Remdesivir impairs mouse preimplantation embryo development at therapeutic concentrations.
Remdesivir impairs mouse preimplantation embryo development at therapeutic concentrations.
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DOI：
10.1016/j.reprotox.2022.05.012
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发表时间：
2022-08
影响因子：
3.3
通讯作者：
Alarcon, Vernadeth B.
中科院分区：
文献类型：
--
作者：
Marikawa, Yusuke;Alarcon, Vernadeth B.
关键词：
瑞德西韦（Remdesivir， RDV）是美国食品和药物管理局批准的首个用于治疗COVID-19的抗病毒药物。虽然研究了RDV的一般安全性，但其生殖风险，包括胚胎毒性，在很大程度上是未知的。在这里，为了深入了解其胚胎毒性潜力，我们研究了RDV在与治疗血浆水平相当的浓度下对体外培养的小鼠着床前胚胎的影响。暴露于RDV（2-8µM）中不影响囊胚形成的开始，尽管由于细胞死亡增加，8µM的腔体无法维持。虽然暴露在2-4µM中可以维持腔，但与内细胞团（ICM）谱系相关的发育调节基因的表达显著减少。RDV的副作用取决于暴露的持续时间和时间，因为在8细胞囊胚期到早期囊胚期之间的处理最敏感地影响腔扩张、基因表达和细胞增殖，特别是ICM而不是滋养外胚层谱系。GS-441524是RDV的主要代谢物，虽然它以不同于RDV的方式改变基因表达，但它不会损害囊胚的形成或腔的扩张。此外，RDV比GS-441524更有效地降低了作为人类ICM谱系模型的人胚胎干细胞的活力。这些发现表明，RDV具有潜在的胚胎毒性，损害多能谱系，并将有助于进一步设计和解释RDV生殖毒性的体外和体内研究。
Remdesivir (RDV) is the first antiviral drug to be approved by the US Food and Drug Administration for the treatment of COVID-19. While the general safety of RDV has been studied, its reproductive risk, including embryotoxicity, is largely unknown. Here, to gain insights into its embryotoxic potential, we investigated the effects of RDV on mouse preimplantation embryos cultured in vitro at the concentrations comparable to the therapeutic plasma levels. Exposure to RDV (2–8 µM) did not affect the initiation of blastocyst formation, although the maintenance of the cavity failed at 8 µM due to increased cell death. While exposure to 2–4 µM permitted the cavity maintenance, expressions of developmental regulator genes associated with the inner cell mass (ICM) lineage were significantly diminished. Adverse effects of RDV depended on the duration and timing of exposure, as treatment between the 8-cell to early blastocyst stage most sensitively affected cavity expansion, gene expressions, and cell proliferation, particularly of the ICM than the trophectoderm lineage. GS-441524, a major metabolite of RDV, did not impair blastocyst formation or cavity expansion, although it altered gene expressions in a manner differently from RDV. Additionally, RDV reduced the viability of human embryonic stem cells, which were used as a model for the human ICM lineage, more potently than GS-441524. These findings suggest that RDV is potentially embryotoxic to impair the pluripotent lineage, and will be useful for designing and interpreting further in vitro and in vivo studies on the reproductive toxicity of RDV.
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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
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33.5
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Fan Y;Min Z;Alsolami S;Ma Z;Zhang E;Chen W;Zhong K;Pei W;Kang X;Zhang P;Wang Y;Zhang Y;Zhan L;Zhu H;An C;Li R;Qiao J;Tan T;Li M;Yu Y
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Yu Y
影响因子：
10.4
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通讯作者：
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影响因子：
11.8
作者：
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通讯作者：
Robson, Paul
影响因子：
9.8
作者：
Fan X;Tang D;Liao Y;Li P;Zhang Y;Wang M;Liang F;Wang X;Gao Y;Wen L;Wang D;Wang Y;Tang F
通讯作者：
Tang F