Kasteel Emma E J, Westerink Remco H S
Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 TD, Utrecht, The Netherlands.
Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 TD, Utrecht, The Netherlands.
Toxicol Lett. 2017 Mar 15;270:12-16. doi: 10.1016/j.toxlet.2017.02.014. Epub 2017 Feb 10.
Tetrodotoxin (TTX) is an extremely toxic marine neurotoxin. TTX inhibits voltage-gated sodium channels, resulting in a potentially lethal inhibition of neurotransmission. Despite numerous intoxications in Asia and Europe, limited (human) toxicological data are available for TTX. Additionally, the degree of interspecies differences for TTX is not well established, hampering the use of available (animal) data for human risk assessment and establishing regulatory limits for TTX concentrations in (shell)fish. We therefore used micro-electrode array (MEA) recordings as an integrated measure of neurotransmission to demonstrate that TTX inhibits neuronal electrical activity in both primary rat cortical cultures and human-induced pluripotent stem cell (hIPSC)-derived iCell neurons in co-culture with hIPSC-derived iCell astrocytes, with IC values of 7 and 10nM, respectively. From these data combined with LD values and IC concentrations of voltage-gated sodium channels derived from literature it can be concluded that interspecies differences are limited for TTX. Consequently, we used experimental animal data to derive a human acute reference dose of 1.33μg/kg body weight, which corresponds to maximum concentration of TTX in shellfish of 200μg/kg.
河豚毒素（TTX）是一种剧毒的海洋神经毒素。TTX抑制电压门控钠通道，导致对神经传递产生潜在的致命性抑制。尽管在亚洲和欧洲有众多中毒事件，但关于TTX的（人类）毒理学数据有限。此外，TTX种间差异的程度尚未明确，这妨碍了利用现有的（动物）数据进行人类风险评估以及确定（贝类）中TTX浓度的监管限值。因此，我们使用微电极阵列（MEA）记录作为神经传递的综合测量方法，以证明TTX在原代大鼠皮层培养物以及与源自人类诱导多能干细胞（hIPSC）的iCell星形胶质细胞共培养的源自hIPSC的iCell神经元中均抑制神经元电活动，其半数抑制浓度（IC）值分别为7和10nM。结合这些数据以及文献中报道的电压门控钠通道的半数致死剂量（LD）值和IC浓度可以得出结论，TTX的种间差异有限。因此，我们利用实验动物数据得出人类急性参考剂量为1.33μg/千克体重，这相当于贝类中TTX的最大浓度为200μg/千克。
