National Center for Computational Toxicology (NCCT).
National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), U.S. Environmental Protection Agency (USEPA), Research Triangle Park, North Carolina.
Toxicol Sci. 2020 Apr 1;174(2):189-209. doi: 10.1093/toxsci/kfaa014.
The Stemina devTOX quickPredict platform is a human pluripotent stem cell-based assay that predicts the developmental toxicity potential based on changes in cellular metabolism following chemical exposure [Palmer, J. A., Smith, A. M., Egnash, L. A., Conard, K. R., West, P. R., Burrier, R. E., Donley, E. L. R., and Kirchner, F. R. (2013). Establishment and assessment of a new human embryonic stem cell-based biomarker assay for developmental toxicity screening. Birth Defects Res. B Dev. Reprod. Toxicol. 98, 343-363]. 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%-82% accuracy with high specificity (> 84%) but modest sensitivity (< 67%) when compared with in vivo animal models of human prenatal developmental toxicity, (3) sensitivity improved as more stringent weights 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.
Stemina devTOX quickPredict 平台是一种基于人多能干细胞的检测方法，可根据化学暴露后细胞代谢的变化预测发育毒性潜力[Palmer, J. A., Smith, A. M., Egnash, L. A., Conard, K. R., West, P. R., Burrier, R. E., Donley, E. L. R., and Kirchner, F. R. (2013). Establishment and assessment of a new human embryonic stem cell-based biomarker assay for developmental toxicity screening. Birth Defects Res. B Dev. Reprod. Toxicol. 98, 343-363]。我们使用该检测方法对 1065 种 ToxCast 一期和二期化学品进行了单点浓度或浓度反应筛查，针对的是靶向生物标志物（从培养基中分泌或消耗的鸟氨酸与胱氨酸之比）。Stemina（STM）检测法的数据集在 ToxCast 投资组合中被标注为 STM。从 ToxCast_STM 数据集分析中得出的主要发现包括：（1）1065 种化学物质中有 19%预测具有发育毒性，（2）与人类产前发育毒性的体内动物模型相比，当与体内动物模型相比时，检测法的性能达到了 79%-82%的准确率，具有较高的特异性（>84%）但敏感性较低（<67%），（3）随着对动物研究应用更严格的证据权重要求，敏感性提高，（4）对 ToxCast 中特定生化靶标上最有效化学物质的统计分析显示与 STM 反应呈阳性和阴性关联，为靶向终点及其生物学域的机制基础提供了深入了解。这项研究的结果将有助于提高我们基于体外数据和计算模型预测体内发育毒物的能力。
