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次世代プレシジョンメディシンとゼブラフィッシュ創薬Next Generation Precision Medicine

》Systems pharmacology of teratogenic action by valproic acid


Systems pharmacology of teratogenic action by valproic acid

Soichiro Murakami1, Yuhei Nishimura1,2,3,4,5, Yoshifumi Ashikawa1, Noriko Umemoto1,2, Miko Kawabata1, Shota Sasagawa1, Beibei Zhang1, Yasuhito Shimada1,2,3,4,5, and Toshio Tanaka1,2,3,4,5

1Dept. of Mol. and Cell. Pharmacology, Pharmacogeno and Pharmacoinfo, Mie Univ. Grad. Sch. of Med, Mie 514-8507, 2Dept. of Systems Pharmacology, Mie Univ. Grad. Sch. of Med, Mie 514-8507, 3Mie Univ. Medical Zebrafish Research Center, Mie 514-8507, 4Dept. of Omics Medicine, Mie Univ. Industrial Technology Innovation Institute, Mie 514-8507, 5Dept. of Bioinfo., Mie Univ. Life Sci. Res. Center, Mie 514-8507

It is well known that exposure to valproic acid (VPA) during developmental period may cause fetal valproate syndrome. However, the detailed mechanism has been unknown. To elucidate the molecular mechanism, we exposed VPA to fertilized eggs of zebrafish and analyzed the gene expression variations comprehensively using DNA microarray. Besides, we compared the transcriptome data in Gene Expression Omnibus data repository. The microarray data included the gene expression variations in embryos of zebrafish or mouse, and mouse embryonic stem cell exposed to VPA. As a result, we discovered that the expression of epc2 was significantly decreased by VPA exposure. EPC2 is one of the polycomb genes and related to 2q23.1 microdeletion syndrome characterized by psychomotor retardation, seizure, and stereotypic repetitive behavior. Then, we knocked out epc2 gene in zebrafish using TALEN to analyze the functional role of epc2 downregulation by VPA exposure. Epc2-KO zebrafish showed a skeletal malformation and monoculus, but the frequency of both phenotypes was not so high. We were able to demonstrate that the expression of several genes were similarly dysregulated between zebrafish exposed to VPA and epc2-KO zebrafish, suggesting that epc2 may be involved at least partly in fetal valproate syndrome.