Impact of drug solvents on C. elegans pharyngeal pumping
Impact of drug solvents on C. elegans pharyngeal pumping
Caenorhabditis elegans provides a multi-cellular model organism for toxicology and drug discovery. These studies usually require solvents such as dimethyl sulfoxide (DMSO), ethanol or acetone as a vehicle. This raises the need to carefully consider whether the chemical vehicles used in these screens are anodyne towards C. elegans. Here, we use pharyngeal pumping as a bioassay to assess this. Pharyngeal pumping is a visually scoreable behaviour that is controlled by environmental cues activating sensory and integrative neural signalling to coordinate pharyngeal activity. As such it serves as a rich bioassay to screen for chemical modulation. We found that while pumping was insensitive to high concentrations of the widely used drug solvents ethanol and acetone, it was perturbed by concentrations of DMSO above 0.5 % v/v encompassing concentrations used as drug vehicle. This was manifested as an inhibition of pharyngeal pump rate followed by a slow recovery in the continued presence of the solvent. The inhibition was not observed in a neuroligin mutant, nlg-1, consistent with DMSO acting at the level of sensory processing that modulates pumping. We found that bus-17 mutants, which have enhanced cuticle penetration to drugs are more sensitive to DMSO. The effect of DMSO is accompanied by a progressive morphological disruption in which internal membrane-like structures of varying size accumulate. These internal structures are seen in all three genotypes investigated in this study and likely arise independent of the effects on pharyngeal pumping. Overall, these results highlight sensory signalling and strain dependent vehicle sensitivity. Although we define concentrations at which this can be mitigated, it highlights the need to consider time- dependent vehicle effects when evaluating control responses in C. elegans chemical biology.
Bioassay readouts, Dose-response, Drug screening, High-throughput experiments
1240-1247
Calahorro Nunez, Fernando
dddfa373-d3cc-433f-8851-9ca37f2f3950
Holden-Dye, Linda
8032bf60-5db6-40cb-b71c-ddda9d212c8e
O'connor, Vincent
8021b06c-01a0-4925-9dde-a61c8fe278ca
17 June 2021
Calahorro Nunez, Fernando
dddfa373-d3cc-433f-8851-9ca37f2f3950
Holden-Dye, Linda
8032bf60-5db6-40cb-b71c-ddda9d212c8e
O'connor, Vincent
8021b06c-01a0-4925-9dde-a61c8fe278ca
Calahorro Nunez, Fernando, Holden-Dye, Linda and O'connor, Vincent
(2021)
Impact of drug solvents on C. elegans pharyngeal pumping.
Toxicology Reports, 8, .
(doi:10.1016/j.toxrep.2021.06.007).
Abstract
Caenorhabditis elegans provides a multi-cellular model organism for toxicology and drug discovery. These studies usually require solvents such as dimethyl sulfoxide (DMSO), ethanol or acetone as a vehicle. This raises the need to carefully consider whether the chemical vehicles used in these screens are anodyne towards C. elegans. Here, we use pharyngeal pumping as a bioassay to assess this. Pharyngeal pumping is a visually scoreable behaviour that is controlled by environmental cues activating sensory and integrative neural signalling to coordinate pharyngeal activity. As such it serves as a rich bioassay to screen for chemical modulation. We found that while pumping was insensitive to high concentrations of the widely used drug solvents ethanol and acetone, it was perturbed by concentrations of DMSO above 0.5 % v/v encompassing concentrations used as drug vehicle. This was manifested as an inhibition of pharyngeal pump rate followed by a slow recovery in the continued presence of the solvent. The inhibition was not observed in a neuroligin mutant, nlg-1, consistent with DMSO acting at the level of sensory processing that modulates pumping. We found that bus-17 mutants, which have enhanced cuticle penetration to drugs are more sensitive to DMSO. The effect of DMSO is accompanied by a progressive morphological disruption in which internal membrane-like structures of varying size accumulate. These internal structures are seen in all three genotypes investigated in this study and likely arise independent of the effects on pharyngeal pumping. Overall, these results highlight sensory signalling and strain dependent vehicle sensitivity. Although we define concentrations at which this can be mitigated, it highlights the need to consider time- dependent vehicle effects when evaluating control responses in C. elegans chemical biology.
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More information
Accepted/In Press date: 14 June 2021
e-pub ahead of print date: 17 June 2021
Published date: 17 June 2021
Additional Information:
Funding Information:
F.C. is supported by Biotechnology and Biological Sciences (BBSRC) grant number BB/T002867/1 . Some C. elegans strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ).
Publisher Copyright:
© 2021 The Author(s)
Keywords:
Bioassay readouts, Dose-response, Drug screening, High-throughput experiments
Identifiers
Local EPrints ID: 450091
URI: http://eprints.soton.ac.uk/id/eprint/450091
ISSN: 2214-7500
PURE UUID: a0d1c0ea-b4f0-4f3a-b525-1afb505b2249
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Date deposited: 09 Jul 2021 16:33
Last modified: 17 Mar 2024 03:32
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