Ehashi Tomo, Suzuki Noriyuki, Ando Satoshi, Sumida Kayo, Saito Koichi
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd.
J Toxicol Sci. 2014 Jun;39(3):383-90. doi: 10.2131/jts.39.383.
The widely used antiepileptic drug valproic acid (VPA) is known to exhibit teratogenicity in the form of a failure of the neural tube in humans. Embryonic stem cells (ESCs) are reported to be a promising cell source for evaluating chemical teratogenicity, because they are capable of reproducing embryonic developmental model and enable reduction in the number of experimental animals used. We previously investigated 22 genes for which expressions are altered by teratogens, specifically focusing on neural differentiation of mouse ESCs. In the present study, expressions of the investigated genes were evaluated by quantitative real-time PCR and compared during differentiation of human ESCs into neurons with or without VPA. Under the conditions, almost all gene expressions significantly changed in VPA-containing culture. Specifically, in neural development-related genes such as DCX, ARX, MAP2, and NNAT, more than 2-fold expression was observed. The findings suggest that the genes focused on in this study may help to elucidate the teratogenic effects of VPA and might be a useful tool to analyze embryotoxic potential of chemicals in humans.
广泛使用的抗癫痫药物丙戊酸（VPA）已知会在人类中以神经管缺陷的形式表现出致畸性。据报道，胚胎干细胞（ESC）是评估化学物质致畸性的一种有前景的细胞来源，因为它们能够重现胚胎发育模型，并能减少实验动物的使用数量。我们之前研究了22个因致畸剂而改变表达的基因，特别关注小鼠胚胎干细胞的神经分化。在本研究中，通过定量实时PCR评估所研究基因的表达，并在有或无VPA的情况下将人类胚胎干细胞分化为神经元的过程中进行比较。在这些条件下，几乎所有基因的表达在含VPA的培养物中都有显著变化。具体而言，在与神经发育相关的基因如双皮质素（DCX）、雄激素受体相关X连锁基因（ARX）、微管相关蛋白2（MAP2）和神经元正五聚蛋白3（NNAT）中，观察到超过2倍的表达变化。这些发现表明，本研究中关注的基因可能有助于阐明VPA的致畸作用，并且可能是分析化学物质对人类胚胎毒性潜力的有用工具。
