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High-throughput toxicogenomic screening of chemicals in the environment using metabolically competent hepatic cell cultures.


ABSTRACT: 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.

SUBMITTER: Franzosa JA 

PROVIDER: S-EPMC7840683 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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High-throughput toxicogenomic screening of chemicals in the environment using metabolically competent hepatic cell cultures.

Franzosa Jill A JA   Bonzo Jessica A JA   Jack John J   Baker Nancy C NC   Kothiya Parth P   Witek Rafal P RP   Hurban Patrick P   Siferd Stephen S   Hester Susan S   Shah Imran I   Ferguson Stephen S SS   Houck Keith A KA   Wambaugh John F JF  

NPJ systems biology and applications 20210127 1


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 HepaRG<sup>TM</sup> cells, a human liver-derived cell model understood to ef  ...[more]

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