title: A Modified Murine Embryonic Stem Cell Test for Evaluating the Teratogenic Effects of Drugs on Early Embryogenesis.
abstract: Mammalian fetal development is easily disrupted by exogenous agents, making it essential to test new drug candidates for embryotoxicity and teratogenicity. To standardize the testing of drugs that might be used to treat pregnant women, the U.S. Food and Drug Administration (FDA) formulated special grade categories, labeled A, B, C, D and X, that define the level of risk associated with the use of a specific drug during pregnancy. Drugs in categories (Cat.) D and X are those with embryotoxic and/or teratogenic effects on humans and animals. However, which stages of pregnancy are affected by these agents and their molecular mechanisms are unknown. We describe here an embryonic stem cell test (EST) that classifies FDA pregnancy Cat.D and Cat.X drugs into 4 classes based on their differing effects on primitive streak formation. We show that ~84% of Cat.D and Cat.X drugs target this period of embryogenesis. Our results demonstrate that our modified EST can identify how a drug affects early embryogenesis, when it acts, and its molecular mechanism. Our test may thus be a useful addition to the drug safety testing armamentarium.
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.
authors.forename: Ruoxing
authors.initials: R
authors.lastname: Yu
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Miyamura
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Okamoto-Uchida
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Arima
authors.affiliation: Chemical Biology Screening Center, and Department of Organic and Medicinal Chemistry, Institute of Biomaterials and Bioengineering, TMDU, Tokyo, 101-0062, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ishigami-Yuasa
authors.affiliation: Chemical Biology Screening Center, and Department of Organic and Medicinal Chemistry, Institute of Biomaterials and Bioengineering, TMDU, Tokyo, 101-0062, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D058732:Embryoid Bodies / Q000187:drug effects / Q000502:physiology; D047108:Embryonic Development / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000187:drug effects* / Q000502:physiology; D064793:Teratogenesis; D013723:Teratogens / Q000145:classification / Q000633:toxicity*; D018675:Toxicity Tests; D014212:Tretinoin / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D013723:Teratogens; D001569:Benzodiazepines; D014212:Tretinoin