Developmental toxicity of remdesivir, an anti-COVID-19 drug, is implicated by in vitro assays using morphogenetic embryoid bodies of mouse and human pluripotent stem cells.
Developmental toxicity of remdesivir, an anti-COVID-19 drug, is implicated by in vitro assays using morphogenetic embryoid bodies of mouse and human pluripotent stem cells.
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DOI：
10.1002/bdr2.2111
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发表时间：
2023-01-15
影响因子：
2.1
通讯作者：
Marikawa, Yusuke
中科院分区：
文献类型：
--
作者：
Kirkwood-Johnson, Lauren;Marikawa, Yusuke
Remdesivir是一种被批准用于治疗COVID-19的抗病毒药物，其发育毒性尚不清楚。对于受持续大流行影响的有生育能力的人群，迫切需要更多关于Remdesivir安全性的信息。形态发生类胚体（MEB）是多能干细胞的三维（3D）聚集体，其在体外重现胚胎体模式，并已被用作有效的胚胎模型来特异性和灵敏地检测化学暴露的发育毒性。MEB由小鼠P19 C5和人H9多能干细胞产生，并用于检查Remdesivir的作用。通过分析暴露于不同浓度的Remdesivir后MEBs的形态学参数来评估形态学效应。通过测量发育调节基因的转录水平来评估Remdesivir的分子影响。1-8 μM的Remdesivir可损害小鼠MEB形态发生。Remdesivir以依赖于代谢转化的方式影响MEB，其效力高于GS-441524和GS-621763，这两种推定的抗COVID-19药物与Remdesivir作用相似。发育调节基因的表达，特别是那些参与轴向和体节模式的基因，被瑞德西韦失调。MEB发展的早期阶段比晚期阶段更容易受到Remdesivir暴露的影响。1-8 μM的Remdesivir也会损害人MEB的形态发生和基因表达谱。Remdesivir在与人类治疗血浆水平相当的浓度下损害小鼠和人类MEB，敦促进一步研究Remdesivir对发育中胚胎的潜在影响。
Remdesivir is an antiviral drug approved for the treatment of COVID‐19, whose developmental toxicity remains unclear. More information about the safety of remdesivir is urgently needed for people of childbearing potential, who are affected by the ongoing pandemic. Morphogenetic embryoid bodies (MEBs) are three‐dimensional (3D) aggregates of pluripotent stem cells that recapitulate embryonic body patterning in vitro, and have been used as effective embryo models to detect the developmental toxicity of chemical exposures specifically and sensitively. MEBs were generated from mouse P19C5 and human H9 pluripotent stem cells, and used to examine the effects of remdesivir. The morphological effects were assessed by analyzing the morphometric parameters of MEBs after exposure to varying concentrations of remdesivir. The molecular impact of remdesivir was evaluated by measuring the transcript levels of developmental regulator genes. The mouse MEB morphogenesis was impaired by remdesivir at 1–8 μM. Remdesivir affected MEBs in a manner dependent on metabolic conversion, and its potency was higher than GS‐441524 and GS‐621763, presumptive anti‐COVID‐19 drugs that act similarly to remdesivir. The expressions of developmental regulator genes, particularly those involved in axial and somite patterning, were dysregulated by remdesivir. The early stage of MEB development was more vulnerable to remdesivir exposure than the later stage. The morphogenesis and gene expression profiles of human MEBs were also impaired by remdesivir at 1–8 μM. Remdesivir impaired mouse and human MEBs at concentrations that are comparable to the therapeutic plasma levels in humans, urging further investigation into the potential impact of remdesivir on developing embryos.
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影响因子：
16.6
作者：
Kokic G;Hillen HS;Tegunov D;Dienemann C;Seitz F;Schmitzova J;Farnung L;Siewert A;Höbartner C;Cramer P
通讯作者：
Cramer P
影响因子：
2.1
作者：
Li ASW;Marikawa Y
通讯作者：
Marikawa Y
DOI：
10.1093/toxsci/kfac046
发表时间：
2022-06-28
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
--
作者：
通讯作者：
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影响因子：
3.2
作者：
Saroyo YB;Rumondang A;Febriana IS;Harzif AK;Irwinda R
通讯作者：
Irwinda R
影响因子：
2.7
作者：
Arias, Alfonso Martinez;Marikawa, Yusuke;Moris, Naomi
通讯作者：
Moris, Naomi