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Profiling the ToxCast library with a pluripotent human (H9) stem cell line-based biomarker assay for developmental toxicity [in Toxicological Sciences, February 2020]

Todd J. Zurlinden, Katerine S. Saili, Nathaniel Rush, Parth Kothiya, Richard S. Judson, Keith A. Houck, E. Sidney Hunter, Nancy C. Baker, Jessica A. Palmer, Russell S. Thomas, Thomas B. Knudsen

Abstract

The Stemina devTOX quickPredict platform (devTOXqP) is a human pluripotent stem cell-based assay that predicts the developmental toxicity potential based on changes in cellular metabolism following chemical exposure [Palmer et al. 2013]. Using this assay, we screened 1065 ToxCast Phase I and II chemicals in single-concentration or concentration-response for the targeted biomarker (ratio of ornithine to cystine secreted or consumed from the media). The dataset from the Stemina (STM) assay is annotated in the ToxCast portfolio as STM. Major findings from the analysis of ToxCast_STM dataset include: [1] 19% of 1065 chemicals yielded a prediction of developmental toxicity; [2] assay performance reached 79% to 82% accuracy with high specificity (>84%) but modest sensitivity (<67%) when compared to in vivo animal models of human prenatal developmental toxicity; [3] sensitivity improved as more stringent weight of evidence requirements were applied to the animal studies; and [4] statistical analysis of the most potent chemical hits on specific biochemical targets in ToxCast revealed positive and negative associations with the STM response, providing insights into the mechanistic underpinnings of the targeted endpoint and its biological domain. The results of this study will be useful to improving our ability to predict in vivo developmental toxicants based on in vitro data and in silico models.

Read the full publication [early online access 02/19/2020]