German Federal Institute for Risk Assessment (BfR), Department of Experimental Toxicology and ZEBET, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany.
Toxicology. 2013 Dec 6;314(1):135-47. doi: 10.1016/j.tox.2013.09.012. Epub 2013 Oct 2.
As the developing brain is exquisitely vulnerable to chemical disturbances, testing for developmental neurotoxicity of a substance is an important aspect of characterizing its tissue specific toxicity. Mouse embryonic stem cells (mESCs) can be differentiated toward a neural phenotype, and this can be used as a model for early brain development. We developed a new in vitro assay using mESCs to predict adverse effects of chemicals and other compounds on neural development - the so-called DNT-EST. After treatment of differentiating stem cells for 48h or 72h, at two key developmental stages endpoint for neural differentiation, viability, and proliferation were assessed. As a reference, we similarly treated undifferentiated stem cells 2 days after plating for 48h or 72h in parallel to the differentiating stem cells. Here, we show that chemical testing of a training set comprising nine substances (six substances of known developmental toxicity and three without specific developmental neurotoxicity) enabled a mathematical prediction model to be formulated that provided 100% predictivity and accuracy for the given substances, including in leave-one-out cross-validation. The described test method can be performed within two weeks, including data analysis, and provides a prediction of the developmental neurotoxicity potency of a substance.
由于发育中的大脑对化学干扰极其敏感，因此测试物质的发育神经毒性是描述其组织特异性毒性的重要方面。小鼠胚胎干细胞（mESCs）可以向神经表型分化，这可以作为早期大脑发育的模型。我们开发了一种新的使用 mESCs 的体外测定法，用于预测化学物质和其他化合物对神经发育的不良影响 - 即所谓的 DNT-EST。在分化的干细胞处理 48 小时或 72 小时后，在神经分化的两个关键发育阶段终点评估细胞活力和增殖。作为参考，我们在类似的情况下将未分化的干细胞在接种后 2 天进行处理，平行于分化的干细胞进行 48 小时或 72 小时的处理。在这里，我们表明，对包含九种物质（六种已知具有发育毒性的物质和三种没有特定发育神经毒性的物质）的训练集进行化学测试，使得可以制定一个数学预测模型，该模型对所给物质提供了 100％的预测性和准确性，包括在留一交叉验证中。该描述的测试方法可以在两周内完成，包括数据分析，并提供物质发育神经毒性效力的预测。
