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High-throughput toxicogenomic screening of chemicals in the environment using metabolically competent hepatic cell cultures
Citation:
Franzosa, J., J. Bonzo, J. Jack, Nancy C. Baker, P. Kothiya, R. Witek, P. Hurban, S. Siferd, S. Hester, I. Shah, S. Ferguson, K. Houck, AND J. Wambaugh. High-throughput toxicogenomic screening of chemicals in the environment using metabolically competent hepatic cell cultures. npj Systems Biology and Applications. Springer Nature, New York, NY, 7:Article 7, (2021). https://doi.org/10.1038/s41540-020-00166-2
Impact/Purpose:
High throughput transcriptomics data were an important part of the first 309 chemicals of ToxCast, this research expands from 14 to 93 transcripts tested across 1060 ToxCast chemicals. The new assays presented here make use of HepaRG™ cell cultures, which are reproducible and metabolically-competent, allowing for more physiologically-relevant screening of chemicals. A new methodology was developed for analyzing transcriptomic concentration response data that allowed the identification of molecular initiating events for the chemical library. These data inform potential adverse outcome pathways for risk assessment of the ToxCast chemical library.
Description:
The ToxCast in vitro screening program has provided concentration-response bioactivity data across more than a thousand assay endpoints for thousands of chemicals found in our environment and commerce. However, most ToxCast screening assays have evaluated individual biological targets in cancer cell lines lacking integrated physiological functionality (such as receptor signaling, metabolism). We evaluated differentiated HepaRGTM cells, a human liver-derived cell model understood to effectively model physiologically relevant hepatic signaling. Expression of 93 gene transcripts was measured by quantitative polymerase chain reaction using Fluidigm 96.96 dynamic arrays in response to 1060 chemicals tested in eight-point concentration-response. A Bayesian framework quantitatively modeled chemical-induced changes in gene expression via six transcription factors including: aryl hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, farnesoid X receptor, androgen receptor, and peroxisome proliferator-activated receptor alpha. For these chemicals the network model translates transcriptomic data into Bayesian inferences about molecular targets known to activate toxicological adverse outcome pathways. These data also provide new insights into the molecular signaling network of HepaRGTM cell cultures.
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DOI: High-throughput toxicogenomic screening of chemicals in the environment using metabolically competent hepatic cell cultures
https://pubmed.ncbi.nlm.nih.gov/33504769/