An Evaluation of Human Induced Pluripotent Stem Cells to Test for Cardiac Developmental Toxicity.

To prevent congenital defects arising from maternal exposure, safety regulations require pre-market developmental toxicity screens for industrial chemicals and pharmaceuticals. Traditional embryotoxicity approaches depend heavily on the use of low-throughput animal models which may not adequately predict human risk. The validated embryonic stem cell test (EST) developed in murine embryonic stem cells addressed the former problem over 15 years ago. Here, we present a proof-of-concept study to address the latter challenge by updating all three endpoints of the classic mouse EST with endpoints derived from human induced pluripotent stem cells (hiPSCs) and human fibroblasts. Exposure of hiPSCs to selected test chemicals inhibited differentiation at lower concentrations than observed in the mouse EST. The hiPSC-EST also discerned adverse developmental outcomes driven by novel environmental toxicants. Evaluation of the early cardiac gene TBX5 yielded similar toxicity patterns as the full-length hiPSC-EST. Together, these findings support the further development of hiPSCs and early molecular endpoints as a biologically relevant embryotoxicity screening approach for individual chemicals and mixtures.

为防止因母体接触而产生先天性缺陷，安全法规要求对工业化学品和药品进行上市前的发育毒性筛查。传统的胚胎毒性方法在很大程度上依赖于低通量动物模型的使用，而这些模型可能无法充分预测人类风险。15年前，在小鼠胚胎干细胞中开发的经过验证的胚胎干细胞试验（EST）解决了前一个问题。在此，我们进行了一项概念验证研究，通过用人诱导多能干细胞（hiPSCs）和人成纤维细胞衍生的终点更新经典小鼠EST的所有三个终点来应对后一个挑战。将hiPSCs暴露于选定的测试化学品时，其抑制分化的浓度低于在小鼠EST中所观察到的浓度。hiPSC - EST还能识别由新型环境毒物导致的不良发育结果。对早期心脏基因TBX5的评估产生了与全长hiPSC - EST相似的毒性模式。总之，这些发现支持进一步开发hiPSCs和早期分子终点，将其作为一种对单个化学品和混合物具有生物学相关性的胚胎毒性筛查方法。