Journal Article

Activation and Potentiation of Human GABA<sub>A</sub> Receptors by Non-Dioxin–Like PCBs Depends on Chlorination Pattern

Elsa C. Antunes Fernandes, Hester S. Hendriks, Regina G. D. M. van Kleef, Ad Reniers, Patrik L. Andersson, Martin van den Berg and Remco H. S. Westerink

in Toxicological Sciences

Volume 118, issue 1, pages 183-190
Published in print November 2010 | ISSN: 1096-6080
Published online September 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq257
Activation and Potentiation of Human GABAA Receptors by Non-Dioxin–Like PCBs Depends on Chlorination Pattern

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The neurotoxic potential of non-dioxin-like polychlorinated biphenyls (NDL-PCBs) is characterized by disruption of presynaptic processes, including calcium homeostasis and neurotransmitter transport. Recently, using a limited set of congeners, we demonstrated that PCB28 and PCB52 can potentiate postsynaptic GABAA receptors. In the present study, effects of 20 NDL-PCBs and 2 dioxin-like PCBs, selected based on their chemical variation and abundance in the environment, on human GABAA receptors were investigated. GABAA receptors were expressed in Xenopus oocytes, and NDL-PCB effects were determined using the two-electrode voltage-clamp technique. Results demonstrate that lower chlorinated PCB19, PCB28, PCB47, PCB51, PCB52, PCB95, and PCB100 act as a partial agonists (at low receptor occupancy), i.e., potentiating the receptor response during coapplication with GABA (at EC20). Importantly, PCB19, PCB47, PCB51, and PCB100 can also act as full agonist, i.e., activate the GABAA receptor in the absence of GABA. Potentiation and activation of the GABAA receptor is concentration dependent and limited to NDL-PCBs that have 3–5 chlorine atoms, 1–3 ortho-substitutions, an equal number (0–1) of meta-substitutions on both phenyl rings, and do not have an adjacent para- and meta-substitution on the same phenyl ring. Activation and potentiation of the GABAA receptor by PCB47, the most potent congener (lowest observed effect concentration of 10nM), is attenuated when coapplied with PCB19, PCB28, PCB153, or PCB180, indicative for competitive binding. Considering the importance of GABA-ergic signaling for brain development, motor coordination, learning, and memory, this mode of action can contribute to the previously observed NDL-PCB–induced neurobehavioral and neurodevelopmental effects and should be included in human risk assessment.

Keywords: non-dioxin-like PCB; human GABAA receptor; receptor activation and potentiation; binary mixture; structure-activity relationship; human risk assessment

Journal Article.  5425 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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