Zebrafish models for human acute organophosphorus poisoning

Abstract

15 p.-7 fig. Faria, Melissa et al. ; 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. ; This work was supported in part by the US Army ERDC-IRO (W912HZ-13-BAA-01; D.R., N.G.R., and P.J.B.) and Environmental Quality Research Program (N.G.R.), the NATO SfP project MD.SFPP 984777 (D.R., N.G.R., and P.J.B.), the National Science Foundation EPSCOR Grant EPS-0903787 (N.G.R.), the Portuguese Foundation for Science and Technology Grant SFRH/BPD/78342/2011 (Programme POPH – QREN through the Portuguese Ministry of Education and Science and the European Social Fund; M.F.), the Advanced Grant ERC-2012-AdG-320737 (D.R.) and the Spanish Government (CTM2014-51985-R; D.R.). ; Peer reviewed