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. 2002 Jun;110(Suppl 3):377–386. doi: 10.1289/ehp.02110s3377

Electrophysiologic and behavioral effects of perinatal and acute exposure of rats to lead and polychlorinated biphenyls.

David O Carpenter 1, Rifat J Hussain 1, David F Berger 1, John P Lombardo 1, Hye-Youn Park 1
PMCID: PMC1241186  PMID: 12060832

Abstract

Lead and polychlorinated biphenyls (PCBs) both cause a reduction of intelligence quotient and behavioral abnormalities in exposed children that have features in common with attention deficit hyperactivity disorder. We have used rats as a model to study the effects of both perinatal and acute exposure to lead or PCBs in an effort to compare and understand the mechanisms of these nervous system decrements. Long-term potentiation (LTP) is an electrophysiologic measurement that correlates well with cognitive ability. We have determined the effects of chronic perinatal exposure to lead or PCB 153 as well as acute application of these substances to isolated brain slices, with recordings in two areas of the hippocampus, CA1 and CA3. Both substances, whether chronically or acutely applied, significantly reduced LTP in CA1 in animals at age 30 and 60 days. In CA3, they reduced LTP in 30-day animals but potentiated it in 60-day animals. Although neither lead nor PCB 153 alters baseline synaptic transmission at low stimulus strengths, at higher levels they induce changes in the same direction as those of LTP. These results show surprisingly similar actions of these quite different chemicals, and the similarity of effects on chronic and acute application indicates that effects are both pharmacologic and developmental. Behavioral studies of rats exposed to PCBs from contaminated fish show hyperactivity, impulsiveness, and increased frustration relative to unexposed controls. These results demonstrate that lead and PCBs have similar effects on synaptic plasticity and behavior and suggest that the compounds may act through a common mechanism.

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Selected References

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  1. Alber S. A., Strupp B. J. An in-depth analysis of lead effects in a delayed spatial alternation task: assessment of mnemonic effects, side bias, and proactive interference. Neurotoxicol Teratol. 1996 Jan-Feb;18(1):3–15. doi: 10.1016/0892-0362(95)02026-8. [DOI] [PubMed] [Google Scholar]
  2. Altmann L., Mundy W. R., Ward T. R., Fastabend A., Lilienthal H. Developmental exposure of rats to a reconstituted PCB mixture or aroclor 1254: effects on long-term potentiation and [3H]MK-801 binding in occipital cortex and hippocampus. Toxicol Sci. 2001 Jun;61(2):321–330. doi: 10.1093/toxsci/61.2.321. [DOI] [PubMed] [Google Scholar]
  3. Altmann L., Weinsberg F., Sveinsson K., Lilienthal H., Wiegand H., Winneke G. Impairment of long-term potentiation and learning following chronic lead exposure. Toxicol Lett. 1993 Jan;66(1):105–112. doi: 10.1016/0378-4274(93)90085-c. [DOI] [PubMed] [Google Scholar]
  4. Angenstein F., Hirschfelder M., Staak S. Activation of metabotropic glutamate receptors increases endogenous protein kinase C substrate phosphorylation in adult hippocampal slices. Brain Res. 1997 Jan 16;745(1-2):46–54. doi: 10.1016/s0006-8993(96)01129-8. [DOI] [PubMed] [Google Scholar]
  5. Bach M. E., Barad M., Son H., Zhuo M., Lu Y. F., Shih R., Mansuy I., Hawkins R. D., Kandel E. R. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5280–5285. doi: 10.1073/pnas.96.9.5280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berger D. F., Lombardo J. P., Jeffers P. M., Hunt A. E., Bush B., Casey A., Quimby F. Hyperactivity and impulsiveness in rats fed diets supplemented with either Aroclor 1248 or PCB-contaminated St. Lawrence river fish. Behav Brain Res. 2001 Nov 29;126(1-2):1–11. doi: 10.1016/s0166-4328(01)00244-3. [DOI] [PubMed] [Google Scholar]
  7. Berger D. F., Sagvolden T. Sex differences in operant discrimination behaviour in an animal model of attention-deficit hyperactivity disorder. Behav Brain Res. 1998 Jul;94(1):73–82. doi: 10.1016/s0166-4328(97)00171-x. [DOI] [PubMed] [Google Scholar]
  8. Bliss T. V., Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 1973 Jul;232(2):331–356. doi: 10.1113/jphysiol.1973.sp010273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bowman R. E., Heironimus M. P., Barsotti D. A. Locomotor hyperactivity in PCB-exposed rhesus monkeys. Neurotoxicology. 1981 Oct;2(2):251–268. [PubMed] [Google Scholar]
  10. Braak H., Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–259. doi: 10.1007/BF00308809. [DOI] [PubMed] [Google Scholar]
  11. Chen Y. C., Guo Y. L., Hsu C. C. Cognitive development of children prenatally exposed to polychlorinated biphenyls (Yu-Cheng children) and their siblings. J Formos Med Assoc. 1992 Jul;91(7):704–707. [PubMed] [Google Scholar]
  12. Chen Y. C., Yu M. L., Rogan W. J., Gladen B. C., Hsu C. C. A 6-year follow-up of behavior and activity disorders in the Taiwan Yu-cheng children. Am J Public Health. 1994 Mar;84(3):415–421. doi: 10.2105/ajph.84.3.415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Colley P. A., Routtenberg A. Long-term potentiation as synaptic dialogue. Brain Res Brain Res Rev. 1993 Jan-Apr;18(1):115–122. doi: 10.1016/0165-0173(93)90009-o. [DOI] [PubMed] [Google Scholar]
  14. Fletcher J. M., Shaywitz S. E., Shaywitz B. A. Comorbidity of learning and attention disorders. Separate but equal. Pediatr Clin North Am. 1999 Oct;46(5):885-97, vi. doi: 10.1016/s0031-3955(05)70161-9. [DOI] [PubMed] [Google Scholar]
  15. Geller A. M., Oshiro W. M., Haykal-Coates N., Kodavanti P. R., Bushnell P. J. Gender-dependent behavioral and sensory effects of a commercial mixture of polychlorinated biphenyls (Aroclor 1254) in rats. Toxicol Sci. 2001 Feb;59(2):268–277. doi: 10.1093/toxsci/59.2.268. [DOI] [PubMed] [Google Scholar]
  16. Goldman-Rakic P. S. Cellular basis of working memory. Neuron. 1995 Mar;14(3):477–485. doi: 10.1016/0896-6273(95)90304-6. [DOI] [PubMed] [Google Scholar]
  17. Grandjean P., Weihe P., White R. F., Debes F., Araki S., Yokoyama K., Murata K., Sørensen N., Dahl R., Jørgensen P. J. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol. 1997 Nov-Dec;19(6):417–428. doi: 10.1016/s0892-0362(97)00097-4. [DOI] [PubMed] [Google Scholar]
  18. Guillette E. A., Meza M. M., Aquilar M. G., Soto A. D., Garcia I. E. An anthropological approach to the evaluation of preschool children exposed to pesticides in Mexico. Environ Health Perspect. 1998 Jun;106(6):347–353. doi: 10.1289/ehp.98106347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gutowski M., Altmann L., Sveinsson K., Wiegand H. Postnatal development of synaptic plasticity in the CA3 hippocampal region of control and lead-exposed Wistar rats. Brain Res Dev Brain Res. 1997 Jan 2;98(1):82–90. doi: 10.1016/s0165-3806(96)00178-2. [DOI] [PubMed] [Google Scholar]
  20. Gómez R. A., Pozzo Miller L. D., Aoki A., Ramírez O. A. Long-term potentiation-induced synaptic changes in hippocampal dentate gyrus of rats with an inborn low or high learning capacity. Brain Res. 1990 Dec 24;537(1-2):293–297. doi: 10.1016/0006-8993(90)90371-h. [DOI] [PubMed] [Google Scholar]
  21. Haddow J. E., Palomaki G. E., Allan W. C., Williams J. R., Knight G. J., Gagnon J., O'Heir C. E., Mitchell M. L., Hermos R. J., Waisbren S. E. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999 Aug 19;341(8):549–555. doi: 10.1056/NEJM199908193410801. [DOI] [PubMed] [Google Scholar]
  22. Holene E., Nafstad I., Skaare J. U., Krogh H., Sagvolden T. Behavioural effects in female rats of postnatal exposure to sub-toxic doses of polychlorinated biphenyl congener 153. Acta Paediatr Suppl. 1999 May;88(429):55–63. doi: 10.1111/j.1651-2227.1999.tb01291.x. [DOI] [PubMed] [Google Scholar]
  23. Holene E., Nafstad I., Skaare J. U., Sagvolden T. Behavioural hyperactivity in rats following postnatal exposure to sub-toxic doses of polychlorinated biphenyl congeners 153 and 126. Behav Brain Res. 1998 Jul;94(1):213–224. doi: 10.1016/s0166-4328(97)00181-2. [DOI] [PubMed] [Google Scholar]
  24. Hori N., Büsselberg D., Matthews M. R., Parsons P. J., Carpenter D. O. Lead blocks LTP by an action not at NMDA receptors. Exp Neurol. 1993 Feb;119(2):192–197. doi: 10.1006/exnr.1993.1020. [DOI] [PubMed] [Google Scholar]
  25. Hori N., Hirotsu I., Davis P. J., Carpenter D. O. Long-term potentiation is lost in aged rats but preserved by calorie restriction. Neuroreport. 1992 Dec;3(12):1085–1088. doi: 10.1097/00001756-199212000-00013. [DOI] [PubMed] [Google Scholar]
  26. Hussain R. J., Gyori J., DeCaprio A. P., Carpenter D. O. In vivo and in vitro exposure to PCB 153 reduces long-term potentiation. Environ Health Perspect. 2000 Sep;108(9):827–831. doi: 10.1289/ehp.00108827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hussain R. J., Parsons P. J., Carpenter D. O. Effects of lead on long-term potentiation in hippocampal CA3 vary with age. Brain Res Dev Brain Res. 2000 Jun 30;121(2):243–252. doi: 10.1016/s0165-3806(00)00051-1. [DOI] [PubMed] [Google Scholar]
  28. Jacobson J. L., Jacobson S. W. Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med. 1996 Sep 12;335(11):783–789. doi: 10.1056/NEJM199609123351104. [DOI] [PubMed] [Google Scholar]
  29. Kodavanti P. R., Derr-Yellin E. C., Mundy W. R., Shafer T. J., Herr D. W., Barone S., Choksi N. Y., MacPhail R. C., Tilson H. A. Repeated exposure of adult rats to Aroclor 1254 causes brain region-specific changes in intracellular Ca2+ buffering and protein kinase C activity in the absence of changes in tyrosine hydroxylase. Toxicol Appl Pharmacol. 1998 Dec;153(2):186–198. doi: 10.1006/taap.1998.8533. [DOI] [PubMed] [Google Scholar]
  30. Leech S. L., Richardson G. A., Goldschmidt L., Day N. L. Prenatal substance exposure: effects on attention and impulsivity of 6-year-olds. Neurotoxicol Teratol. 1999 Mar-Apr;21(2):109–118. doi: 10.1016/s0892-0362(98)00042-7. [DOI] [PubMed] [Google Scholar]
  31. Mannuzza S., Klein R. G., Bessler A., Malloy P., LaPadula M. Adult outcome of hyperactive boys. Educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry. 1993 Jul;50(7):565–576. doi: 10.1001/archpsyc.1993.01820190067007. [DOI] [PubMed] [Google Scholar]
  32. Martin S. J., Grimwood P. D., Morris R. G. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci. 2000;23:649–711. doi: 10.1146/annurev.neuro.23.1.649. [DOI] [PubMed] [Google Scholar]
  33. Muldoon S. B., Cauley J. A., Kuller L. H., Morrow L., Needleman H. L., Scott J., Hooper F. J. Effects of blood lead levels on cognitive function of older women. Neuroepidemiology. 1996;15(2):62–72. doi: 10.1159/000109891. [DOI] [PubMed] [Google Scholar]
  34. Needleman H. L., Gunnoe C., Leviton A., Reed R., Peresie H., Maher C., Barrett P. Deficits in psychologic and classroom performance of children with elevated dentine lead levels. N Engl J Med. 1979 Mar 29;300(13):689–695. doi: 10.1056/NEJM197903293001301. [DOI] [PubMed] [Google Scholar]
  35. Needleman H. L., Schell A., Bellinger D., Leviton A., Allred E. N. 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. doi: 10.1056/NEJM199001113220203. [DOI] [PubMed] [Google Scholar]
  36. Niemi W. D., Audi J., Bush B., Carpenter D. O. PCBs reduce long-term potentiation in the CA1 region of rat hippocampus. Exp Neurol. 1998 May;151(1):26–34. doi: 10.1006/exnr.1998.6793. [DOI] [PubMed] [Google Scholar]
  37. Rice D. C. Behavioral effects of lead: commonalities between experimental and epidemiologic data. Environ Health Perspect. 1996 Apr;104 (Suppl 2):337–351. doi: 10.1289/ehp.96104s2337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Rice D. C. Behavioral impairment produced by low-level postnatal PCB exposure in monkeys. Environ Res. 1999 Feb;80(2 Pt 2):S113–S121. doi: 10.1006/enrs.1998.3917. [DOI] [PubMed] [Google Scholar]
  39. Rice D. C. Lead-induced changes in learning: evidence for behavioral mechanisms from experimental animal studies. Neurotoxicology. 1993 Summer-Fall;14(2-3):167–178. [PubMed] [Google Scholar]
  40. Rice D. C. Parallels between attention deficit hyperactivity disorder and behavioral deficits produced by neurotoxic exposure in monkeys. Environ Health Perspect. 2000 Jun;108 (Suppl 3):405–408. doi: 10.1289/ehp.00108s3405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Rosen J. F., Mushak P. Primary prevention of childhood lead poisoning--the only solution. N Engl J Med. 2001 May 10;344(19):1470–1471. doi: 10.1056/NEJM200105103441910. [DOI] [PubMed] [Google Scholar]
  42. SCOVILLE W. B., MILNER B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957 Feb;20(1):11–21. doi: 10.1136/jnnp.20.1.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sakimura K., Kutsuwada T., Ito I., Manabe T., Takayama C., Kushiya E., Yagi T., Aizawa S., Inoue Y., Sugiyama H. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature. 1995 Jan 12;373(6510):151–155. doi: 10.1038/373151a0. [DOI] [PubMed] [Google Scholar]
  44. Schantz S. L., Gasior D. M., Polverejan E., McCaffrey R. J., Sweeney A. M., Humphrey H. E., Gardiner J. C. Impairments of memory and learning in older adults exposed to polychlorinated biphenyls via consumption of Great Lakes fish. Environ Health Perspect. 2001 Jun;109(6):605–611. doi: 10.1289/ehp.01109605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Schantz S. L., Moshtaghian J., Ness D. K. Spatial learning deficits in adult rats exposed to ortho-substituted PCB congeners during gestation and lactation. Fundam Appl Toxicol. 1995 Jun;26(1):117–126. doi: 10.1006/faat.1995.1081. [DOI] [PubMed] [Google Scholar]
  46. Schwartz B. S., Stewart W. F., Bolla K. I., Simon P. D., Bandeen-Roche K., Gordon P. B., Links J. M., Todd A. C. Past adult lead exposure is associated with longitudinal decline in cognitive function. Neurology. 2000 Oct 24;55(8):1144–1150. doi: 10.1212/wnl.55.8.1144. [DOI] [PubMed] [Google Scholar]
  47. Seegal R. F., Bush B., Brosch K. O. Decreases in dopamine concentrations in adult, non-human primate brain persist following removal from polychlorinated biphenyls. Toxicology. 1994 Jan 26;86(1-2):71–87. doi: 10.1016/0300-483x(94)90054-x. [DOI] [PubMed] [Google Scholar]
  48. Seegal R. F., Bush B., Shain W. Lightly chlorinated ortho-substituted PCB congeners decrease dopamine in nonhuman primate brain and in tissue culture. Toxicol Appl Pharmacol. 1990 Oct;106(1):136–144. doi: 10.1016/0041-008x(90)90113-9. [DOI] [PubMed] [Google Scholar]
  49. Shain W., Bush B., Seegal R. Neurotoxicity of polychlorinated biphenyls: structure-activity relationship of individual congeners. Toxicol Appl Pharmacol. 1991 Oct;111(1):33–42. doi: 10.1016/0041-008x(91)90131-w. [DOI] [PubMed] [Google Scholar]
  50. Son H., Carpenter D. O. Protein kinase C activation is necessary but not sufficient for induction of long-term potentiation at the synapse of mossy fiber-CA3 in the rat hippocampus. Neuroscience. 1996 May;72(1):1–13. doi: 10.1016/0306-4522(95)00532-3. [DOI] [PubMed] [Google Scholar]
  51. Sun X., Tian X., Tomsig J. L., Suszkiw J. B. Analysis of differential effects of Pb2+ on protein kinase C isozymes. Toxicol Appl Pharmacol. 1999 Apr 1;156(1):40–45. doi: 10.1006/taap.1999.8622. [DOI] [PubMed] [Google Scholar]
  52. Swanson J. M., Sergeant J. A., Taylor E., Sonuga-Barke E. J., Jensen P. S., Cantwell D. P. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet. 1998 Feb 7;351(9100):429–433. [PubMed] [Google Scholar]
  53. Taylor E., Chadwick O., Heptinstall E., Danckaerts M. Hyperactivity and conduct problems as risk factors for adolescent development. J Am Acad Child Adolesc Psychiatry. 1996 Sep;35(9):1213–1226. doi: 10.1097/00004583-199609000-00019. [DOI] [PubMed] [Google Scholar]
  54. Tomsig J. L., Suszkiw J. B. Multisite interactions between Pb2+ and protein kinase C and its role in norepinephrine release from bovine adrenal chromaffin cells. J Neurochem. 1995 Jun;64(6):2667–2673. doi: 10.1046/j.1471-4159.1995.64062667.x. [DOI] [PubMed] [Google Scholar]
  55. Widholm J. J., Clarkson G. B., Strupp B. J., Crofton K. M., Seegal R. F., Schantz S. L. Spatial reversal learning in Aroclor 1254-exposed rats: sex-specific deficits in associative ability and inhibitory control. Toxicol Appl Pharmacol. 2001 Jul 15;174(2):188–198. doi: 10.1006/taap.2001.9199. [DOI] [PubMed] [Google Scholar]
  56. Yu M. L., Hsu C. C., Guo Y. L., Lai T. J., Chen S. J., Luo J. M. Disordered behavior in the early-born Taiwan Yucheng children. Chemosphere. 1994 Nov-Dec;29(9-11):2413–2422. doi: 10.1016/0045-6535(94)90410-3. [DOI] [PubMed] [Google Scholar]
  57. Zola-Morgan S. M., Squire L. R. The primate hippocampal formation: evidence for a time-limited role in memory storage. Science. 1990 Oct 12;250(4978):288–290. doi: 10.1126/science.2218534. [DOI] [PubMed] [Google Scholar]

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