de Jong Esther, Louisse Jochem, Verwei Miriam, Blaauboer Bas J, van de Sandt Johannes J M, Woutersen Ruud A, Rietjens Ivonne M C M, Piersma Aldert H
National Institute of Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands.
Toxicol Sci. 2009 Jul;110(1):117-24. doi: 10.1093/toxsci/kfp083. Epub 2009 Apr 28.
The embryonic stem cell test (EST) has been proposed as an in vitro assay that might reduce animal experimentation in regulatory developmental toxicology. So far, evaluation of the EST was not performed using compounds within distinct chemical classes. Evaluation within a distinct class of chemically related compounds can define the usefulness of the assay for the chemical class tested. The aim of the present study was to evaluate the relative sensitivity of the EST for a selected series of homologous compounds and to compare the data to the relative developmental toxicity of the compounds in vivo. To this end a series of proximate developmentally toxic glycol ether alkoxy acid metabolites was tested in the EST. All glycol ether alkoxy acid metabolites tested showed a concentration-dependent inhibition of cardiomyocyte differentiation at noncytotoxic concentrations, with methoxyacetic acid as the most potent compound followed by ethoxyacetic acid, butoxyacetic acid, and phenoxyacetic acid, respectively. The potency ranking of the compounds in the EST corresponds with the available in vivo data. The relative differences between the potencies of the compounds appeared more pronounced in the in vivo studies than in the EST. A possible explanation for this discrepancy could be the difference in the kinetics of the compounds in vivo as compared with their in vitro kinetics. This study illustrates that the EST can be used to set priorities for developmental toxicity testing within classes of related compounds.
胚胎干细胞试验（EST）已被提议作为一种体外试验，有望减少监管发育毒理学中的动物实验。到目前为止，尚未使用不同化学类别的化合物对EST进行评估。在一类化学相关化合物中进行评估可以确定该试验对所测试化学类别的有用性。本研究的目的是评估EST对选定系列同源化合物的相对敏感性，并将数据与这些化合物在体内的相对发育毒性进行比较。为此，在EST中测试了一系列近期具有发育毒性的二醇醚烷氧基酸代谢物。所有测试的二醇醚烷氧基酸代谢物在非细胞毒性浓度下均显示出对心肌细胞分化的浓度依赖性抑制，其中甲氧基乙酸是最有效的化合物，其次分别是乙氧基乙酸、丁氧基乙酸和苯氧基乙酸。EST中化合物的效力排名与现有的体内数据一致。化合物效力之间的相对差异在体内研究中比在EST中更为明显。这种差异的一个可能解释是化合物在体内的动力学与其体外动力学不同。本研究表明，EST可用于确定相关化合物类别内发育毒性测试的优先级。
