PCB-47, PBDE-47, and 6-OH-PBDE-47 Differentially Modulate Human GABAA and a4b2 Nicotinic Acetylcholine Receptors

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 GABAA 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 GABAA receptors only. We therefore investigated effects of PCB-47, PBDE-47, and 6-OH-PBDE-47 on the inhibitory GABAA and excitatory a4b2 nicotinic acetylcholine (nACh) receptor expressed in Xenopus oocytes using the twoelectrode 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 GABAA 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 GABAA 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 GABAA and nACh receptors are affected differently by PCB-47 and 6-OH-PBDE-47, with inhibitory GABAA-mediated signaling being potentiated and excitatory a4b2 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