We have located links that may give you full text access.
The Power of Resolution: Contextualized Understanding of Biological Responses to Liver Injury Chemicals using High-throughput Transcriptomics and Benchmark Concentration Modeling.
Prediction of human response to chemical exposures is a major challenge in both pharmaceutical and toxicological research. Transcriptomics has been a powerful tool to explore chemical-biological interactions, however, limited throughput, high-costs and complexity of transcriptomic interpretations have yielded numerous studies lacking sufficient experimental context for predictive application. To address these challenges, we have utilized a novel high-throughput transcriptomics (HTT) platform, TempO-Seq, to apply the interpretive power of concentration-response modeling with exposures to 24 reference compounds in both differentiated and non-differentiated human HepaRG cell cultures. Our goals were to 1) explore transcriptomic characteristics distinguishing liver injury compounds, 2) assess impacts of differentiation state of HepaRG cells on baseline and compound-induced responses (e.g., metabolically-activated), and 3) identify and resolve reference biological-response pathways through benchmark concentration modeling. Study data revealed the predictive utility of this approach to identify human liver injury compounds by their respective benchmark concentrations (BMCs) in relation to human internal exposure plasma concentrations, and effectively distinguished drug analogues with varied associations of human liver injury (e.g., withdrawn therapeutics trovafloxacin and troglitazone). Impacts of cellular differentiation state (proliferated vs. differentiated) were revealed on baseline drug metabolizing enzyme expression, hepatic receptor signaling, and responsiveness to metabolically-activated toxicants (e.g., cyclophosphamide, benzo(a)pyrene, and aflatoxin B1). Finally, concentration-response modeling enabled efficient identification and resolution of plausibly-relevant biological-response pathways through their respective pathway-level BMCs. Taken together, these findings revealed HTT paired with differentiated in vitro liver models as an effective tool to model, explore and interpret toxicological and pharmacological interactions.
Full text links
Related Resources
Trending Papers
Challenges in Septic Shock: From New Hemodynamics to Blood Purification Therapies.Journal of Personalized Medicine 2024 Februrary 4
Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection.International Journal of Molecular Sciences 2024 April 4
Perioperative echocardiographic strain analysis: what anesthesiologists should know.Canadian Journal of Anaesthesia 2024 April 11
The 'Ten Commandments' for the 2023 European Society of Cardiology guidelines for the management of endocarditis.European Heart Journal 2024 April 18
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app