A High-Throughput Screen for Teratogens Using Human Pluripotent Stem Cells

• DOI: 10.1093/toxsci/kft239
• Publication Date: 2013-10-24T02:18:25Z
• Authors: Sei Kameoka; Joshua Babiarz; Kyle Kolaja; Eric Chiao
• Keywords: Developmental toxicity; In vitro toxicology

There is need in the pharmaceutical and chemical industries for high-throughput human cell-based assays identifying hazardous chemicals, thereby reducing overall reliance on animal studies predicting risk of toxic responses humans. Despite instances human-specific teratogens such as thalidomide, use cell-teratogenicity has just started to be explored. Herein, a pluripotent stem cell test (hPST) described, benchmarking vitro findings traditional preclinical toxicology teratogenicity when available teratogenic outcomes The hPST method employs 3-day monolayer directed differentiation embryonic cells. compound gauged by measuring reduction nuclear translocation transcription factor SOX17 mesendodermal Decreased model was strongly correlated with vivo teratogenicity. Specifically, 71 drug-like compounds known effects, including were examined hPST. A threshold 5μM demonstrated 94% accuracy (97% sensitivity 92% specificity). Furthermore, 15 environmental toxicants physicochemical properties distinct from small molecule agents similarly strong concordance observed. Finally, assess suitability screens, library 300 kinase inhibitors tested, demonstrating platform's utility interrogating mechanisms drug safety prediction. Thus, assay robust predictor appears an improvement over existing models.