Comprehensive Search for Genes Involved in Thalidomide Teratogenicity Using Early Differentiation Models of Human Induced Pluripotent Stem Cells: Potential Applications in Reproductive and Developmental Toxicity Testing
Yu Kato,
Takeshi Inaba,
Koudai Shinke,
Noriko Hiramatsu,
Tetsuhiro Horie,
Takuya Sakamoto,
Yuko Hata,
Eiji Sugihara,
Tetsuya Takimoto,
Noriaki Nagai,
Yasuhito Ishigaki,
Hajime Kojima,
Osamu Nagano,
Naoki Yamamoto,
Hideyuki Saya
Affiliations
Yu Kato
Oncology Innovation Center, Research Promotion Headquarters, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Takeshi Inaba
Graduate School of Health Sciences, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Koudai Shinke
Graduate School of Health Sciences, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Noriko Hiramatsu
Center for Society-Academia Collaboration, Research Promotion Headquarters, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Tetsuhiro Horie
Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
Takuya Sakamoto
Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
Yuko Hata
Open Facility Center, Research Promotion Headquarters, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Eiji Sugihara
Oncology Innovation Center, Research Promotion Headquarters, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Tetsuya Takimoto
Oncology Innovation Center, Research Promotion Headquarters, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Noriaki Nagai
Faculty of Pharmacy, Kindai University, Higashiosaka 577-8502, Osaka, Japan
Yasuhito Ishigaki
Medical Research Institute, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
Hajime Kojima
Department of Pharmaceutical Engineering, Faculty of Engineering, Sanyo-Onoda City University, Sanyo-Onoda 756-0884, Yamaguchi, Japan
Osamu Nagano
Oncology Innovation Center, Research Promotion Headquarters, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Naoki Yamamoto
Center for Society-Academia Collaboration, Research Promotion Headquarters, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Hideyuki Saya
Oncology Innovation Center, Research Promotion Headquarters, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Developmental toxicity testing is essential to identify substances that may harm embryonic development. This study aimed to establish a protocol for evaluating developmental toxicity using human induced pluripotent stem cells (iPSCs) by analyzing cellular activity and gene expression changes. Two ICH S5(R3) positive substances, valproic acid (VPA), which is a substance previously detected as positive by other test methods, and thalidomide (Thalido), were examined during early trichoderm differentiation without fetal bovine serum. RNA-seq analysis identified seven candidate genes, including TP63, associated with altered expression following exposure to VPA or Thalido. These genes were implicated in pathways related to tissue development, cell growth, and molecular interactions. While the assay effectively detected VPA and Thalido, its limitations include testing only soluble substances and focusing on early differentiation stages. Nevertheless, the protocol demonstrates potential for the classification and evaluation of emerging modality drugs based on physical properties such as solubility, polarity, and pH. Integration with AI analysis may enhance its capacity to uncover genetic variations and evaluate previously uncharacterized substances. This study provides a foundation for alternative developmental toxicity testing methods, with further refinements in the culture method expected to improve accuracy and applicability in regulatory toxicology.
