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Additivity of Pyrethroid Actions on Sodium Influx in Cortical Neuronsin vitro
Citation:
Cao, Z., TIM SHAFER, K. M. CROFTON, C. Gennings, AND T. F. Murray. Additivity of Pyrethroid Actions on Sodium Influx in Cortical Neuronsin vitro. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 119(9):1239-1246, (2011).
Impact/Purpose:
These data provide in vitro relative potency and efficacy measurements for 7 pyrethroid compounds in intact mammalian neurons
Description:
Background: Pyrethroid insecticides bind to voltage-gated sodium channels (VGSCs) and modify their gating kinetics, thereby disrupting neuronal function. While previous work has tested the additivity of pyrethroids in vivo, the additivity of these compounds at the major target site has not been assessed using a functional measure. Objectives: To determine the potency of eleven structurally diverse food use pyrethroids to evoke Na+ influx (increase intracellular Na+ concentration ([Na+h) in neuronal cells, and then test the hypothesis of dose-additivity for a mixture of these same 11 compounds. Methods: Pyrethroid-induced increases in Na+ influx in primary cultures of mouse neocortical neurons were determined using the Naf-sensitive dye SBFI. Concentration-dependent responses for 11 pyrethroids were determined, and the response to dilutions of a mixture of all 11 compounds at an equimolar mixing ratio was determined. Additivity was tested assuming a dose-additive model. Results: Seven pyrethroids produced concentration-dependent, tetrodotoxin (TTX)-sensitive elevations in Na+ influx. EC30 values ranged from 600-2000 nM and the rank order of potency for these pyrethroids was deltamethrin> S-bioallethrin> ~ -cyfluthrin> A-cyhalothrin> esfenvalerate> telfluthrin> fenpropathrin. Cypermethrin and bifenthrin produced TTx-sensitive, but not concentration-dependent increases in Na+ influx, while permethrin and resmethrin were inactive on Na+ influx. When all 11 of 3 these compounds were present at an equimolar mixing ratio, their actions on Na+ influx were consistent with a dose-additive model. Conclusion: These data provide in vitro relative potency and efficacy measurements for 7 pyrethroid compounds in intact mammalian neurons. Moreover, the data demonstrate that for Na+ influx, the actions of a mixture of all 11 pyrethroids are additive in vitro.These results are consistent with a previous report of the additivity of pyrethroids in vivo.