title: Activation and potentiation of human GABAA receptors by non-dioxin-like PCBs depends on chlorination pattern.
abstract: 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 GABA(A) 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 GABA(A) receptors were investigated. GABA(A) 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 EC(20)). Importantly, PCB19, PCB47, PCB51, and PCB100 can also act as full agonist, i.e., activate the GABA(A) receptor in the absence of GABA. Potentiation and activation of the GABA(A) 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 GABA(A) 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.
authors.affiliation: Neurotoxicology Research Group, Toxicology Division, Institute for Risk Assessment Sciences, Utrecht University, NL-3508 TD Utrecht, The Netherlands. e.c.antunesfernandes@uu.nl
authors.forename: Elsa C Antunes
authors.initials: EC
authors.lastname: Fernandes
authors.forename: Hester S
authors.initials: HS
authors.lastname: Hendriks
authors.forename: Regina G D M
authors.initials: RG
authors.lastname: van Kleef
authors.forename: Ad
authors.initials: A
authors.lastname: Reniers
authors.forename: Patrik L
authors.initials: PL
authors.lastname: Andersson
authors.forename: Martin
authors.initials: M
authors.lastname: van den Berg
authors.forename: Remco H S
authors.initials: RH
authors.lastname: Westerink
mesh_terms: D000818:Animals; D002713:Chlorine / Q000737:chemistry*; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D058785:GABA-A Receptor Agonists / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000633:toxicity*; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D004785:Environmental Pollutants; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D002713:Chlorine; D005680:gamma-Aminobutyric Acid; D011078:Polychlorinated Biphenyls