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

Abstract

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.

Neurological mechanism of sensory deficits after developmental exposure to non-dioxin-like polychlorinated biphenyls (PCBs)

“…The authors report that the osmotic neuronal swelling alters neuronal activity. This study thus provides new evidence that GABA is involved in the neurobehavioral mode of action of higher chlorinated NDL PCBs, as has been shown for lower chlorinated congeners (Fernandes et al 2010).…”

Analysis of the toxicogenomic effects of exposure to persistent organic pollutants (POPs) in Slovakian girls: Correlations between gene expression and disease risk

“…(Kruger et al, 2008, Long et al, 2007). Toxicological potential other than endocrine disruption have also been observed for these chemicals (Faroon et al, 2001; Farnandes et al, 2010). …”

Modulation of GABAA-Receptors by Honokiol and Derivatives: Subtype Selectivity and Structure–Activity Relationship

“…The biphenyl substructure, which shows very good general binding affinity to proteins, is found in 4.3% of all known drugs and hence provides a suitable template for the discovery of new drugs . Related structures such as polychlorinated biphenyls and bisphenol A have been previously shown to modulate GABA A receptors. , Various GABA A receptor modulators (flavonoids like methyl-apigenin or wogonin, , polyacetylene structures from Cussonia zimmermannii , and valerenic acid in Valeriana spp …”