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 muscle weakness, hypertension, and neuron damage that may lead to epileptic seizures and permanent psychomotor 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.

Background/Objectives: Sulfur mustard (SM) is an old warfare agent that remains a threat to both military personnel and civilians. SM contamination occurs through three main routes: dermal contact, inhalation, and ocular exposure. The clinical consequences of ocular exposure range from conjunctivitis and ulcerations to blindness. While these pathophysiological consequences are well-established, the mechanisms of action of SM in the eyes are not fully understood. Methods: The present study, which was conducted in rabbits, aimed at quantifying a series of biomarkers resulting from the electrophilic addition of SM to glutathione and nucleic acids in multiple biological matrices. This allowed us to investigate the distribution of SM within the ocular sphere and its diffusion to distant organs. Results: SM biomarkers were detected in large amounts in tears and aqueous humor but at substantially lower levels in the vitreous humor. No evidence of diffusion was observed from the exposed eye to plasma and distant organs, including the brain, liver, and lungs. Conclusions: These results are in agreement with a role for the cornea as a major sink for SM, thereby preventing damage to other ocular compartments and systemic diffusion.