Preclinical zebrafish model for organophosphorus intoxication: neuronal hyperexcitation, behavioral abnormalities and subsequent brain damages

As key compounds for modern cultivation practices, organophosphorus (OP)-containing pesticides have become an important public health and environmental issues, worldwide, causing millions human intoxications each year. OP poisoning induces cholinergic syndrome, associating irreversible brain damages with epileptic seizures, possibly ending in life-threatening status epilepticus. Existing countermeasures are life-saving, but insufficiently effective to prevent long lasting neuronal consequences, emphasizing the dire need for animal models mimicking OP poisoning as tools to identify novel anti-OP countermeasures. Here, we used diisopropylfluorophosphate (DFP), a prototypic and moderately toxic OP compound, to generate a zebrafish OP intoxication model and study the consequences of DFP exposure on neuronal activity, larvae behaviour and neuron network organization. DFP poisoning caused marked acetylcholinesterase (AChE) inhibition, resulting in paralysis, decreased oxygen consumption, overexpression of c-Fos neuron activity marker, increased neuron apoptosis and epileptiform seizure-like activity, which was partially alleviated by diazepam treatment. DFP-exposed larvae also showed altered neuron networks with increased accumulation of NR2B-NMDA receptor combined with decreased GAD65/67 and gephyrin protein accumulation. Thus, we described a zebrafish model of DFP poisoning, which should (i) provide important insights into the pathophysiological mechanisms underlying OP intoxication and ensuing brain damage, and (ii) help identify novel therapeutic agents to restore CNS functions following acute OP poisoning.