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From cell lines to tissues: extrapolation of transcriptional effects to human tissues (SOT)
Citation:
Wambaugh, J. From cell lines to tissues: extrapolation of transcriptional effects to human tissues (SOT). Presented at Society of Toxicology Annual Meeting, San Diego, CA, March 22 - 26, 2015. https://doi.org/10.23645/epacomptox.5082772
Impact/Purpose:
This presentation is part of a Symposium/Workshop at the Society of Toxicology Annual meeting in San Diego, presented on March 25, 2015. The session is entitled "INTEGRATING GENE EXPRESSION PROFILING INTO HIGH THROUGHPUT TOXICITY TESTING."
Description:
A new suite of assays in the metabolically-competent, human hepatocyte-derived HepaRG cell line has been added to the ToxCast screening suite. For 1066 chemicals we have evaluated the chemical treatment-induced changes in expression for a diverse set of 93 genes representative of various biological processes and disease states including: cell proliferation, survival, and death; nuclear receptor (NR) mediated metabolism and transport; oxidative stress; steatosis and fibrosis. Many of the genes are known to be transcriptionally regulated by key NRs, including CAR, PXR, PPARa, and HNF4a. The profiled chemicals include industrial compounds, pesticides, reference in vivo toxicants, and a mix of failed and successful pharmaceuticals. Many of the chemicals are found in the environment and have little or no in vivo data. Through statistical analysis we assess both likely NR activation (as a molecular initiating event) and likely in vivo toxicity assay result (as an adverse outcome) to putatively assign chemicals to adverse outcome pathways wherever possible. For a subset of these ToxCast chemicals, for which in vitro toxicokinetic data exists, we use this putative AOP activity to predict in vivo doses which we then compare to the extant in vivo data for the onset of adverse outcomes. This abstract does not necessarily reflect U.S. EPA policy.
URLs/Downloads:
DOI: From cell lines to tissues: extrapolation of transcriptional effects to human tissues (SOT)