Abstract
Polychlorinated biphenyls (PCBs) are persistent organic pollutants present in human blood and milk. Exposure to PCBs during pregnancy and lactation leads to cognitive impairment in children. Perinatal exposure to PCB 153 or PCB 126 impairs the glutamate–nitric oxide–cGMP pathway in cerebellum in vivo and learning ability in adult rats. The aims of this work were: (1) to assess whether long-term exposure of primary cultures of cerebellar neurons to PCB 153 or PCB 126 reproduces the impairment in the function of the glutamate–nitric oxide–cGMP pathway found in rat cerebellum in vivo; (2) to provide some insight on the steps of the pathway affected by these PCBs; (3) to assess whether the mechanisms of interference of the pathway are different for PCB 126 and PCB 153. Both PCB 153 and PCB 126 increase basal levels of cGMP by different mechanisms. PCB 126 increases the amount of soluble guanylate cyclase while PCB 153 does not. PCB 153 reduces the amount of calmodulin while PCB 126 does not. Also both PCBs impair the function of the glutamate–nitric oxide–cGMP pathway by different mechanisms, PCB 153 impairs nitric oxide-induced activation of soluble guanylate cyclase and increase in cGMP while PCB 126 does not. PCB 126 reduces NMDA-induced increase in calcium while PCB 153 does not. When PCB 153 and PCB 126 exhibit the same effect, PCB 126 was more potent than PCB 153, as occurs in vivo.
Similar content being viewed by others
Abbreviations
- NO:
-
Nitric oxide
- NOS:
-
Nitric oxide synthase
- PCBs:
-
Polychlorinated biphenyls
References
Aguilar MA, Minarro J, Felipo V (2000) Chronic moderate hyperammonemia impairs active and passive avoidance behavior and conditional discrimination learning in rats. Exp Neurol 161:704–713
Bellamy TC, Wood J, Garthwaite J (2002) On the activation of soluble guanylyl cyclase by nitric oxide. Proc Natl Acad Sci USA 99:507–510
Cauli O, Rodrigo R, Piedrafita B, Boix J, Felipo V (2007) Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with porto-caval shunts. Hepatology 46:514–519
Erceg S, Monfort P, Hernández-Viadel M, Llansola M, Montoliu C, Felipo V (2005a) Restoration of learning ability in hyperammonemic rats by increasing extracellular cGMP in brain. Brain Res 1036:115–121
Erceg S, Monfort P, Hernández-Viadel M, Rodrigo R, Montoliu C, Felipo V (2005b) Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunt. Hepatology 45:2–10
Fangstrom B, Strid A, Grandjean P, Weihe P, Bergman A (2005) A retrospective study of PBDEs and PCBs in human milk from the Faroe Islands. Environ Health 4:12
Faroon O, Jones D, de Rosa C (2001) Effects of polychlorinated biphenyls on the nervous system. Toxicol Ind Health 16:305–333
Felipo V, Grau E, Miñana MD, Grisolía S (1993) Ammonium injection induces an N methyl D aspartate receptor mediated proteolysis of the microtubule associated protein MAP 2. J Neurochem 60:1626–1630
Felipo V, Miñana MD, Cabedo H, Grisolía S (1994) L-carnitine increases the affinity of glutamate for quisqualate receptors and prevents glutamate neurotoxicity. Neurochem Res 19:373–377
Gray KA, Klebanoff MA, Brock JW, Zhou H, Darden R, Needham L, Longnecker MP (2005) In utero exposure to background levels of polychlorinated biphenyls and cognitive functioning among school-age children. Am J Epidemiol 162:17–26
Hermenegildo C, Montoliu C, Llansola M, Munoz MD, Gaztelu JM, Minana MD, Felipo V (1998) Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo. Eur J NeuroSci 10:3201–3209
Inoue K, Harada K, Takenaka K, Uehara S, Kono M, Shimizu T, Takasuga T, Senthilkumar K, Yamashita F, Koizumi A (2006) Levels and concentration ratios of polychlorinated biphenyls and polybrominated diphenyl ethers in serum and breast milk in Japanese mothers. Environ Health Perspect 114:1179–1185
Jacobson JL, Jacobson SW (1996) Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med 335:783–789
Landrigan PJ (2001) Pesticides and polychlorinated biphenyls (PCBs): an analysis of the evidence that they impair children’s neurobehavioral development. Mol Genet Metab 73:11–17
Minana MD, Montoliu C, Llansola M, Grisolia S, Felipo V (1998) Nicotine prevents glutamate-induced proteolysis of the microtubule-associated protein MAP-2 and glutamate neurotoxicity in primary cultures of cerebellar neurons. Neuropharmacology 37:847–857
Monfort P, Corbalán R, Martinez L, López-Talavera JC, Córdoba J, Felipo V (2001) Altered content and modulation of soluble guanylate cyclase in the cerebellum of rats with portacaval anastomosis. Neuroscience 104:1119–1125
Montoliu C, Llansola M, Kosenko E, Corbalán R, Felipo V (1999) Role of cyclic GMP in glutamate neurotoxicity in primary cultures of cerebellar neurons. Neuropharmacology 38:1883–1891
Piedrafita B, Cauli O, Montoliu C, Felipo V (2007) The function of the glutamate-nitric oxide-cGMP pathway in brain in vivo and learning ability decrease in parallel in mature compared to young rats. Learn Mem 14:254–258
Piedrafita B, Erceg S, Cauli O, Monfort P, Felipo V (2008) Developmental exposure to polychlorinated biphenyls PCB153 or PCB126 impairs learning ability in young but not in adult rats. Eur J Neurosci 27:177–182
Schantz SL, Seo BW, Moshtaghian J, Peterson RE, Moore RW (1996) Effects of gestational and lactational exposure to TCDD or coplanar PCBs on spatial learning. Neurotoxicol Teratol 18:305–313
Shen J, Harada N, Nakazawa H, Yamashita T (2005) Involvement of the nitric oxide-cyclic GMP pathway and neuronal nitric oxide synthase in ATP-induced Ca2+ signalling in cochlear inner hair cells. Eur J NeuroSci 21:2912–2922
Acknowledgements
This work was supported by grants from the European Commission Program Food Quality and Safety (FOOD-CT-2003-506143) and from Ministerio de Ciencia e Innovacion (SAF2008-00062, SAF2005-06089 and CSD2008-00005) of Spain and by grants from Consellería de Empresa, Universidad y Ciencia (Grupos03/001, GV04B-055, GV04B-012, GVS05/082, ACOMP06/005, ACOMP/2007/002) and AP005/06 and EVES 034-2007 from Conselleria de Sanitat of Generalitat Valenciana.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Llansola, M., Piedrafita, B., Rodrigo, R. et al. Polychlorinated Biphenyls PCB 153 and PCB 126 Impair the Glutamate–Nitric Oxide–cGMP Pathway in Cerebellar Neurons in Culture by Different Mechanisms. Neurotox Res 16, 97–105 (2009). https://doi.org/10.1007/s12640-009-9055-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-009-9055-8