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PCB-47, PBDE-47, and 6-OH-PBDE-47 Differentially Modulate Human GABA(A) and alpha(4)beta(2) Nicotinic Acetylcholine Receptors
Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
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2010 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 118, no 2, 635-642 p.Article in journal (Refereed) Published
Abstract [en]

Polychlorinated biphenyls (PCBs) and the structurally related polybrominated diphenyl ethers (PBDEs) are abundant persistent organic pollutants that exert several comparable neurotoxic effects. Importantly, hydroxylated metabolites of PCBs and PBDEs have an increased neurotoxic potency. Recently, we demonstrated that PCBs can act as (partial) agonist on GABA(A) neurotransmitter receptors, with PCB-47 being the most potent congener. It is, however, unknown whether PBDE-47 and its metabolite 6-OH-PBDE-47 exert similar effects and if these effects are limited to GABA(A) receptors only. We therefore investigated effects of PCB-47, PBDE-47, and 6-OH-PBDE-47 on the inhibitory GABA(A) and excitatory alpha(4)beta(2) nicotinic acetylcholine (nACh) receptor expressed in Xenopus oocytes using the two-electrode voltage-clamp technique. Since human exposure is generally not limited to individual compounds, experiments with binary mixtures were also performed. The results demonstrate that PCB-47 and 6-OH-PBDE-47 act as full and partial agonist on the GABA(A) receptor. However, both congeners act as antagonist on the nACh receptor. PBDE-47 does not affect either type of receptor. Binary mixtures of PCB-47 and 6-OH-PBDE-47 induced an additive activation as well as potentiation of GABA(A) receptors, whereas this mixture resulted in an additive inhibition of nACh receptors. Binary mixtures of PBDE-47 and 6-OH-PBDE-47 yielded similar effects as 6-OH-PBDE-47 alone. These findings demonstrate that GABA(A) and nACh receptors are affected differently by PCB-47 and 6-OH-PBDE-47, with inhibitory GABA(A)-mediated signaling being potentiated and excitatory alpha(4)beta(2) nACh-mediated signaling being inhibited. Considering these opposite actions and the additive interaction of the congeners, these effects are likely to be augmented in vivo.

Place, publisher, year, edition, pages
2010. Vol. 118, no 2, 635-642 p.
Keyword [en]
polychlorinated biphenyls, polybrominated diphenyl ethers, human GABA(A) receptor, human nicotinic acetylcholine receptor, binary mixture, persistent organic pollutants
National Category
Pharmacology and Toxicology
Research subject
URN: urn:nbn:se:su:diva-51252DOI: 10.1093/toxsci/kfq284ISI: 000284432600028OAI: diva2:385212
authorCount :5Available from: 2011-01-11 Created: 2011-01-10 Last updated: 2011-01-11Bibliographically approved

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Bergman, Åke
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Department of Materials and Environmental Chemistry (MMK)
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