National Center for Natural Products Research, University of Mississippi, University, Mississippi 38677, USA.
Comp Biochem Physiol C Toxicol Pharmacol. 2012 Apr;155(3):528-37. doi: 10.1016/j.cbpc.2012.01.003. Epub 2012 Jan 11.
Fertilized eggs of Japanese rice fish (medaka) at three developmental stages (Iwamatsu stages 4-30) were exposed to waterborne valproic acid (VPA) (0-80 mM) in hatching solution for 48 h. The amount of valproate to cause 50% mortality (IC(50)) is found to be developmental stage-specific. The embryos were more sensitive to valproate at early stages of development (Iwamatsu stages 4-10) than in the embryos in late stages (Iwamatsu stages 17-30). Valproate exposed embryos have microcephaly and disrupted cardiovasculature with delayed vessel circulation, thrombus formation, and slow heart rate. The hatching efficiency is also reduced by valproate exposure due to developmental delay. The mRNA analysis of nine genes belong to oxidative stress (catalase, gsr, gst), neurogenesis (iro3, wnt1, shh, otx2, nlgn3b) and cell cycle regulation (ccna2) have been done. It was observed that the genes belong to oxidative stress remained unaltered after valproate exposure. However, some of the genes belong to neurogenesis (wnt1,shh, otx2 and nlgn3b) and cell cycle (ccna2) showed developmental stage-specific alteration after valproate exposure. This study indicates that valproate is able to induce some of the phenotypic features which are analogous to human fetal valproate syndrome (FVS). Modulation of genes expressed in neural tissues indicates that this fish can be used to analyze the mechanisms of many neurobehavioral disorders like Autism spectrum disorder (ASD) in human.
受精的日本稻鱼（青鳉）卵在三个发育阶段（岩松阶段 4-30）中暴露于孵化溶液中的水性丙戊酸（VPA）（0-80mM）中 48 小时。引起 50%死亡率的丙戊酸盐量（IC（50））发现是发育阶段特异性的。胚胎在发育早期（岩松阶段 4-10）比晚期胚胎（岩松阶段 17-30）对丙戊酸盐更敏感。丙戊酸盐暴露的胚胎有小头畸形和心血管系统中断，血管循环延迟、血栓形成和心率缓慢。由于发育延迟，丙戊酸盐暴露也降低了孵化效率。对属于氧化应激的九个基因（过氧化氢酶、gsr、gst）、神经发生（iro3、wnt1、shh、otx2、nlgn3b）和细胞周期调节（ccna2）的 mRNA 进行了分析。观察到丙戊酸盐暴露后，属于氧化应激的基因没有改变。然而，一些属于神经发生（wnt1、shh、otx2 和 nlgn3b）和细胞周期（ccna2）的基因在丙戊酸盐暴露后表现出发育阶段特异性改变。这项研究表明，丙戊酸盐能够诱导一些类似于人类胎儿丙戊酸盐综合征（FVS）的表型特征。神经组织中表达的基因的调节表明，这种鱼类可用于分析人类自闭症谱系障碍（ASD）等许多神经行为障碍的机制。
