Potentiation of the human GABA(A) receptor as a novel mode of action of lower-chlorinated non-dioxin-like PCBs.
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 neurotoxicity, 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 microM, PCB28 is more potent than PCB52 (maximum potentiation at 10 muM amounting to 98.3 +/- 12.5% and 25.5 +/- 1.4%, respectively). Importantly, coapplication of PCB28 (0.3 microM) and PCB52 (10 microM) resulted in an apparently additive potentiation of the GABA(A) response, whereas coapplication of PCB28 (0.3 microM) and PCB153 (10 microM) 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.
Fernandes
Elsa C Antunes
EC
Neurotoxicology Research Group, Toxicology Division, Institute for Risk Assessment Sciences, Utrecht University, P.O. Box 80.177, NL-3508 TD Utrecht, The Netherlands. E.C.AntunesFernandes@uu.nl
Hendriks
Hester S
HS
van Kleef
Regina G D M
RG
van den Berg
Martin
M
Westerink
Remco H S
RH
D000818:Animals; D001667:Binding, Competitive; D002713:Chlorine / Q000737:chemistry*; D005260:Female; D058785:GABA-A Receptor Agonists; D006801:Humans; D018408:Patch-Clamp Techniques; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis
D058785:GABA-A Receptor Agonists; D002713:Chlorine; D011078:Polychlorinated Biphenyls