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Modeling Nuclear Receptor-Mediated Activity and Hepatotoxicity with Boolean Networks
Citation:
JACK, J. AND I. A. SHAH. Modeling Nuclear Receptor-Mediated Activity and Hepatotoxicity with Boolean Networks. Presented at Society of Toxicology Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
Virtual Liver project
Description:
Predicting the human health risk of chronic exposure to environmental contaminants remains an open problem. Chronic exposure to a wide array of chemicals – e.g., conazoles, perfluourinated chemicals and phthalates – has been associated with a range of hepatic lesions in rodents that can progress to cancer, but extrapolating these effects to humans remains challenging. The US EPA Virtual Liver (v-Liver) project applies in silico methods to gain insight into in vitro assay results and the pathways perturbed by chemicals, their relationship to adverse effects, and the degree of conservation between rodents and humans. As a proof of concept, we focus on 20 environmental chemicals in the ToxCastTM project that activate nuclear receptors (NR) and are implicated in rodent liver cancer. We developed a model of NR-mediated molecular interactions using curated information from the v-Liver Knowledgebase (KB). The model captures the putative signaling, gene expression and enzymatic interactions mediated by CAR, PXR, PPAR-α, LXR and FXR in human hepatocytes. A Boolean Network formalism was used to simulate pathway perturbations and crosstalk due to the activation of NRs by environmental chemicals. We investigated the dynamics of the system using human in vitro data on NR activation from ToxCast. The 20 chemicals perturbed the system by differentially activating NRs, resulting in variable changes to downstream gene expression and protein activation. The NR-mediated network is being further developed to investigate signaling cascades that are potentially responsible for the altered hepatocellular phenotypes observed in acute tissue lesions.
URLs/Downloads:
Modeling Nuclear Receptor-Mediated Activity and Hepatotoxicity with Boolean Networks (slides) (PDF, NA pp, 2079 KB, about PDF)Modeling Nuclear Receptor-Mediated Activity and Hepatotoxicity with Boolean Networks (PDF, NA pp, 50 KB, about PDF)