Zebrafish Models for Human Acute Organophosphorus Poisoning

Abstract

Terrorist use of organophosphorus-based nerve agents and toxic industrial chemicals against civilian populations constitutes a real threat, as demonstrated by the terrorist attacks in Japan in the 1990 s or, even more recently, in the Syrian civil war. Thus, development of more effective countermeasures against acute organophosphorus poisoning is urgently needed. Here, we have generated and validated zebrafish models for mild, moderate and severe acute organophosphorus poisoning by exposing zebrafish larvae to different concentrations of the prototypic organophosphorus compound chlorpyrifos-oxon. Our results show that zebrafish models mimic most of the pathophysiological mechanisms behind this toxidrome in humans, including acetylcholinesterase inhibition, N-methyl-D-aspartate receptor activation, and calcium dysregulation as well as inflammatory and immune responses. The suitability of the zebrafish larvae to in vivo high-throughput screenings of small molecule libraries makes these models a valuable tool for identifying new drugs for multifunctional drug therapy against acute organophosphorus poisoning.

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication

“…At the gross morphological level, this zebrafish model was characterized by a compacted head with areas of opacification, which indicates brain necrosis (Rodriguez and Driever 1997). Further histopathological analyses confirmed the presence of severe brain damage underlying the observed morphological changes (Faria et al 2015). Moreover, we demonstrated that the zebrafish severe acute OP intoxication model displays many of the pathophysiological mechanisms, including AChE inhibition, NMDA receptor activation, calcium dysregulation and activation of inflammatory and immune responses, underlying this toxidrome in humans.…”

“…For the severe acute OP intoxication model generation, zebrafish larvae were transferred to 48-well plates (1 larva per well) at 7 days post-fertilization (dpf) and exposed for 24 h to 4 µM CPO, which corresponds to 1 × LC 50 (Faria et al 2015), in a dark incubator at 28.5 °C. Control larvae were exposed to the same concentration of the carrier (0.1 % DMSO) under identical conditions.…”

“…Recently, we generated a zebrafish chemical model of severe acute OP intoxication using chlorpyrifos oxon (CPO) as a prototypic OP compound (Faria et al 2015). At the gross morphological level, this zebrafish model was characterized by a compacted head with areas of opacification, which indicates brain necrosis (Rodriguez and Driever 1997).…”

Zebrafish: A Model for the Study of Toxicants Affecting Muscle Development and Function

“…The inhibition of AChE by OP compounds leads to accumulation of the neurotransmitter ACh at the cholinergic synaptic clefts, with the consequent long-term activation of the nicotinic and muscarinic ACh receptors (AChR) and overstimulation of cholinergic neurons as well as hyperexcitation and seizures. Following the initial cholinergic overstimulation, a cascade of downstream events occurs that lead to secondary neuronal muscle toxicity [63,126,127]. …”

“…The highest CPO concentration led to complete embryo paralysis. These symptoms significantly mimicked many effects of OPs in humans [63]. …”