Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1990 Nov;89:43–48. doi: 10.1289/ehp.908943

Comparative observations on inorganic and organic lead neurotoxicity.

M A Verity 1
PMCID: PMC1567786  PMID: 1982434

Abstract

Environmental and occupational exposure to lead still generates concern, and recent studies have focused such concern on the role of body burden of lead during the fetal/neonatal period, especially in the genesis of disturbed central nervous system development. This discussion provides some comparative observations on the neurotoxicity of inorganic and organic lead species. The characteristics acute, predominantly cerebellar encephalopathy associated with neonatal high lead exposure contrasts to the subtle, axo-dendritic disorganization shown to be associated with low-level neonatal inorganic Pb2+ exposure. There is a preferential involvement of the hippocampus in both low-level inorganic Pb2+ and organolead exposure, and the clinical syndromes of irritability, hyperactivity, aggression, and seizures are common features of disturbed hippocampal function. Neurotransmitter system abnormalities have been described with inorganic Pb2+, but recent attention has focused on the abnormalities in glutamate, dopamine and/or gamma-aminobutyric acid (GABA) uptake, efflux, and metabolism. Abnormalities of GABA and glutamate metabolism are also found with the organolead species. While the pathogenesis is still unclear, the interactive role of Pb2+ on mitochondrial energy metabolism, Ca2+ uptake, intracellular Ca2+ homeostasis, and neurotransmitter influx/efflux is considered. Consideration is given to low-dose inorganic Pb2+ and organolead effects on mitochondrial and/or plasmalemmal membranes inducing either Cl-/OH- antiport-linked depolarization, inhibition of intracellular ATP biosynthesis and transduction. and/or abnormalities induced due to the preferential affinity of Pb2+ for intracellular Ca2(+)-cytoplasmic protein, e.g. calmodulin. Testable hypotheses are presented that may provide an understanding of the pathogenesis underlying dystrophic neuronal development under the influence of inorganic or organolead intoxication.

Full text

PDF
43

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aldridge W. N., Street B. W., Skilleter D. N. Oxidative phosphorylation. Halide-dependent and halide-independent effects of triorganotin and trioganolead compounds on mitochondrial functions. Biochem J. 1977 Dec 15;168(3):353–364. doi: 10.1042/bj1680353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alfano D. P., Petit T. L. Neonatal lead exposure alters the dendritic development of hippocampal dentate granule cells. Exp Neurol. 1982 Feb;75(2):275–288. doi: 10.1016/0014-4886(82)90160-1. [DOI] [PubMed] [Google Scholar]
  3. Allen J. R., McWey P. J., Suomi S. J. Pathobiological and behavioral effects of lead intoxication in the infant rhesus monkey. Environ Health Perspect. 1974 May;7:239–246. doi: 10.1289/ehp.747239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Avery D. D., Cross H. A., Schroeder T. The effects of tetraethyl lead on behavior in the rat. Pharmacol Biochem Behav. 1974 Jul-Aug;2(4):473–479. doi: 10.1016/0091-3057(74)90006-9. [DOI] [PubMed] [Google Scholar]
  5. Bennett M. R., White W. The survival and development of cholinergic neurons in potassium-enriched media. Brain Res. 1979 Sep 21;173(3):549–553. doi: 10.1016/0006-8993(79)90250-6. [DOI] [PubMed] [Google Scholar]
  6. Blaustein M. P. Effects of potassium, veratridine, and scorpion venom on calcium accumulation and transmitter release by nerve terminals in vitro. J Physiol. 1975 Jun;247(3):617–655. doi: 10.1113/jphysiol.1975.sp010950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bondy S. C., Anderson C. L., Harrington M. E., Prasad K. N. The effects of organic and inorganic lead and mercury on neurotransmitter high-affinity transport and release mechanisms. Environ Res. 1979 Jun;19(1):102–111. doi: 10.1016/0013-9351(79)90038-0. [DOI] [PubMed] [Google Scholar]
  8. CREMER J. E. Biochemical studies on the toxicity of tetraethyl lead and other organo-lead compounds. Br J Ind Med. 1959 Jul;16:191–199. doi: 10.1136/oem.16.3.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Campbell J. B., Woolley D. E., Vijayan V. K., Overmann S. R. Morphometric effects of postnatal lead exposure on hippocampal development of the 15-day-old rat. Brain Res. 1982 Apr;255(4):595–612. doi: 10.1016/0165-3806(82)90056-6. [DOI] [PubMed] [Google Scholar]
  10. Carroll P. T., Silbergeld E. K., Goldberg A. M. Alteration of central cholinergic function by chronic lead acetate exposure. Biochem Pharmacol. 1977 Mar 1;26(5):397–402. doi: 10.1016/0006-2952(77)90198-8. [DOI] [PubMed] [Google Scholar]
  11. Chalazonitis A., Fischbach G. D. Elevated potassium induces morphological differentiation of dorsal root ganglionic neurons in dissociated cell culture. Dev Biol. 1980 Jul;78(1):173–183. doi: 10.1016/0012-1606(80)90327-9. [DOI] [PubMed] [Google Scholar]
  12. Choi D. W. Ionic dependence of glutamate neurotoxicity. J Neurosci. 1987 Feb;7(2):369–379. doi: 10.1523/JNEUROSCI.07-02-00369.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Clasen R. A., Hartmann J. F., Starr A. J., Coogan P. S., Pandolfi S., Laing I., Becker R., Hass G. M. Electron microscopic and chemical studies of the vascular changes and edema of lead encephalopathy. A comparative study of the human and experimental disease. Am J Pathol. 1974 Feb;74(2):215–240. [PMC free article] [PubMed] [Google Scholar]
  14. Collins M. F., Hrdina P. D., Whittle E., Singhal R. L. Lead in blood and brain regions of rats chronically exposed to low doses of the metal. Toxicol Appl Pharmacol. 1982 Sep 15;65(2):314–322. doi: 10.1016/0041-008x(82)90014-x. [DOI] [PubMed] [Google Scholar]
  15. Erneux C., Passareiro H., Nunez J. Interaction between calmodulin and microtubule-associated proteins prepared at different stages of brain development. FEBS Lett. 1984 Jul 9;172(2):315–320. doi: 10.1016/0014-5793(84)81148-5. [DOI] [PubMed] [Google Scholar]
  16. Fjerdingstad E. J., Danscher G., Fjerdingstad E. Hippocampus: selective concentration of lead in the normal rat brain. Brain Res. 1974 Nov 15;80(2):350–354. doi: 10.1016/0006-8993(74)90699-4. [DOI] [PubMed] [Google Scholar]
  17. Gallo V., Kingsbury A., Balázs R., Jørgensen O. S. The role of depolarization in the survival and differentiation of cerebellar granule cells in culture. J Neurosci. 1987 Jul;7(7):2203–2213. doi: 10.1523/JNEUROSCI.07-07-02203.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gmerek D. E., McCafferty M. R., O'Neill K. J., Melamed B. R., O'Neill J. J. Effect of inorganic lead on rat brain mitochondrial respiration and energy production. J Neurochem. 1981 Mar;36(3):1109–1113. doi: 10.1111/j.1471-4159.1981.tb01706.x. [DOI] [PubMed] [Google Scholar]
  19. Govoni S., Memo M., Spano P. F., Trabucchi M. Chronic lead treatment differentially affects dopamine synthesis in various rat brain areas. Toxicology. 1979 Mar-Apr;12(3):343–349. doi: 10.1016/0300-483x(79)90081-7. [DOI] [PubMed] [Google Scholar]
  20. Goyer R. A., Rhyne B. C. Pathological effects of lead. Int Rev Exp Pathol. 1973;12:1–77. [PubMed] [Google Scholar]
  21. Holtzman D., Hsu J. S. Early effects of inorganic lead on immature rat brain mitochondrial respiration. Pediatr Res. 1976 Jan;10(1):70–75. doi: 10.1203/00006450-197601000-00014. [DOI] [PubMed] [Google Scholar]
  22. Holtzman D., Shen Hsu J., Mortell P. In vitro effects of inorganic lead on isolated rat brain mitochondrial respiration. Neurochem Res. 1978 Apr;3(2):195–206. doi: 10.1007/BF00964060. [DOI] [PubMed] [Google Scholar]
  23. Jason K. M., Kellogg C. K. Neonatal lead exposure: effects on development of behavior and striatal dopamine neurons. Pharmacol Biochem Behav. 1981 Oct;15(4):641–649. doi: 10.1016/0091-3057(81)90223-9. [DOI] [PubMed] [Google Scholar]
  24. Kauppinen R. A., Komulainen H., Taipale H. T. Chloride-dependent uncoupling of oxidative phosphorylation by triethyllead and triethyltin increases cytosolic free calcium in guinea pig cerebral cortical synaptosomes. J Neurochem. 1988 Nov;51(5):1617–1625. doi: 10.1111/j.1471-4159.1988.tb01132.x. [DOI] [PubMed] [Google Scholar]
  25. Kiràly E., Jones D. G. Dendritic spine changes in rat hippocampal pyramidal cells after postnatal lead treatment: a Golgi study. Exp Neurol. 1982 Jul;77(1):236–239. doi: 10.1016/0014-4886(82)90158-3. [DOI] [PubMed] [Google Scholar]
  26. Konat G., Clausen J. The effect of ?long-term administration of triethyl lead on the developing rat brain. Environ Physiol Biochem. 1974;4(5):236–242. [PubMed] [Google Scholar]
  27. Krigman M. R., Druse M. J., Traylor T. D., Wilson M. H., Newell L. R., Hogan E. L. Lead encephalopathy in the developing rat: effect on cortical ontogenesis. J Neuropathol Exp Neurol. 1974 Oct;33(5):671–686. doi: 10.1097/00005072-197410000-00007. [DOI] [PubMed] [Google Scholar]
  28. Lucchi L., Memo M., Airaghi M. L., Spano P. F., Trabucchi M. Chronic lead treatment induces in rat a specific and differential effect on dopamine receptors in different brain areas. Brain Res. 1981 Jun 1;213(2):397–404. doi: 10.1016/0006-8993(81)90244-4. [DOI] [PubMed] [Google Scholar]
  29. MacLean P. D. The internal-external bonds of the memory process. J Nerv Ment Dis. 1969 Jul;149(1):40–47. doi: 10.1097/00005053-196907000-00006. [DOI] [PubMed] [Google Scholar]
  30. Mailman R. B., Krigman M. R., Mueller R. A., Mushak P., Breese G. R. Lead exposure during infancy permanently increases lithium-induced polydipsia. Science. 1978 Aug 18;201(4356):637–639. doi: 10.1126/science.675249. [DOI] [PubMed] [Google Scholar]
  31. Mailman R. B. Lithium-induced polydipsia: dependence on nigrostriatal dopamine pathway and relationship to changes in the renin-angiotensin system. Psychopharmacology (Berl) 1983;80(2):143–149. doi: 10.1007/BF00427958. [DOI] [PubMed] [Google Scholar]
  32. Marcum J. M., Dedman J. R., Brinkley B. R., Means A. R. Control of microtubule assembly-disassembly by calcium-dependent regulator protein. Proc Natl Acad Sci U S A. 1978 Aug;75(8):3771–3775. doi: 10.1073/pnas.75.8.3771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Markovac J., Goldstein G. W. Picomolar concentrations of lead stimulate brain protein kinase C. Nature. 1988 Jul 7;334(6177):71–73. doi: 10.1038/334071a0. [DOI] [PubMed] [Google Scholar]
  34. 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. doi: 10.1111/j.1365-2990.1979.tb00665.x. [DOI] [PubMed] [Google Scholar]
  35. Niklowitz W. J. Ultrastructural effects of acute tetraethyllead poisoning on nerve cells of the rabbit brain. Environ Res. 1974 Aug;8(1):17–36. doi: 10.1016/0013-9351(74)90060-7. [DOI] [PubMed] [Google Scholar]
  36. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986 Jul 18;233(4761):305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  37. Nunez J. Differential expression of microtubule components during brain development. Dev Neurosci. 1986;8(3):125–141. doi: 10.1159/000112248. [DOI] [PubMed] [Google Scholar]
  38. Parr D. R., Harris E. J. The effect of lead on the calcium-handling capacity of rat heart mitochondria. Biochem J. 1976 Aug 15;158(2):289–294. doi: 10.1042/bj1580289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Pentschew A., Garro F. Lead encephalo-myelopathy of the suckling rat and its implications on the porphyrinopathic nervous diseases. With special reference to the permeability disorders of the nervous system's capillaries. Acta Neuropathol. 1966 Jun 1;6(3):266–278. doi: 10.1007/BF00687857. [DOI] [PubMed] [Google Scholar]
  40. Pentschew A. Morphology and morphogenesis of lead encephalopathy. Acta Neuropathol. 1965 Nov 18;5(2):133–160. doi: 10.1007/BF00686515. [DOI] [PubMed] [Google Scholar]
  41. Petit T. L., Alfano D. P., LeBoutillier J. C. Early lead exposure and the hippocampus: a review and recent advances. Neurotoxicology. 1983 Spring;4(1):79–94. [PubMed] [Google Scholar]
  42. Petit T. L., LeBoutillier J. C. Effects of lead exposure during development on neocortical dendritic and synaptic structure. Exp Neurol. 1979 Jun;64(3):482–492. doi: 10.1016/0014-4886(79)90226-7. [DOI] [PubMed] [Google Scholar]
  43. Pfleger H., Wolf H. U. Activation of membrane-bound high-affinity calcium ion-sensitive adenosine triphosphatase of human erythrocytes by bivalent metal ions. Biochem J. 1975 May;147(2):359–361. doi: 10.1042/bj1470359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. ROSSI C. S., LEHNINGER A. L. STOICHIOMETRIC RELATIONSHIPS BETWEEN ACCUMULATION OF IONS BY MITOCHONDRIA AND THE ENERGY-COUPLING SITES IN THE RESPIRATORY CHAIN. Biochem Z. 1963;338:698–713. [PubMed] [Google Scholar]
  45. Raimondi A. J., Beckman F., Evans J. P. Fine structural changes in human lead encephalopathy. J Neuropathol Exp Neurol. 1968 Jan;27(1):154–154. [PubMed] [Google Scholar]
  46. Repko J. D., Corum C. R. Critical review and evaluation of the neurological and behavioral sequelae of inorganic lead absorption. CRC Crit Rev Toxicol. 1979 Jan;6(2):135–187. doi: 10.3109/10408447909113048. [DOI] [PubMed] [Google Scholar]
  47. Sauerhoff M. W., Michaelson I. A. Hyperactivity and brain catecholamines in lead-exposed developing rats. Science. 1973 Dec 7;182(4116):1022–1024. doi: 10.1126/science.182.4116.1022. [DOI] [PubMed] [Google Scholar]
  48. Schanne F. A., Kane A. B., Young E. E., Farber J. L. Calcium dependence of toxic cell death: a final common pathway. Science. 1979 Nov 9;206(4419):700–702. doi: 10.1126/science.386513. [DOI] [PubMed] [Google Scholar]
  49. Scott K. M., Hwang K. M., Jurkowitz M., Brierley G. P. Ion transport by heart mitochondria. 23. The effects of lead on mitochondrial reactions. Arch Biochem Biophys. 1971 Dec;147(2):557–567. doi: 10.1016/0003-9861(71)90413-9. [DOI] [PubMed] [Google Scholar]
  50. Seawright A. A., Brown A. W., Aldridge W. N., Verschoyle R. D., Street B. W. Neuropathological changes caused by trialkyllead compounds in the rat. Dev Toxicol Environ Sci. 1980;8:71–74. [PubMed] [Google Scholar]
  51. Seidman B. C., Olsen R. W., Verity M. A. Triethyllead inhibits gamma-aminobutyric acid binding to uptake sites in synaptosomal membranes. J Neurochem. 1987 Aug;49(2):415–420. doi: 10.1111/j.1471-4159.1987.tb02881.x. [DOI] [PubMed] [Google Scholar]
  52. Seidman B. C., Verity M. A. Selective inhibition of synaptosomal gamma-aminobutyric acid uptake by triethyllead: role of energy transduction and chloride ion. J Neurochem. 1987 Apr;48(4):1142–1149. doi: 10.1111/j.1471-4159.1987.tb05639.x. [DOI] [PubMed] [Google Scholar]
  53. Selwyn M. J., Dawson A. P., Stockdale M., Gains N. Chloride-hydroxide exchange across mitochondrial, erythrocyte and artificial lipid membranes mediated by trialkyl- and triphenyltin compounds. Eur J Biochem. 1970 May 1;14(1):120–126. doi: 10.1111/j.1432-1033.1970.tb00268.x. [DOI] [PubMed] [Google Scholar]
  54. Shier W. T., DuBourdieu D. J. Stimulation of phospholipid hydrolysis and cell death by mercuric chloride: evidence for mercuric ion acting as a calcium-mimetic agent. Biochem Biophys Res Commun. 1983 Feb 10;110(3):758–765. doi: 10.1016/0006-291x(83)91026-4. [DOI] [PubMed] [Google Scholar]
  55. Shier W. T., Dubourdieu D. J. Evidence for two calcium-dependent steps and a sodium-dependent step in the mechanism of cell killing by calcium ions in the presence of ionophore A23187. Am J Pathol. 1985 Aug;120(2):304–315. [PMC free article] [PubMed] [Google Scholar]
  56. Shih T. M., Hanin I. Chronic lead exposure in immature animals: neurochemical correlates. Life Sci. 1978 Sep 4;23(9):877–888. doi: 10.1016/0024-3205(78)90212-6. [DOI] [PubMed] [Google Scholar]
  57. Silbergeld E. K., Hruska R. E., Miller L. P., Eng N. Effects of lead in vivo and in vitro on GABAergic neurochemistry. J Neurochem. 1980 Jun;34(6):1712–1718. doi: 10.1111/j.1471-4159.1980.tb11265.x. [DOI] [PubMed] [Google Scholar]
  58. Simons T. J. Cellular interactions between lead and calcium. Br Med Bull. 1986 Oct;42(4):431–434. doi: 10.1093/oxfordjournals.bmb.a072162. [DOI] [PubMed] [Google Scholar]
  59. Simons T. J., Pocock G. Lead enters bovine adrenal medullary cells through calcium channels. J Neurochem. 1987 Feb;48(2):383–389. doi: 10.1111/j.1471-4159.1987.tb04105.x. [DOI] [PubMed] [Google Scholar]
  60. Skilleter D. N. The decrease of mitochondrial substrate uptake caused by trialkyltin and trialkyl-lead compounds in chloride media and its relevance to inhibition of oxidative phosphorylation. Biochem J. 1975 Feb;146(2):465–471. doi: 10.1042/bj1460465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Stockdale M., Dawson A. P., Selwyn M. J. Effects of trialkyltin and triphenyltin compounds on mitochondrial respiration. Eur J Biochem. 1970 Aug;15(2):342–351. doi: 10.1111/j.1432-1033.1970.tb01013.x. [DOI] [PubMed] [Google Scholar]
  62. Sturrock R. R. A quantitative histological study of the effects of acute triethyl lead poisoning on the adult mouse brain. Neuropathol Appl Neurobiol. 1979 Nov-Dec;5(6):419–431. doi: 10.1111/j.1365-2990.1979.tb00641.x. [DOI] [PubMed] [Google Scholar]
  63. WIESEL T. N., HUBEL D. H. EFFECTS OF VISUAL DEPRIVATION ON MORPHOLOGY AND PHYSIOLOGY OF CELLS IN THE CATS LATERAL GENICULATE BODY. J Neurophysiol. 1963 Nov;26:978–993. doi: 10.1152/jn.1963.26.6.978. [DOI] [PubMed] [Google Scholar]
  64. Walsh T. J., Tilson H. A. Neurobehavioral toxicology of the organoleads. Neurotoxicology. 1984 Fall;5(3):67–86. [PubMed] [Google Scholar]
  65. Winder C., Garten L. L., Lewis P. D. The morphological effects of lead on the developing central nervous system. Neuropathol Appl Neurobiol. 1983 Mar-Apr;9(2):87–108. doi: 10.1111/j.1365-2990.1983.tb00328.x. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES