C. elegans as a model organism for organophosphate nerve agent investigations

Abstract

Organophosphate poisoning is a prevalent issue, associated with agriculture exposure, self-poisoning and terrorist attacks. The latter being associated with the more toxic class of organophosphates called nerve agents. Organophosphates irreversibly inhibit the enzyme acetylcholinesterase, causing an accumulation of acetylcholine which overstimulates muscarinic and nicotinic acetylcholine receptors. This elicits a range of toxic effects, including lethality due to cessation of breathing. Current treatment relies on drugs that act against the overstimulation of muscarinic acetylcholine receptors and enhancing inhibitory GABAergic signalling to combat central nervous system excitability. Whilst a major determinant of the exposure is overactivity at nicotinic acetylcholine receptors in muscles, there is no current therapy to address this. The toxic nature of these compounds combined with limitations in the current treatments suggests further work to improve current therapies.
In order to develop new therapies to organophosphate poisoning, good models of mammalian poisoning are required. Mammalian models are used however, have strict licensing and are low throughput. Small invertebrate model organisms have been investigated for organophosphate research in recent years. This is because they do not require licensing, have homology with mammalian cholinergic pathways and can achieve high-throughput assays. In this work, C. elegans was used to model organophosphate exposure. This was firstly investigated to develop a high-throughput model. Different behaviours were assessed for their capability of measuring concentration responses over time and discussing their advantages and limitations.
C. elegans has been previously used to assess toxic effects of organophosphates. This work added to previous work by measuring behaviour and AChE activity with organophosphate nerve agents. It was shown that OPs inhibited AChE activity and behaviour with an order of potency of sarin>soman>paraoxon-ethyl>VX. C. elegans neuromuscular-dependent behaviours recovered following transfer to OP-free plates, which is not observed in biochemical in vitro AChE activity. These data support the use of C. elegans to model nerve agent exposure and recovery.
The use of C. elegans was later investigated to assess its use in investigating new therapies of organophosphate poisoning. In particular, the ortholog of the muscle nicotinic acetylcholine receptor was investigated as there is no current therapy. The use of genetic mutations in the C. elegans body wall muscle nAChR demonstrated mitigation to OP. In particular, it was found that reduced rather than loss of function receptors best protected against OP exposure. This idea is further supported by pharmacological experiments in which a drug that modulates ACh receptor function, MB327, shows mitigation of OP exposure in the C. elegans bioassay. Altogether, this work supports the notion that allosteric modulation to reduce nAChR function rather than complete blockade provides an untapped route to further protect against OP poisoning.

More information

Identifiers

ORCID for Jo Haszczyn: orcid.org/0000-0002-7012-7125

ORCID for Vincent O'connor: orcid.org/0000-0003-3185-5709

ORCID for Lindy Holden-Dye: orcid.org/0000-0002-9704-1217

Catalogue record

Export record