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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 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-ERB?, 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.

SUBMITTER: Fader KA

PROVIDER: S-EPMC6478849 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Fader Kelly A KA Nault Rance R Doskey Claire M CM Fling Russell R RR Zacharewski Timothy R TR

Scientific reports 20190424 1

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, Cloc ...[more]

PMID: 31015483

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Project description:Background2,3,7,8-tetrachlorodibenzo-p-dixion (TCDD) is the most potent of the dioxin congeners, capable of causing a wide range of toxic effects across numerous animal models. Previous studies have demonstrated that males and females of the same species can display divergent sensitivity phenotypes to TCDD toxicities. Although it is now clear that most TCDD-induced toxic outcomes are mediated by the aryl hydrocarbon receptor (AHR), the mechanism of differential responses to TCDD exposure between sexes remains largely unknown. To investigate the differential sensitivities in male and female mice, we profiled the hepatic transcriptomic responses 4 days following exposure to various amounts of TCDD (125, 250, 500 or 1000 μg/kg) in adult male and female C57BL/6Kuo mice.ResultsSeveral key findings were revealed by our study. 1) Hepatic transcriptomes varied significantly between the sexes at all doses examined. 2) The liver transcriptome of males was more dysregulated by TCDD than that of females. 3) The alteration of "AHR-core" genes was consistent in magnitude, regardless of sex. 4) A subset of genes demonstrated sex-dependent TCDD-induced transcriptional changes, including Fmo3 and Nr1i3, which were significantly induced in livers of male mice only. In addition, a meta-analysis was performed to contrast transcriptomic profiles of various organisms and tissues following exposure to equitoxic doses of TCDD. Minimal overlap was observed in the differences between TCDD-sensitive or TCDD-resistant models.ConclusionsSex-dependent sensitivities to TCDD exposure are associated with a set of sex-specific TCDD-responsive genes. In addition, complex interactions between the aryl hydrocarbon and sex hormone receptors may affect the observable differences in sensitivity phenotypes between the sexes. Further work is necessary to better understand the roles of those genes altered by TCDD in a sex-dependent manner, and their association with changes to sex hormones and receptors.

Dataset Information

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

Publications

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

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