A Genomics-Based Analysis of Relative Potencies of Dioxin-Like Compounds in Primary Rat Hepatocytes

• Published in: Toxicological sciences Vol. 136; no. 2; pp. 595 - 604
• Main Authors: Rowlands, J. Craig, Budinsky, Robert, Gollapudi, Bhaskar, Black, Michael B., Wolfinger, Russell D., Cukovic, Daniela, Dombkowski, Alan, Thompson, Chad M., Urban, Jonathan D., Thomas, Russell S.
• Format: Journal Article
• Language: English
• Published: United States 01.12.2013
• Subjects: Animals; Cells, Cultured; Dioxins - toxicity; Female; Gene Expression Regulation - drug effects; Genomics; Hepatocytes - drug effects; Hepatocytes - metabolism; Oligonucleotide Array Sequence Analysis; Rats; Rats, Sprague-Dawley; Signal Transduction; risk assessment; dioxin; dose response; toxicogenomics; aryl hydrocarbon receptor
• DOI: 10.1093/toxsci/kft203
• ISSN: 1096-6080; 1096-0929

Toxic equivalency factors (TEFs) for dioxin-like compounds are largely based on relative potency (REP) values derived from biochemical endpoints such as enzyme activity. As of yet, REPs based on gene expression changes have not been accounted for in the TEF values. In this study, primary rat hepatocytes were treated for 24h with 11 concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), or 2,3,7,8-tetrachlorodibenzofuran (TCDF) ranging from 0.00001 to 100 nM. Differential changes in gene expression were analyzed using analysis of variance to assess the relative contributions of concentration, congener, and the interaction between concentration and congener for each gene. A total of 3283 genes showed significant changes with concentration (false discovery rate < .05 and fold-change ± 1.5 in at least 1 concentration for 1 congener). Among these genes, 399 were significant for both concentration and congener effects indicating parallel concentration-response curves with significant differences in potency. Only 8 genes showed a significant concentration and congener interaction term indicating a minority of genes show nonparallel dose-response curves among the 3 congeners. Benchmark dose (BMD) modeling was used to derive BMD values for induced individual genes and signaling pathways. The REP values for 4-PeCDF and TCDF were generally 3- to 5-fold lower than the World Health Organization (WHO) TEF values on both a gene and pathway basis. These findings suggest that the WHO TEF values may possibly overpredict the potency of these polychlorinated dibenzofuran congeners and demonstrate the importance of identifying functional pathways relevant to the toxicological modes of action for establishing pertinent REPs.