Impact of drug solvents on C. elegans pharyngeal pumping.
Impact of drug solvents on C. elegans pharyngeal pumping.
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DOI：
10.1016/j.toxrep.2021.06.007
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发表时间：
2021
影响因子：
--
通讯作者：
O'Connor V
中科院分区：
文献类型：
--
作者：
Calahorro F;Holden-Dye L;O'Connor V
DMSO对C. elegans摄食行为的短期和可逆的方式。DMSO影响C.优美的nlg-1突变体对DMSO诱导的泵抑制不敏感。对DMSO在C.优雅的秀丽隐杆线虫为毒理学和药物发现提供了多细胞模式生物。这些研究通常需要溶剂，如二甲基亚砜（DMSO），乙醇或丙酮作为媒介物。这就需要仔细考虑这些屏幕中使用的化学媒介物是否对C有止痛作用。优雅的在这里，我们使用咽泵作为生物测定来评估这一点。咽部泵送是一种视觉上可评分的行为，其由激活感觉和整合神经信号以协调咽部活动的环境线索控制。因此，它作为一种丰富的生物测定，以筛选化学调节。我们发现，虽然泵送对高浓度的广泛使用的药物溶剂乙醇和丙酮不敏感，但它受到浓度高于0.5%v/v的DMSO的干扰，包括用作药物载体的浓度。这表现为咽泵速率的抑制，随后在溶剂持续存在下缓慢恢复。在神经连接素突变体nlg-1中未观察到抑制作用，这与DMSO在调节泵送的感觉处理水平上起作用一致。我们发现，总线-17突变体，增强了角质层渗透的药物更敏感的DMSO。DMSO的作用伴随着进行性形态学破坏，其中积累了不同大小的内部膜样结构。这些内部结构在本研究中研究的所有三种基因型中都可以看到，并且可能独立于对咽泵的影响而出现。总体而言，这些结果突出了感觉信号传导和应变依赖性媒介物敏感性。虽然我们定义了可以缓解这种情况的浓度，但它强调了在评价C中的对照响应时考虑时间依赖性溶剂效应的必要性。化学生物学
DMSO impacts on C. elegans feeding behaviour in short-term and in a reversible manner. DMSO affects the cellular integrity of C. elegans. nlg-1 mutant is refractory to DMSO induced pumping inhibition. Judicious consideration of the effect of the DMSO in bioassays in C. elegans. 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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