Creighton University, School of Medicine, Department of Pharmacology, Omaha, Nebraska 68178, USA.
Environ Health Perspect. 2011 Sep;119(9):1239-46. doi: 10.1289/ehp.1003394. Epub 2011 Jun 10.
Pyrethroid insecticides bind to voltage-gated sodium channels and modify their gating kinetics, thereby disrupting neuronal function. Although previous work has tested the additivity of pyrethroids in vivo, this has not been assessed directly at the primary molecular target using a functional measure.
We investigated the potency and efficacy of 11 structurally diverse food-use pyrethroids to evoke sodium (Na+) influx in neurons and tested the hypothesis of dose additivity for a mixture of these same 11 compounds.
We determined pyrethroid-induced increases in Na+ influx in primary cultures of cerebrocortical neurons using the Na+-sensitive dye sodium-binding benzofuran isophthalate (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 assessed. Additivity was tested assuming a dose-additive model.
Seven pyrethroids produced concentration-dependent, tetrodotoxin-sensitive Na+ influx. The rank order of potency was deltamethrin > S-bioallethrin > β-cyfluthrin > λ-cyhalothrin > esfenvalerate > tefluthrin > fenpropathrin. Cypermethrin and bifenthrin produced modest increases in Na+ influx, whereas permethrin and resmethrin were inactive. When all 11 pyrethroids were present at an equimolar mixing ratio, their actions on Na+ influx were consistent with a dose-additive model.
These data provide in vitro relative potency and efficacy measurements for 7 pyrethroid compounds in intact mammalian neurons. Despite differences in individual compound potencies, we found the action of a mixture of all 11 pyrethroids to be additive when we used an appropriate statistical model. These results are consistent with a previous report of the additivity of pyrethroids in vivo.
拟除虫菊酯杀虫剂与电压门控钠离子通道结合，并改变其门控动力学，从而破坏神经元功能。尽管先前的工作已经测试了体内拟除虫菊酯的加合作用，但这并没有使用功能测量直接在主要分子靶标上进行评估。
我们研究了 11 种结构不同的食品用拟除虫菊酯诱发神经元钠离子（Na+）内流的效力和效能，并测试了这些相同的 11 种化合物混合物的剂量加合作用假设。
我们使用 Na+敏感染料苯并呋喃异邻苯二甲酸酯（SBFI）测定原代皮质神经元中拟除虫菊酯诱导的 Na+内流增加。确定了 11 种拟除虫菊酯的浓度依赖性反应，并评估了等摩尔混合比下所有 11 种化合物混合物稀释液的反应。假设剂量加合模型，测试了加合性。
7 种拟除虫菊酯产生浓度依赖性、四氢毒蕈碱敏感的 Na+内流。效力的顺序为氯氟氰菊酯> S-生物烯丙菊酯>β-氯氟氰菊酯>λ-氯氰菊酯>乙氰菊酯>七氟菊酯>氟丙菊酯。氯氰菊酯和溴氰菊酯仅引起适度的 Na+内流增加，而氯菊酯和溴氰菊酯则没有作用。当所有 11 种拟除虫菊酯以等摩尔混合比存在时，它们对 Na+内流的作用与剂量加合模型一致。
这些数据提供了 7 种拟除虫菊酯化合物在完整哺乳动物神经元中的体外相对效力和效能测量值。尽管个别化合物的效力存在差异，但当我们使用适当的统计模型时，我们发现所有 11 种拟除虫菊酯混合物的作用是加合的。这些结果与先前关于体内拟除虫菊酯加合作用的报告一致。
