Urban J, Rowlands JC, Budinsky R, Dombkowski A, Thompson CM, Thomas RS. 2012. A genomics-based benchmark dose analyses of relative potencies of dioxin-like compounds in primary rat hepatocytes. Presented at the Society of Toxicology’s 51st Annual Meeting, March 11-15, San Francisco, CA.
Toxic Equivalency Factors (TEFs) are central to characterizing risk associated with mixtures of dioxin-like compounds (DLCs), and genomic technologies have the potential of contributing to the estimation of meaningful TEF values. In this study, Sprague-Dawley primary hepatocytes were treated for 24 hours with 0.00001-100 nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), or 2,3,7,8-tetrachlorodibenzofuran (TCDF). Approximately 1600 genes were significantly altered by all 3 congeners by ANOVA (FDR ≤ 0.05). Hierarchical clustering revealed that these genes generally responded in a similar fashion to the 3 congeners. Automated benchmark dose (BMD) modeling was performed to derive BMD values for all individual gene changes as well as GeneGo Metacore canonical signaling pathways. TCDD-based relative potency values (REPs) based on the median BMD values for all individual gene changes were in close agreement with WHO TEF values for PeCDF (0.3) and TCDF (0.1), as were REPs based on specific aryl hydrocarbon receptor (AHR) battery genes. Functional enrichment analysis (FDR ≤ 0.05) of the 1600 genes identified 14 canonical signaling pathways, including the AHR signaling pathway. REPs based on the AHR signaling pathway were generally similar to WHO TEFs, while median REPs for the other 13 pathways were lower (PeCDF REP = 0.09, TCDF REP = 0.03). That the REPs derived from the AHR signaling pathway approximate the WHO TEFs is not unexpected given that the WHO REP database is comprised of many AHRmediated biochemical endpoints (e.g. EROD) in rodents. REPs based on the other enriched pathways, potentially relevant to the mode of action and toxicity of DLCs, could provide meaningful measures of relative potency and thus might be considered for future addition to the WHO database.