Citation:

Zurlinden, T., K. Saili, N. Rush, P. Kothiya, R. Judson, K. Houck, E. Hunter, N. Baker, J. Palmer, R. Thomas, AND T. Knudsen. Profiling the ToxCast Library With a Pluripotent Human (H9) Stem Cell Line-Based Biomarker Assay for Developmental Toxicity. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 174(2):189-209, (2020). https://doi.org/10.1093/toxsci/kfaa014

Impact/Purpose:

This manuscript describes a new assay for the ToxCast prioritization and screening program that provides high-throughput screening (HTS) data predicting a developmental hazard in the H9 human embryonic stem cell line. The manuscript describes the assay platform, data generation on 1065 chemicals, processing through the tcpl data analysis pipeline, quality control and performance assessment in predicting a point of departure for embryo-fetal toxicity.

Description:

The Stemina devTOX quickPredict platform (STM) 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 1062 ToxCast Phase I and II chemicals in single- or concentration-response profiles for the targeted biomarker (ratio of ornithine to cystine secreted or consumed from the media) and cell viability. Major findings from the study include: [1] 17% of 1062 chemicals yielded a prediction of developmental toxicity; [2] overall assay performance reached 76% to 84% balanced accuracy with high specificity (>88%) but modest sensitivity (<66%) when compared to in vivo animal models of human prenatal developmental toxicity studies; [3] sensitivity improved as more stringent weight of evidence requirements were applied to the animal studies; [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 potential molecular initiating events (MIEs); and [5] integration of these potential MIEs across multiple annotation systems revealed some insights into the applicability domain of the assay for predicting developmental toxicity. The results of this study will markedly increase the diversity of in vitro assays used to evaluate prenatal developmental toxicity with less reliance on animal testing.

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