An investigation into the use of Caenorhabditis elegans as a model organism for nerve agent exposure research

Nerve agents exert their toxicological effects via inhibition of acetylcholinesterase (AChE). This inhibition results in excessive cholinergic signalling, which can result in fatality through cessation of breathing. Current therapies for nerve agent poisoning antagonise the overstimulation of muscarinic acetylcholine receptors and use benzodiazepines to enhance GABAergic inhibition as a counter to increased excitability in the central nervous system. Caenorhabditis elegans (C. elegans) can be effectively used to assess the toxic effects of AChE inhibition by paraoxon-ethyl, which shares the same mode of action of AChE inhibition as organophosphate (OP) nerve agents. In particular, the C. elegans behaviours pharyngeal pumping and motility can serve as bioassays of neuromuscular function and intoxication in the intact animal. This is reinforced by measuring the OP inhibition of AChE activity from homogenates of treated worms. Here, we demonstrate that paraoxon-ethyl, sarin, soman and VX elicit an irreversible inhibition of AChE activity with an order of potency sarin>soman>paraoxon-ethyl>VX. Importantly, this order of potency is maintained when pharyngeal pumping and motility are used to assess nerve agent exposure in vivo. C. elegans neuromuscular-dependent behaviours recover following transfer to OP-free plates, which is not observed for biochemical in vitro AChE activity. Interestingly, we see recovery of extracted in vitro AChE activity following removal of the intoxicated worms to OP-free plates. These data support the use of C. elegans to model nerve agent inhibition and recovery. In particular, the molecular mechanism(s) underpinning behavioural recovery merit further investigation.