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ToxCast Profiling in a Human Stem Cell Assay for Developmental Toxicity (CompTox CoP)
Citation:
Knudsen, T. ToxCast Profiling in a Human Stem Cell Assay for Developmental Toxicity (CompTox CoP). Presented at CompTox COP, webinar, March 24, 2016. https://doi.org/10.23645/epacomptox.5077585
Impact/Purpose:
Presentation to EPA's Computational Toxicology Communities of Practice webinar series, describing the data stream for an important new assay platform being incorporated into the ToxCast portfolio (devTOXqP).
Description:
Standard practice for assessing disruptions in embryogenesis involves testing pregnant animals of two species, typically rats and rabbits, exposed during major organogenesis and evaluated just prior to term. Under this design the major manifestations of developmental toxicity are observed as one or more apical endpoints including intrauterine death, fetal growth retardation, structural malformations and variations. Alternative approaches to traditional developmental toxicity testing have been proposed in the form of in vitro data (e.g., embryonic stem cells, zebrafish embryos, HTS assays) and in silico models (e.g., computational toxicology). To increase the diversity of assays used to assess developmental toxicity in EPA’s ToxCast program, we tested the chemicals in Stemina’s metabolomics-based platform that utilizes the commecrially available H9 human embryonic stem cell line. The devTOXqP dataset for ToxCast of high-quality based on replicate samples and model performance (82% balanced accuracy, 0.71 sensitivity and 1.00 specificity). To date, 136 ToxCast chemicals (12.8% of 1065 tested) were positive in this platform; 48 triggered the biomarker signal without any change in hESC viability and 88 triggered activity concurrent with effects on cell viability. Work is in progress to complete the STM dataset entry into the TCPL, compare data with results from zFish and mESC platforms, profile bioactivity (ToxCastDB), endpoints (ToxRefDB), chemotypes (DSSTox), and conduct exposure-based prediction models (HTTK, ExpoCast).
URLs/Downloads:
DOI: ToxCast Profiling in a Human Stem Cell Assay for Developmental Toxicity (CompTox CoP)
KNUDSEN_COP_03242016.PDF (PDF, NA pp, 1648.907 KB, about PDF)