2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice

• Published in: Scientific reports Vol. 9; no. 1; pp. 6514 - 18
• Main Authors: Fader, Kelly A., Nault, Rance, Doskey, Claire M., Fling, Russell R., Zacharewski, Timothy R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.04.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 45/15; 45/91; 631/337/2019; 631/45/320; 692/699/317; 82/58; Animals; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Carbohydrate Metabolism - drug effects; Carbohydrate Metabolism - genetics; Circadian rhythm; Circadian Rhythm Signaling Peptides and Proteins - genetics; Circadian Rhythm Signaling Peptides and Proteins - metabolism; Circadian rhythms; Cryptochromes; Dioxins; Energy storage; Environmental Pollutants - pharmacology; Gene expression; Gene Expression Profiling - methods; Gluconeogenesis; Gluconeogenesis - drug effects; Gluconeogenesis - genetics; Glucose metabolism; Glycogen; Heme; Humanities and Social Sciences; Lipid metabolism; Lipid Metabolism - drug effects; Lipid Metabolism - genetics; Lipids; Liver; Liver - drug effects; Liver - metabolism; Liver Glycogen - metabolism; Male; Mass spectrometry; Mass spectroscopy; Metabolism; Metabolites; Metabolomics - methods; Mice, Inbred C57BL; multidisciplinary; Period 1 protein; Periodicity; Polychlorinated Dibenzodioxins - pharmacology; Protein folding; Regulation; Science; Science (multidisciplinary); TCDD
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-42760-3

Aryl hydrocarbon receptor (AhR) activation is reported to alter the hepatic expression of circadian clock regulators, however the impact on clock-controlled metabolism has not been thoroughly investigated. This study examines the effects of AhR activation on hepatic transcriptome and metabolome rhythmicity in male C57BL/6 mice orally gavaged with 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) every 4 days for 28 days. TCDD diminished the rhythmicity of several core clock regulators (e.g. Arntl , Clock , Nr1d1 , Per1 , Cry1 , Nfil3 ) in a dose-dependent manner, involving either a ≥ 3.3-fold suppression in amplitude or complete loss of oscillation. Accordingly, protein levels (ARNTL, REV-ERBα, NFIL3) and genomic binding (ARNTL) of select regulators were reduced and arrhythmic following treatment. As a result, the oscillating expression of 99.6% of 5,636 clock-controlled hepatic genes was abolished including genes associated with the metabolism of lipids, glucose/glycogen, and heme. For example, TCDD flattened expression of the rate-limiting enzymes in both gluconeogenesis ( Pck1 ) and glycogenesis ( Gys2 ), consistent with the depletion and loss of rhythmicity in hepatic glycogen levels. Examination of polar hepatic extracts by untargeted mass spectrometry revealed that virtually all oscillating metabolites lost rhythmicity following treatment. Collectively, these results suggest TCDD disrupted circadian regulation of hepatic metabolism, altering metabolic efficiency and energy storage.