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

Abstract 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 metabo...

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Autores principales:	Kelly A. Fader, Rance Nault, Claire M. Doskey, Russell R. Fling, Timothy R. Zacharewski
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9a17274562514ae6a763ae55659ce0bb
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spelling	oai:doaj.org-article:9a17274562514ae6a763ae55659ce0bb2021-12-02T15:09:14Z2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice10.1038/s41598-019-42760-32045-2322https://doaj.org/article/9a17274562514ae6a763ae55659ce0bb2019-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-42760-3https://doaj.org/toc/2045-2322Abstract 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.Kelly A. FaderRance NaultClaire M. DoskeyRussell R. FlingTimothy R. ZacharewskiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-18 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kelly A. Fader Rance Nault Claire M. Doskey Russell R. Fling Timothy R. Zacharewski 2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice
description	Abstract 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.
format	article
author	Kelly A. Fader Rance Nault Claire M. Doskey Russell R. Fling Timothy R. Zacharewski
author_facet	Kelly A. Fader Rance Nault Claire M. Doskey Russell R. Fling Timothy R. Zacharewski
author_sort	Kelly A. Fader
title	2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice
title_short	2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice
title_full	2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice
title_fullStr	2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice
title_full_unstemmed	2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice
title_sort	2,3,7,8-tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/9a17274562514ae6a763ae55659ce0bb
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2,3,7,8-Tetrachlorodibenzo-p-dioxin abolishes circadian regulation of hepatic metabolic activity in mice

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