Genome-Scale Characterization of Toxicity-Induced Metabolic Alterations in Primary Hepatocytes

• DOI: 10.1093/toxsci/kfz197
• Publication Date: 2019-09-05T19:27:15Z
• Authors: Kristopher D Rawls; Edik M Blais; Bonnie V Dougherty; Kalyan C Vinnakota; Venkat R Pannala; Anders Wallqvist; Glynis L Kolling; Jason A Papin
• Keywords: Primary (astronomy)

Context-specific GEnome-scale metabolic Network REconstructions (GENREs) provide a means to understand cellular metabolism at deeper level of physiological detail. Here, we use transcriptomics data from chemically-exposed rat hepatocytes constrain GENRE hepatocyte and predict biomarkers liver toxicity using the Transcriptionally Inferred Metabolic Biomarker Response algorithm. We profiled alterations in following vitro exposure four toxicants (acetaminophen, carbon tetrachloride, 2,3,7,8-tetrachlorodibenzodioxin, trichloroethylene) for six hour. TIMBR predictions were compared with paired fresh spent media metabolomics same conditions. Agreement between computational model experimental led identification specific metabolites thus pathways associated toxicant exposure. identified changes TCA citrate alpha-ketoglutarate along carbohydrate interruptions ATP production Cycle. Where disagreed, testable hypotheses reconcile differences data. The presented pipeline provides framework interrogating multiple omics datasets generate mechanistic insight toxicological responses.