to low doses of lead in childhood. An 11-year follow-up report. N Engl J Med. 1990 Jan 11;322(2):83–88. [PubMed]
  • Shannon MW, Graef JW. Lead intoxication in infancy. Pediatrics. 1992 Jan;89(1):87–90. [PubMed]
  • Silbergeld EK. Mechanisms of lead neurotoxicity, or looking beyond the lamppost. FASEB J. 1992 Oct;6(13):3201–3206. [PubMed]
  • Bellinger D, Leviton A, Waternaux C, Needleman H, Rabinowitz M. Longitudinal analyses of prenatal and postnatal lead exposure and early cognitive development. N Engl J Med. 1987 Apr 23;316(17):1037–1043. [PubMed]
  • Chisolm JJ., Jr Mobilization of lead by calcium disodium edetate. A reappraisal. Am J Dis Child. 1987 Dec;141(12):1256–1257. [PubMed]
  • Aposhian HV, Aposhian MM. meso-2,3-Dimercaptosuccinic acid: chemical, pharmacological and toxicological properties of an orally effective metal chelating agent. Annu Rev Pharmacol Toxicol. 1990;30:279–306. [PubMed]
  • Smith DR, Flegal AR. Stable isotopic tracers of lead mobilized by DMSA chelation in low lead-exposed rats. Toxicol Appl Pharmacol. 1992 Sep;116(1):85–91. [PubMed]
  • Graziano JH, Lolacono NJ, Meyer P. Dose-response study of oral 2,3-dimercaptosuccinic acid in children with elevated blood lead concentrations. J Pediatr. 1988 Oct;113(4):751–757. [PubMed]
  • Graziano JH, Lolacono NJ, Moulton T, Mitchell ME, Slavkovich V, Zarate C. Controlled study of meso-2,3-dimercaptosuccinic acid for the management of childhood lead intoxication. J Pediatr. 1992 Jan;120(1):133–139. [PubMed]
  • Cline HT, Constantine-Paton M. NMDA receptor antagonists disrupt the retinotectal topographic map. Neuron. 1989 Oct;3(4):413–426. [PubMed]
  • Cholewa M, Hanson AL, Jones KW, McNally WP, Fand I. Regional distribution of lead in the brains of lead-intoxicated adult mice. Neurotoxicology. 1986 Spring;7(1):9–18. [PubMed]
  • Jones KW, Bockman RS, Bronner F. Microdistribution of lead in bone: a new approach. Neurotoxicology. 1992 Winter;13(4):835–841. [PubMed]
  • Langer R, Folkman J. Polymers for the sustained release of proteins and other macromolecules. Nature. 1976 Oct 28;263(5580):797–800. [PubMed]
  • Reh TA, Constantine-Paton M. Eye-specific segregation requires neural activity in three-eyed Rana pipiens. J Neurosci. 1985 May;5(5):1132–1143. [PubMed]
  • Schlaggar BL, O'Leary DD. Patterning of the barrel field in somatosensory cortex with implications for the specification of neocortical areas. Perspect Dev Neurobiol. 1993;1(2):81–91. [PubMed]
  • Simon DK, Prusky GT, O'Leary DD, Constantine-Paton M. N-methyl-D-aspartate receptor antagonists disrupt the formation of a mammalian neural map. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10593–10597. [PMC free article] [PubMed]
  • Rabacchi S, Bailly Y, Delhaye-Bouchaud N, Mariani J. Involvement of the N-methyl D-aspartate (NMDA) receptor in synapse elimination during cerebellar development. Science. 1992 Jun 26;256(5065):1823–1825. [PubMed]
  • Godement P, Wang LC, Mason CA. Retinal axon divergence in the optic chiasm: dynamics of growth cone behavior at the midline. J Neurosci. 1994 Nov;14(11 Pt 2):7024–7039. [PubMed]
  • Regan CM, Keegan K. Neuroteratological consequences of chronic low-level lead exposure. Dev Pharmacol Ther. 1990;15(3-4):189–195. [PubMed]
  • Lagunowich LA, Stein AP, Reuhl KR. N-cadherin in normal and abnormal brain development. Neurotoxicology. 1994 Spring;15(1):123–132. [PubMed]
  • Pamphlett R, Bayliss A. The effect of nerve crush and botulinum toxin on lead uptake in motor axons. Acta Neuropathol. 1992;84(1):89–93. [PubMed]
  • Simons TJ. Influence of lead ions on cation permeability in human red cell ghosts. J Membr Biol. 1985;84(1):61–71. [PubMed]
  • Evans ML, Büsselberg D, Carpenter DO. Pb2+ blocks calcium currents of cultured dorsal root ganglion cells. Neurosci Lett. 1991 Aug 5;129(1):103–106. [PubMed]
  • Wang YX, Quastel DM. Actions of lead on transmitter release at mouse motor nerve terminals. Pflugers Arch. 1991 Oct;419(3-4):274–280. [PubMed]
  • Reuveny E, Narahashi T. Potent blocking action of lead on voltage-activated calcium channels in human neuroblastoma cells SH-SY5Y. Brain Res. 1991 Apr 5;545(1-2):312–314. [PubMed]
  • Büsselberg D, Evans ML, Rahmann H, Carpenter DO. Lead and zinc block a voltage-activated calcium channel of Aplysia neurons. J Neurophysiol. 1991 Apr;65(4):786–795. [PubMed]
  • Constantine-Paton M, Cline HT, Debski E. Patterned activity, synaptic convergence, and the NMDA receptor in developing visual pathways. Annu Rev Neurosci. 1990;13:129–154. [PubMed]
  • Cline HT. Activity-dependent plasticity in the visual systems of frogs and fish. Trends Neurosci. 1991 Mar;14(3):104–111. [PubMed]
  • 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 Feb 12;261(1):124–130. [PubMed]
  • Cline HT, Constantine-Paton M. The differential influence of protein kinase inhibitors on retinal arbor morphology and eye-specific stripes in the frog retinotectal system. Neuron. 1990 Jun;4(6):899–908. [PubMed]
  • O'Rourke NA, Cline HT, Fraser SE. Rapid remodeling of retinal arbors in the tectum with and without blockade of synaptic transmission. Neuron. 1994 Apr;12(4):921–934. [PubMed]
  • Legare ME, Castiglioni AJ, Jr, Rowles TK, Calvin JA, Snyder-Armstead C, Tiffany-Castiglioni E. Morphological alterations of neurons and astrocytes in guinea pigs exposed to low levels of inorganic lead. Neurotoxicology. 1993 Spring;14(1):77–80. [PubMed]
  • Reuhl KR, Rice DC, Gilbert SG, Mallett J. Effects of chronic developmental lead exposure on monkey neuroanatomy: visual system. Toxicol Appl Pharmacol. 1989 Jul;99(3):501–509. [PubMed]
  • Kiràly E, Jones DG. Dendritic spine changes in rat hippocampal pyramidal cells after postnatal lead treatment: a Golgi study. Exp Neurol. 1982 Jul;77(1):236–239. [PubMed]
  • Alfano DP, Petit TL. Neonatal lead exposure alters the dendritic development of hippocampal dentate granule cells. Exp Neurol. 1982 Feb;75(2):275–288. [PubMed]
  • McConnell P, Berry M. The effects of postnatal lead exposure on Purkinje cell dendritic development in the rat. Neuropathol Appl Neurobiol. 1979 Mar-Apr;5(2):115–132. [PubMed]
  • Lorton D, Anderson WJ. Altered pyramidal cell dendritic development in the motor cortex of lead intoxicated neonatal rats. A Golgi study. Neurobehav Toxicol Teratol. 1986 Jan-Feb;8(1):45–50. [PubMed]
  • Niklowitz WJ. Ultrastructural effects of acute tetraethyllead poisoning on nerve cells of the rabbit brain. Environ Res. 1974 Aug;8(1):17–36. [PubMed]
  • Pounds JG. Effect of lead intoxication on calcium homeostasis and calcium-mediated cell function: a review. Neurotoxicology. 1984 Fall;5(3):295–331. [PubMed]
  • Markovac J, Goldstein GW. Picomolar concentrations of lead stimulate brain protein kinase C. Nature. 1988 Jul 7;334(6177):71–73. [PubMed]
  • Murakami K, Feng G, Chen SG. Inhibition of brain protein kinase C subtypes by lead. J Pharmacol Exp Ther. 1993 Feb;264(2):757–761. [PubMed]
  • Goldstein GW. Evidence that lead acts as a calcium substitute in second messenger metabolism. Neurotoxicology. 1993 Summer-Fall;14(2-3):97–101. [PubMed]
  • Bixby JL. Protein kinase C is involved in laminin stimulation of neurite outgrowth. Neuron. 1989 Sep;3(3):287–297. [PubMed]
  • Cabell L, Audesirk G. Effects of selective inhibition of protein kinase C, cyclic AMP-dependent protein kinase, and Ca(2+)-calmodulin-dependent protein kinase on neurite development in cultured rat hippocampal neurons. Int J Dev Neurosci. 1993 Jun;11(3):357–368. [PubMed]
  • Campenot RB, Walji AH, Draker DD. Effects of sphingosine, staurosporine, and phorbol ester on neurites of rat sympathetic neurons growing in compartmented cultures. J Neurosci. 1991 Apr;11(4):1126–1139. [PubMed]
  • Goshima Y, Ohsako S, Yamauchi T. Overexpression of Ca2+/calmodulin-dependent protein kinase II in Neuro2a and NG108-15 neuroblastoma cell lines promotes neurite outgrowth and growth cone motility. J Neurosci. 1993 Feb;13(2):559–567. [PubMed]
  • Zou DJ, Cline HT. Expression of constitutively active CaMKII in target tissue modifies presynaptic axon arbor growth. Neuron. 1996 Mar;16(3):529–539. [PubMed]
  • Fox DA, Katz LM. Developmental lead exposure selectively alters the scotopic ERG component of dark and light adaptation and increases rod calcium content. Vision Res. 1992 Feb;32(2):249–255. [PubMed]
  • Bushnell PJ, Bowman RE, Allen JR, Marlar RJ. Scotopic vision deficits in young monkeys exposed to lead. Science. 1977 Apr 15;196(4287):333–335. [PubMed]
  • Fjerdingstad EJ, Danscher G, Fjerdingstad E. Hippocampus: selective concentration of lead in the normal rat brain. Brain Res. 1974 Nov 15;80(2):350–354. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...