Organophosphorus diisopropylfluorophosphate (DFP) intoxication in zebrafish larvae causes behavioral defects, neuronal hyperexcitation and neuronal death.
Organophosphorus diisopropylfluorophosphate (DFP) intoxication in zebrafish larvae causes behavioral defects, neuronal hyperexcitation and neuronal death.
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DOI：
10.1038/s41598-020-76056-8
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发表时间：
2020-11-05
影响因子：
4.6
通讯作者：
Soussi-Yanicostas N
中科院分区：
文献类型：
--
作者：
Brenet A;Somkhit J;Hassan-Abdi R;Yanicostas C;Romain C;Bar O;Igert A;Saurat D;Taudon N;Dal-Bo G;Nachon F;Dupuis N;Soussi-Yanicostas N
每年有数百万人中毒，超过200，000人死亡，有机磷（OP）化合物是全球重要的公共卫生问题。OP中毒诱导胆碱能综合征，伴有呼吸窘迫、高血压和神经元损伤，可能导致癫痫发作和永久性认知缺陷。现有的对策可以挽救生命，但不能防止长期的神经元共病，强调迫切需要动物模型，以更好地了解OP神经毒性和确定新的解毒剂。在这里，使用二异丙基氟磷酸盐（DFP），一种原型和中等毒性的OP，与斑马鱼幼虫相结合，我们首先表明，DFP中毒引起主要的乙酰胆碱酯酶抑制，导致瘫痪和中枢神经系统神经元过度激活，如增加的神经元钙瞬变和过表达的立即早期基因fosab，junBa，npas 4 b和atf 3所示。除了这些癫痫样癫痫样事件，DFP暴露的幼虫表现出增加的神经元凋亡，这都是部分缓解地西泮治疗，表明神经元过度兴奋和细胞死亡之间的因果关系。最后，DFP中毒引起谷氨酸能/GABA能突触活性平衡改变，NR 2B-NMDA受体积累增加，GAD 65/67和桥蛋白积累减少。因此，本文提出的斑马鱼DFP模型为OP中毒的病理生理学提供了重要的新见解，使其成为鉴定新型解毒剂的有前途的模型。
With millions of intoxications each year and over 200,000 deaths, organophosphorus (OP) compounds are an important public health issue worldwide. OP poisoning induces cholinergic syndrome, with respiratory distress, hypertension, and neuron damage that may lead to epileptic seizures and permanent cognitive deficits. Existing countermeasures are lifesaving but do not prevent long-lasting neuronal comorbidities, emphasizing the urgent need for animal models to better understand OP neurotoxicity and identify novel antidotes. Here, using diisopropylfluorophosphate (DFP), a prototypic and moderately toxic OP, combined with zebrafish larvae, we first showed that DFP poisoning caused major acetylcholinesterase inhibition, resulting in paralysis and CNS neuron hyperactivation, as indicated by increased neuronal calcium transients and overexpression of the immediate early genes fosab, junBa, npas4b, and atf3. In addition to these epileptiform seizure-like events, DFP-exposed larvae showed increased neuronal apoptosis, which were both partially alleviated by diazepam treatment, suggesting a causal link between neuronal hyperexcitation and cell death. Last, DFP poisoning induced an altered balance of glutamatergic/GABAergic synaptic activity with increased NR2B-NMDA receptor accumulation combined with decreased GAD65/67 and gephyrin protein accumulation. The zebrafish DFP model presented here thus provides important novel insights into the pathophysiology of OP intoxication, making it a promising model to identify novel antidotes.
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斑马鱼德雷维综合征模型中的兴奋/抑制突触平衡缺陷和神经元凋亡增加
影响因子：
6
作者：
Brenet, Alexandre;Hassan-Abdi, Rahma;Soussi-Yanicostas, Nadia
通讯作者：
Soussi-Yanicostas, Nadia
影响因子：
2.9
作者：
LALLEMENT, G;CARPENTIER, P;BLANCHET, G
通讯作者：
BLANCHET, G
影响因子：
3.6
作者：
Gunay, Nurullah;Kose, Beril;Demiryurek, Abdullah T.
通讯作者：
Demiryurek, Abdullah T.
影响因子：
3.3
作者：
Ito, Hironobu;Yamamoto, Naoyuki
通讯作者：
Yamamoto, Naoyuki
影响因子：
3.8
作者：
Li, Yonggang;Lein, Pamela J.;Ford, Byron D.
通讯作者：
Ford, Byron D.