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Nuclear Receptor Activity and Liver Cancer Lesion Progression
Citation:
SHAH, I. A., K. A. HOUCK, R. JUDSON, R. J. KAVLOCK, M. T. MARTIN, J. F. WAMBAUGH, AND D. J. DIX. Nuclear Receptor Activity and Liver Cancer Lesion Progression. Presented at Computational Toxicology Board of Scientific Counselors Review, RTP, NC, September 29 - 30, 2009.
Impact/Purpose:
In this poster we report on this analysis, highlighting putative relationships between NRs and cancer lesion progression.
Description:
Nuclear receptors (NRs) are ligand-activated transcription factors that control diverse cellular processes. Chronic stimulation of some NRs is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. We explored this question using human CAR, PXR, PPARα, LXR, ER, AR and Ahr activity assays for 309 environmental chemicals from ToxCast, and liver histopathology data from long-term rodent testing studies from ToxRefDB. The chemicals activated multiple human NRs in combinations that were informative about rodent liver injury. In addition, some surprising relationships were observed between the degree of human NR activity and the severity of hepatic lesions progressing to cancer. The results have implications for nuclear receptor chemical biology and the extrapolation of in vitro data for predicting liver cancer in humans. In this poster we report on this analysis, highlighting putative relationships between NRs and cancer lesion progression. Furthermore, we describe the selection of chemicals and cellular endpoints for modeling NRmediated mitogenic, mutagenic and cytotoxic processes involved in hepatocarconogenesis. This work was reviewed by EPA and approved for publication but does not necessarily reflect official agency policy.
URLs/Downloads:
Nuclear Receptor Activity and Liver Cancer Lesion Progression (abs) (PDF, NA pp, 38 KB, about PDF)Nuclear Receptor Activity and Liver Cancer Lesion Progression (poster) (PDF, NA pp, 988 KB, about PDF)