Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Sci Rep. 2017 Aug 29;7(1):9839. doi: 10.1038/s41598-017-10454-3.
There is a well-defined regulatory framework governing the approval of chemicals for use as pharmaceuticals or release into the environment. Toxicity assessment is thus a major hurdle in the compound discovery pipeline, currently involving large scale animal testing. The search for alternative testing platforms is therefore an important priority. We have developed a convenient, low cost assay utilising the nematode Caenorhabditis elegans, to rapidly assess both acute toxicity and developmental and reproductive toxicity (DART). However the worm is protected by a robust cuticle that forms a barrier to chemical uptake. We assessed mutants with altered cuticle properties to identify sensitized strains optimized for toxicity assays. Evaluating the trade-off between increased permeability and reduced fitness identifies bus-5(br19) as the most suitable strain for chemical exposure. We demonstrate the applicability of this assay for a range of chemicals with differing properties, including a modified exposure protocol for volatile or less soluble compounds. This work enhances the effectiveness of C. elegans for convenient toxicity assessment, which could contribute to a reduction in the use of vertebrates particularly at the crucial early stages of product development. Strains identified in this work will also enhance the sensitivity of C. elegans based drug discovery platforms.
有一个明确的监管框架来管理用于药物或释放到环境中的化学品的批准。因此，毒性评估是化合物发现管道中的一个主要障碍，目前涉及大规模的动物测试。因此，寻找替代测试平台是一个重要的优先事项。我们开发了一种利用秀丽隐杆线虫的方便、低成本的测定方法，快速评估急性毒性以及发育和生殖毒性（DART）。然而，蠕虫被一层坚固的表皮所保护，这形成了化学物质吸收的屏障。我们评估了具有改变的表皮特性的突变体，以确定用于毒性测定的敏感菌株。评估增加渗透性和降低适应性之间的权衡，可以确定 bus-5(br19) 是最适合化学暴露的菌株。我们证明了该测定法在一系列具有不同特性的化学品中的适用性，包括挥发性或可溶性较低的化合物的改良暴露方案。这项工作提高了秀丽隐杆线虫在方便的毒性评估中的有效性，这可能有助于减少特别是在产品开发的关键早期阶段对脊椎动物的使用。在这项工作中确定的菌株还将提高基于秀丽隐杆线虫的药物发现平台的灵敏度。
