Shift in the urinary metabolome associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin activation of the hepatic aryl hydrocarbon receptor.

Epidemiological evidence suggests an association between dioxin and dioxin-like compound (DLC) exposure and human liver disease. In rodents, the prototypical DLC, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been shown to induce the progression of reversible hepatic steatosis to steatohepatitis with periportal fibrosis and biliary hyperplasia. Although the effects of TCDD are mediated by aryl hydrocarbon receptor (AHR) activation, the underlying mechanisms of induced pathologies have not been resolved. In the present study, male C57BL/6NCrl mice were gavaged every 4 days for 28 days with 0.03-30 μg/kg TCDD or sesame oil vehicle and evaluated for liver histopathology and gene expression as well as complementary 1-dimensional proton magnetic resonance (1-D (1)H NMR) urinary metabolic profiling. Urinary trimethylamine (TMA), trimethylamine N-oxide (TMAO), and 1-methylnicotinamide (1MN) levels were altered at doses of ≤ 3 μg/kg TCDD; other urinary metabolites, such as glycolate, urocanate, and 3-hydroxyisovalerate, were only altered following the induction of moderate to severe steatohepatitis. Hepatic differential gene expression of rate-limiting enzymes of choline, gloxylate, and amino acid metabolism coincided with the altered urinary metabolites. Published single-nuclear RNA-seq (snRNA-seq), AHR ChIP-seq, and AHR knockout gene expression datasets provided further support for hepatic cell-type and AHR-regulated disruption of the affected metabolic pathways.