The Power of Resolution: Contextualized Understanding of Biological Responses to Liver Injury Chemicals Using High-throughput Transcriptomics and Benchmark Concentration Modeling

• DOI: 10.1093/toxsci/kfz065
• Publication Date: 2019-03-06T16:31:09Z
• Authors: Sreenivasa C Rama...; Scott S Auerbach; Trey O Saddler; Julie R Rice; Paul E Dunlap; Nisha S Sipes; Michael J DeVito; Ruchir R Shah; Pierre R Bushel; Bruce A Merrick; Richard S Paules; Stephen S Ferguson
• Keywords: Biological pathway

Prediction of human response to chemical exposures is a major challenge in both pharmaceutical and toxicological research. Transcriptomics has been powerful tool explore chemical-biological interactions, however, limited throughput, high-costs, complexity transcriptomic interpretations have yielded numerous studies lacking sufficient experimental context for predictive application. To address these challenges, we utilized novel high-throughput transcriptomics (HTT) platform, TempO-Seq, apply the interpretive power concentration-response modeling with 24 reference compounds differentiated non-differentiated HepaRG cell cultures. Our goals were (1) characteristics distinguishing liver injury compounds, (2) assess impacts differentiation state cells on baseline compound-induced responses (eg, metabolically-activated), (3) identify resolve biological-response pathways through benchmark concentration (BMC) modeling. Study data revealed utility this approach by their respective BMCs relation internal exposure plasma concentrations, effectively distinguished drug analogs varied associations withdrawn therapeutics trovafloxacin troglitazone). Impacts cellular (proliferated vs differentiated) metabolizing enzyme expression, hepatic receptor signaling, responsiveness metabolically-activated toxicants cyclophosphamide, benzo(a)pyrene, aflatoxin B1). Finally, enabled efficient identification resolution plausibly-relevant pathway-level BMCs. Taken together, findings HTT paired vitro models as an effective model, explore, interpret pharmacological interactions.