2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters hepatic polyunsaturated fatty acid metabolism and eicosanoid biosynthesis in female Sprague-Dawley rats

• Published in: Toxicology and applied pharmacology 2020-07, Vol.398, p.115034-115034, Article 115034
• Main Authors: Doskey, Claire M., Fader, Kelly A., Nault, Rance, Lydic, Todd, Matthews, Jason, Potter, Dave, Sharratt, Bonnie, Williams, Kurt, Zacharewski, Tim
• Format: Article
• Language: English
• Subjects: 2,3,7,8-Tetracholorodibenzo-p-dioxin; Animals; Aryl hydrocarbon receptor; Cytochrome P-450 Enzyme System - metabolism; Eicosanoids; Eicosanoids - metabolism; Fatty Acids, Omega-3 - metabolism; Fatty Acids, Unsaturated - metabolism; Fatty Liver - metabolism; Female; Hepatotoxicity; Leukotrienes; Lipid Metabolism - drug effects; Liver - drug effects; Liver - metabolism; Polychlorinated Dibenzodioxins - pharmacology; Polyunsaturated fatty acids; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon - metabolism
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2020.115034

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent aryl hydrocarbon receptor (AhR) agonist that elicits a broad spectrum of dose-dependent hepatic effects including lipid accumulation, inflammation, and fibrosis. To determine the role of inflammatory lipid mediators in TCDD-mediated hepatotoxicity, eicosanoid metabolism was investigated. Female Sprague-Dawley (SD) rats were orally gavaged with sesame oil vehicle or 0.01–10 μg/kg TCDD every 4 days for 28 days. Hepatic RNA-Seq data was integrated with untargeted metabolomics of liver, serum, and urine, revealing dose-dependent changes in linoleic acid (LA) and arachidonic acid (AA) metabolism. TCDD also elicited dose-dependent differential gene expression associated with the cyclooxygenase, lipoxygenase, and cytochrome P450 epoxidation/hydroxylation pathways with corresponding changes in ω-6 (e.g. AA and LA) and ω-3 polyunsaturated fatty acids (PUFAs), as well as associated eicosanoid metabolites. Overall, TCDD increased the ratio of ω-6 to ω-3 PUFAs. Phospholipase A2 (Pla2g12a) was induced consistent with increased AA metabolism, while AA utilization by induced lipoxygenases Alox5 and Alox15 increased leukotrienes (LTs). More specifically, TCDD increased pro-inflammatory eicosanoids including leukotriene LTB4, and LTB3, known to recruit neutrophils to damaged tissue. Dose-response modeling suggests the cytochrome P450 hydroxylase/epoxygenase and lipoxygenase pathways are more sensitive to TCDD than the cyclooxygenase pathway. Hepatic AhR ChIP-Seq analysis found little enrichment within the regulatory regions of differentially expressed genes (DEGs) involved in eicosanoid biosynthesis, suggesting TCDD-elicited dysregulation of eicosanoid metabolism is a downstream effect of AhR activation. Overall, these results suggest alterations in eicosanoid metabolism may play a key role in TCDD-elicited hepatotoxicity associated with the progression of steatosis to steatohepatitis. •Metabolomics identified perturbation of eicosanoid metabolism in TCDD treated rats.•TCDD increased the ratio of pro- and anti-inflammatory ω-6 to ω-3 PUFAs.•TCDD altered lipoxygenase and cyclooxygenase pathway produced eicosanoids.•Absence of AhR binding at eicosanoid metabolism genes indicates secondary effects.