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Valproic acid alters nitric oxide status in neurulating mouse embryos
Reproductive Toxicology ( IF 3.3 ) Pub Date : 2020-11-04 , DOI: 10.1016/j.reprotox.2020.08.012
Gian Mario Tiboni 1 , Adalisa Ponzano 2 , Alessio Ferrone 3 , Sara Franceschelli 3 , Lorenza Speranza 3 , Antonia Patruno 3
Affiliation  

The molecular bases of the teratogenic effects elicited by valproic acid (VPA) are not fully defined. It was previously shown that inhibition of nitric oxide (NO) synthesis is associated with an enhancement of the teratogenic effects of VPA, while amplification of NO signal by sildenafil prompted a dose-dependent reduction of VPA-induced neural tube defects. In this study, for the first time, the effect of VPA on the NO synthesis was evaluated in mouse embryos during early organogenesis. On gestation day 8, ICR-CD1 mice received 600 mg/kg of VPA. Eight and 24 h later embryos were collected and analyzed for NO synthase (NOS) isoform expression, and for molecular mechanisms involved in their modulation. As main finding, in utero embryonic exposure to VPA determined a time-dependent shift of NOS isoforms expression, with a down regulated expression and activity of constitutive NOS (cNOS) and an increased expression and activity of inducible NOS (iNOS). The teratological relevance of this information remains to be established.



中文翻译:

丙戊酸改变神经形成小鼠胚胎中的一氧化氮状态

丙戊酸 (VPA) 引起的致畸作用的分子基础尚未完全确定。先前表明,抑制一氧化氮 (NO) 合成与增强 VPA 的致畸作用有关,而西地那非对 NO 信号的放大促进了 VPA 诱导的神经管缺陷的剂量依赖性减少。在这项研究中,首次评估了 VPA 对早期器官形成期间小鼠胚胎中 NO 合成的影响。在妊娠第 8 天,ICR-CD1 小鼠接受了 600 mg/kg 的 VPA。收集 8 小时和 24 小时后的胚胎并分析 NO 合酶 (NOS) 同种型表达以及参与其调节的分子机制。作为主要发现,在子宫内胚胎暴露于 VPA 确定了 NOS 同种型表达的时间依赖性转变,组成型 NOS (cNOS) 的表达和活性下调,诱导型 NOS (iNOS) 的表达和活性增加。该信息的致畸相关性仍有待确定。

更新日期:2020-11-04
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