Potentiation of the Human GABA_A Receptor As a Novel Mode of Action of Lower-Chlorinated Non-Dioxin-Like PCBs

摘要

PCBs are still ubiquitous pollutants despite the ban on their industrial and commercial use. To date, risk characterization and assessment of non-dioxin-like PCBs (NDL-PCBs), especially with respect to neurotoxicrty, is hampered by a lack of data. Therefore, the effects of six common NDL congeners (PCB28,52, 101,138,153 and 180) on human GABA_A receptors, expressed in Xenopus oocytes, were investigated using the two-electrode voltage-clamp technique. When coapplied with GABA (at EC_(20)), PCB28 and PCB52 concentration-dependently potentiate the GABA_A receptor-mediated ion current Though the LOEC for both PCB28 and PCB52 is 0.3 μM. PCB28 is more potent than PCB52 (maximum potentiation at 10 μM amounting to 98.3 ± 12.5% and 25.5 ± 1.4%, respectively). Importantly, coapplication of PCB28 (0.3 μM) and PCB52 (10 μM) resulted in an apparently additive potentiation of the GABAa response, whereas coapplication of PCB28 (0.3 μM) and PCB153 (10 μM) attenuated the PCB28-induced potentiation. The present results suggest that the potentiation of human GABA_A receptor function is specific for lower-chlorinated NDL-PCBs and that higher molecular weight PCBs may attenuate this potentiation as a result of competitive binding to human GABA_A receptors. Nonetheless, this novel mode of action could (partly) underlie the previously recognized NDL-PCB-induced neurobehavioral alterations.