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The aim of the present study was to evaluate embryotoxicity of metformin (MET<\/jats:styled-content>) compared with other hypoglycemic drugs (rosiglitazone [RSG<\/jats:styled-content>] and glimepiride [GLIM<\/jats:styled-content>]), the anticancer drug 5\u2010fluorouracil (5\u2010FU<\/jats:styled-content>), the anti\u2010epileptic drug diphenylhydantoin (DPH<\/jats:styled-content>), the antibiotic penicillin G (P<\/jats:styled-content>enG<\/jats:styled-content>), and the cyclo\u2010oxygenase (COX<\/jats:styled-content>)\u20102 inhibitor nimesulide (NIM<\/jats:styled-content>) in an embryonic stem cell test (EST<\/jats:styled-content>).<\/jats:p><\/jats:sec>Methods<\/jats:title>Differences in the expression of developmental marker genes following treatment with the test compounds during the course of differentiation (from embryonic stem cellD<\/jats:styled-content>3 (D<\/jats:styled-content>3 cells) to myocardial cells) were determined using real\u2010time quantitative polymerase chain reaction. In these studies, 5\u2010FU<\/jats:styled-content>was used as a positive control andP<\/jats:styled-content>enG<\/jats:styled-content>was used as a negative control. The cytotoxicity of these drugs againstD<\/jats:styled-content>3 cells and 3T<\/jats:styled-content>3 fibroblasts was determined by the 3\u2010(4,5\u2010dimethyl\u20102 thiazoyl)\u20102,5\u2010diphenyl\u20102H<\/jats:styled-content>\u2010tetrazolium bromide (MTT<\/jats:styled-content>) assay. Embryotoxicity was classified according to the prediction model ofEST<\/jats:styled-content>.<\/jats:p><\/jats:sec>Results<\/jats:title>At concentrations >800\u2009\u03bc<\/jats:italic>g\/mLMET<\/jats:styled-content>had a greater cytotoxic effect onD<\/jats:styled-content>3 cells than 3T<\/jats:styled-content>3 fibroblasts. At the highest concentration ofMET<\/jats:styled-content>(5\u2009mg\/mL), the cell viability ofD<\/jats:styled-content>3 cells and 3T<\/jats:styled-content>3 fibroblasts was <10% and >30%, respectively. The size of the embryonic body (EB<\/jats:styled-content>) differentiation area was almost the same over the concentration range 50\u2013200\u2009\u03bc<\/jats:italic>g\/mLMET<\/jats:styled-content>, and there was no significant difference inEB<\/jats:styled-content>differentiation area until a concentration of 400\u2009\u03bc<\/jats:italic>g\/mLMET<\/jats:styled-content>. At a concentration of 800\u2009\u03bc<\/jats:italic>g\/mLMET<\/jats:styled-content>, the size ofEB<\/jats:styled-content>outgrowth was significantly reduced. The same assays revealedGLIM<\/jats:styled-content>,RSG<\/jats:styled-content>, andNIM<\/jats:styled-content>to be weakly embryotoxic substances.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>Based on theEST<\/jats:styled-content>,MET<\/jats:styled-content>can be classified as a weakly embryotoxic substance, which suggests that it should be prescribed with caution to pregnant women with gestational diabetes.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1753-0407.12251","type":"journal-article","created":{"date-parts":[[2014,12,10]],"date-time":"2014-12-10T13:18:29Z","timestamp":1418217509000},"page":"839-849","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A toxicology study to evaluate the embryotoxicity of metformin compared with the hypoglycemic drugs, the anticancer drug, the anti\u2010epileptic drug, the antibiotic, and the cyclo\u2010oxygenase (COX)\u20102 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