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首页> 外文期刊>Reproductive toxicology >Fetal malformations and early embryonic gene expression response in cynomolgus monkeys maternally exposed to thalidomide.
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Fetal malformations and early embryonic gene expression response in cynomolgus monkeys maternally exposed to thalidomide.

机译：母体接触沙利度胺的食蟹猴的胎儿畸形和早期胚胎基因表达反应。

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The present study was performed to determine experimental conditions for thalidomide induction of fetal malformations and to understand the molecular mechanisms underlying thalidomide teratogenicity in cynomolgus monkeys. Cynomolgus monkeys were orally administered thalidomide at 15 or 20mg/kg-d on days 26-28 of gestation, and fetuses were examined on day 100-102 of gestation. Limb defects such as micromelia/amelia, paw/foot hyperflexion, polydactyly, syndactyly, and brachydactyly were observed in seven of eight fetuses. Cynomolgus monkeys were orally administered thalidomide at 20mg/kg on day 26 of gestation, and whole embryos were removed from the dams 6h after administration. Three embryos each were obtained from the thalidomide-treated and control groups. Total RNA was isolated from individual embryos, amplified to biotinylated cRNA and hybridized to a custom Non-Human Primate (NHP) GeneChip((R)) Array. Altered genes were clustered into genes that were up-regulated (1281 genes) and down-regulated (1081 genes) in thalidomide-exposed embryos. Functional annotation by Gene Ontology (GO) categories revealed up-regulation of actin cytoskeletal remodeling and insulin signaling, and down-regulation of pathways for vasculature development and the inflammatory response. These findings show that thalidomide exposure perturbs a general program of morphoregulatory processes in the monkey embryo. Bioinformatics analysis of the embryonic transcriptome following maternal thalidomide exposure has now identified many key pathways implicated in thalidomide embryopathy, and has also revealed some novel processes that can help unravel the mechanism of this important developmental phenotype.
机译：进行本研究是为了确定沙利度胺诱导胎儿畸形的实验条件，并了解沙利度胺在食蟹猴中致畸作用的分子机制。食蟹猴在妊娠第26-28天以15或20mg / kg-d的剂量口服沙利度胺，并在妊娠第100-102天检查胎儿。在八个胎儿中，有七个发现了肢体缺陷，例如小黑点/弱点，足爪/脚的过度屈曲，多指，间断和近距离畸形。在妊娠的第26天，以20mg / kg口服给予食蟹猴，并在给药后6小时将大胚从大坝中取出。从沙利度胺治疗组和对照组各获得三个胚。从单个胚胎中分离总RNA，扩增为生物素化的cRNA，并与定制的非人类灵长类（NHP）GeneChip（R）阵列杂交。改变的基因在暴露于沙利度胺的胚胎中聚集成上调（1281个基因）和下调（1081个基因）的基因。基因本体论（GO）类别的功能注释显示肌动蛋白细胞骨架重塑和胰岛素信号传导上调，而脉管系统发育和炎症反应的通路下调。这些发现表明，沙利度胺的暴露扰动了猴胚胎中形态调节过程的一般程序。母体thalidomide暴露后胚胎转录组的生物信息学分析现已确定许多与thalidomide胚胎病有关的关键途径，并且还揭示了一些有助于阐明这一重要发育表型机制的新过程。

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