Developmental exposure to valproic acid alters the expression of microRNAs involved in neurodevelopment in zebrafish.
Developmental exposure to valproic acid alters the expression of microRNAs involved in neurodevelopment in zebrafish.
复制标题
DOI：
10.1016/j.ntt.2013.10.001
复制
发表时间：
2013-11
影响因子：
2.9
通讯作者：
Hahn ME
中科院分区：
文献类型：
--
作者：
Aluru N;Deak KL;Jenny MJ;Hahn ME
先天畸形是美国婴儿死亡的普遍原因，其诱发与多种因素有关，包括暴露于致畸剂。然而，致畸性的分子机制尚未完全了解。microRNA是一组重要的小的非编码RNA，调节mRNA的表达。microRNA在早期胚胎发育中的作用已经得到了很好的确立，它们在发育过程中的破坏可能导致异常。我们假设，发育暴露于致畸剂，如丙戊酸改变microRNA表达谱在发育中的胚胎。丙戊酸是一种抗惊厥和情绪稳定药物，用于治疗癫痫、双相情感障碍和偏头痛。为了研究丙戊酸对发育过程中microRNA表达的影响，我们使用斑马鱼胚胎作为脊椎动物发育系统的模型。斑马鱼胚胎从受精后4小时（hpf）开始连续暴露于丙戊酸（1 mM）或载体对照（乙醇），并在48和96 hpf取样以确定发育缺陷发生之前和之后的miRNA表达谱。在96 hpf时，95%的幼虫出现骨骼畸形、异常游泳行为和心包积液。使用Agilent斑马鱼miRNA微阵列进行微阵列表达谱分析。微阵列结果显示，在两个时间点的miRNA表达的变化。13个miRNAs在48 hpf时差异表达，22个miRNAs在96 hpf时改变。其中，6种miRNA（miR-16 a、18 c、122、132、457 b和724）在两个时间点是共同的。生物信息学靶点预测和对已发表文献的研究表明，这些miRNA靶向参与中枢神经系统正常功能的几个基因。这些结果表明，丙戊酸的致畸作用可能涉及改变miRNA表达。
Congenital malformations are a prevalent cause of infant mortality in the United States and their induction has been linked to a variety of factors, including exposure to teratogens. However, the molecular mechanisms of teratogenicity are not fully understood. MicroRNAs are an important group of small, non-coding RNAs that regulate mRNA expression. MicroRNA roles in early embryonic development are well established, and their disruption during development can cause abnormalities. We hypothesized that developmental exposure to teratogens such as valproic acid alters microRNA expression profiles in developing embryos. Valproic acid is an anticonvulsant and mood-stabilizing drug used to treat epilepsy, bipolar disorder and migraines. To examine the effects of valproic acid on microRNA expression during development, we used zebrafish embryos as a model vertebrate developmental system. Zebrafish embryos were continuously exposed to valproic acid (1 mM) or vehicle control (ethanol) starting from 4 hours post-fertilization (hpf) and sampled at 48 and 96 hpf to determine the miRNA expression profiles prior to and after the onset of developmental defects. At 96 hpf, 95% of the larvae showed skeletal deformities, abnormal swimming behavior, and pericardial effusion. Microarray expression profiling was done using Agilent zebrafish miRNA microarrays. Microarray results revealed changes in miRNA expression at both time points. Thirteen miRNAs were differentially expressed at 48 hpf and 22 miRNAs were altered at 96 hpf. Among them, six miRNAs (miR-16a, 18c, 122, 132, 457b, and 724) were common to both time points. Bioinformatic target prediction and examination of published literature revealed that these miRNAs target several genes involved in the normal functioning of the central nervous system. These results suggest that the teratogenic effects of valproic acid could involve altered miRNA expression.