An Evaluation of Human Induced Pluripotent Stem Cells to Test for Cardiac Developmental Toxicity.
An Evaluation of Human Induced Pluripotent Stem Cells to Test for Cardiac Developmental Toxicity.
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评估人类诱导多能干细胞以测试心脏发育毒性。
DOI：
10.3390/ijms22158114
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发表时间：
2021-07-29
影响因子：
5.6
通讯作者：
Zur Nieden NI
中科院分区：
文献类型：
--
作者：
Walker LM;Sparks NRL;Puig-Sanvicens V;Rodrigues B;Zur Nieden NI
为了防止母体接触导致先天性缺陷，安全法规要求对工业化学品和药品进行上市前发育毒性筛查。传统的胚胎毒性方法严重依赖于使用低通量动物模型，这可能无法充分预测人类风险。在小鼠胚胎干细胞中开发的经验证的胚胎干细胞测试（EST）解决了前一个问题。在这里，我们提出了一个概念验证研究，以解决后一个挑战，通过更新所有三个端点的经典小鼠EST与端点来自人类诱导多能干细胞（hiPSC）和人成纤维细胞。将hiPSC暴露于选定的测试化学品在比在小鼠EST中观察到的浓度更低的浓度下抑制分化。hiPSC-EST还发现了由新型环境毒物驱动的不良发育结果。早期心脏基因TBX 5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hiPSC和早期分子终点作为单个化学品和混合物的生物学相关胚胎毒性筛选方法。
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.
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影响因子：
3.5
作者：
Geng, Lin;Kong, Chi-Wing;Li, Ronald A.
通讯作者：
Li, Ronald A.
影响因子：
10.3
作者：
HECHT, SS;ORNAF, RM;HOFFMANN, D
通讯作者：
HOFFMANN, D
DOI：
10.1067/s0002-9378(03)00661-6
发表时间：
2003-10-01
影响因子：
9.8
作者：
England, LJ;Levine, RJ;Cnattingius, S
通讯作者：
Cnattingius, S
影响因子：
5.8
作者：
Lara, Leonardo da Silva;Andrade-Lima, Leonardo;Pereira, Lygia Veiga
通讯作者：
Pereira, Lygia Veiga
DOI：
10.1002/bdrb.21078
发表时间：
2013-08-01
期刊：
Birth defects research. Part B, Developmental and reproductive toxicology
影响因子：
--
作者：
Palmer, Jessica A;Smith, Alan M;Kirchner, Fred R
通讯作者：
Kirchner, Fred R