Using Chemical-Induced Gene Expression in Cultured Human Cells to Predict Chemical Toxicity
- Ruifeng Liu
- ,
- Xueping Yu
- , and
- Anders Wallqvist
Abstract
Chemical toxicity is conventionally evaluated in animal models. However, animal models are resource intensive; moreover, they face ethical and scientific challenges because the outcomes obtained by animal testing may not correlate with human responses. To develop an alternative method for assessing chemical toxicity, we investigated the feasibility of using chemical-induced genome-wide expression changes in cultured human cells to predict the potential of a chemical to cause specific organ injuries in humans. We first created signatures of chemical-induced gene expression in a vertebral-cancer of the prostate cell line for ∼15,000 chemicals tested in the US National Institutes of Health Library of Integrated Network-Based Cellular Signatures program. We then used the signatures to create naı̈ve Bayesian prediction models for chemical-induced human liver cholestasis, interstitial nephritis, and long QT syndrome. Detailed cross-validation analyses indicated that the models were robust with respect to false positives and false negatives in the samples we used to train the models and could predict the likelihood that chemicals would cause specific organ injuries. In addition, we performed a literature search for drugs and dietary supplements, not formally categorized as causing organ injuries in humans but predicted by our models to be most likely to do so. We found a high percentage of these compounds associated with case reports of relevant organ injuries, lending support to the idea that in vitro cell-based experiments can be used to predict the toxic potential of chemicals. We believe that this approach, combined with a robust technique to model human exposure to chemicals, may serve as a promising alternative to animal-based chemical toxicity assessment.
Cited By
This article is cited by 6 publications.
- Andy H. Vo, Terry R. Van Vleet, Rishi R. Gupta, Michael J. Liguori, Mohan S. Rao. An Overview of Machine Learning and Big Data for Drug Toxicity Evaluation. Chemical Research in Toxicology 2020, 33 (1) , 20-37. https://doi.org/10.1021/acs.chemrestox.9b00227
- Ruifeng Liu, Mohamed Diwan M. AbdulHameed, and Anders Wallqvist . Molecular Structure-Based Large-Scale Prediction of Chemical-Induced Gene Expression Changes. Journal of Chemical Information and Modeling 2017, 57 (9) , 2194-2202. https://doi.org/10.1021/acs.jcim.7b00281
- Edward J. Perkins, Tanwir Habib, Barbara L. Escalon, Jenna E. Cavallin, Linnea Thomas, Matthew Weberg, Megan N. Hughes, Kathleen M. Jensen, Michael D. Kahl, Daniel L. Villeneuve, Gerald T. Ankley, and Natàlia Garcia-Reyero . Prioritization of Contaminants of Emerging Concern in Wastewater Treatment Plant Discharges Using Chemical:Gene Interactions in Caged Fish. Environmental Science & Technology 2017, 51 (15) , 8701-8712. https://doi.org/10.1021/acs.est.7b01567
- Srijit Seal, Jordi Carreras-Puigvert, Maria-Anna Trapotsi, Hongbin Yang, Ola Spjuth, Andreas Bender. Integrating cell morphology with gene expression and chemical structure to aid mitochondrial toxicity detection. Communications Biology 2022, 5 (1) https://doi.org/10.1038/s42003-022-03763-5
- Yunyi Wu, Guanyu Wang. Machine Learning Based Toxicity Prediction: From Chemical Structural Description to Transcriptome Analysis. International Journal of Molecular Sciences 2018, 19 (8) , 2358. https://doi.org/10.3390/ijms19082358
- Yvonne C.M. Staal, Jeroen L.A. Pennings, Ellen V.S. Hessel, Aldert H. Piersma. Advanced Toxicological Risk Assessment by Implementation of Ontologies Operationalized in Computational Models. Applied In Vitro Toxicology 2017, 3 (4) , 325-332. https://doi.org/10.1089/aivt.2017.0019