Effects of valproic acid on gene expression during human embryonic stem cell differentiation into neurons.
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.
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd.
Tomo
T
Ehashi
Noriyuki
N
Suzuki
Satoshi
S
Ando
Kayo
K
Sumida
Koichi
K
Saito
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D064793:Teratogenesis / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000633:toxicity*
C469264:ARX protein, human; D000927:Anticonvulsants; C000714328:DCX protein, human; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D018398:Homeodomain Proteins; C489788:MAP2 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C490237:NNAT protein, human; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D014157:Transcription Factors; D014635:Valproic Acid