Abstract
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds elicit a broad spectrum of species-specific effects. Hepatic steatosis is a classic response following exposure to TCDD characterized by increases in lipid accumulation, hepatocellular vacuolization, inflammation, and serum free fatty acids. Many of these effects resemble characteristics of metabolic syndrome (MetS), a multi-factorial disease that includes dyslipidemia, obesity, and can progress into non-alcoholic fatty liver disease (NAFLD) and , and diabetes. We have systematically integrated omic data from genome-wide chromatin immunoprecipitation (ChIPchip), microarray and metabolomic studies with complementary histopathology, and comparative analysis of in vivo and in vitro human, mice and rat models, as well as bioinformatic approaches to further elucidate the mechanisms involved in aryl hydrocarbon receptor (AhR)-mediated hepatic steatosis in female C57BL/6 mice. Our results suggest that TCDD induces hepatic steatosis due to alterations in lipid transport and metabolism that increase fat uptake and inhibit beta oxidation. Lipidomic and gene expression analyses also suggests that there is increased uptake of dietary fatty acids and regulation of fatty acid metabolism that alters saturated, mono-, and poly-unsaturated fatty acid ratios resulting in hepatoxicity. The integration of ChIP-chip data with the genomewide computational identification of dioxin response elements (DREs) is consistent with AhR-AhR nuclear translocator (ARNT)- mediated regulation for many of these responses. However, ~50% of AhR enriched regions in our ChIP-chip data did not contain a DRE. Bioinformatic analyses with supporting microarray data suggest that the AhR interacts with DNA to regulate gene expression by dimerizing with other transcription factors to alter lipid metabolism and transport. Collectively, these results not only further elucidate the mechanisms involved in TCDD-induced steatosis, but also suggest that TCDD and related compounds may contribute to the development of MetS and its associated diseases by increasing hepatic fat accumulation.
