Dataset Information

Targeted metabolomic analysis in hepatic extracts, serum, and urine of female mice gavaged with TCDD every 4 days for 28 days

ABSTRACT: TCDD is an environmental contaminant that elicits a number of hepatic effects including fat accumulation, inflammation, and fibrosis that can progress to hepatocellular carcinoma. RNA-Seq and targeted metabolomics were integrated with complementary dioxin response element (DRE) location and aryl hydrocarbon receptor (AhR) ChIP-Seq data to further investigate the hepatotoxicity of TCDD. Our integrative analysis identified changes similar to the Warburg effect observed in cancer cells, including pyruvate kinase isoform switching (PKM1 to PKM2), and an increase in the glutaminase (GLS1) GAC:KGA isoform ratio. Consequently, metabolites are redirected towards the pentose phosphate pathway, serine biosynthesis, and glutaminolysis. We propose that the effects of TCDD on central carbon and amino acid metabolism represents AhR-mediated hepatic metabolic reprogramming in order to increase NADPH production as an oxidative stress counter-measure.

OTHER RELATED OMICS DATASETS IN: PRJNA382532PRJNA258418PXD006204PRJNA323582

INSTRUMENT(S): Xevo TQ-S (Waters), TSQ Vantage (Thermo Scientific)

SUBMITTER: Rance Nault

PROVIDER: MTBLS225 | MetaboLights | 2017-02-02

REPOSITORIES: MetaboLights

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Publications

Pyruvate Kinase Isoform Switching and Hepatic Metabolic Reprogramming by the Environmental Contaminant 2,3,7,8-Tetrachlorodibenzo-p-Dioxin.

Nault Rance R Fader Kelly A KA Kirby Mathew P MP Ahmed Shaimaa S Matthews Jason J Jones A Daniel AD Lunt Sophia Y SY Zacharewski Timothy R TR

Toxicological sciences : an official journal of the Society of Toxicology 20151117 2

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits dose-dependent hepatotoxicity that includes fat accumulation, inflammation, and fibrosis that may progress to hepatocellular carcinoma. To further investigate these effects, RNA-Seq data were integrated with computationally identified putative dioxin response elements, and complementary targeted metabolomic and aryl hydrocarbon receptor (AhR) ChIP-Seq data from female C57BL/6 mice gavaged with TCDD every 4 days for ...[more]

PMID: 26582802

Publication: 1/2

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Project description:Aryl-hydrocarbon receptor protects against endochondral ossification of modulated smooth muscle cells in atherosclerosis Introduction: Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease (CAD) risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC. Methods: We combined RNA-Seq, ChIP-Seq, ATAC-Seq and in-vitro assays in human coronary artery SMC (HCASMC), with single-cell RNA-Seq (scRNA-Seq), histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease. Results: Genomic studies coupled with functional assays in cultured HCASMC revealed that AHR modulates HCASMC phenotype and suppresses ossification in these cells. Lineage tracing and activity tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMC in the atherosclerotic lesion cap. Furthermore, scRNA-Seq studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMC expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term chondromyocytes (CMC), were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMC in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout compared to wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses. Conclusion: Overall, we conclude that AHR promotes maintenance of lesion cap integrity and diminishes the disease related SMC-to-CMC transition in atherosclerotic tissues.

Dataset Information

Targeted metabolomic analysis in hepatic extracts, serum, and urine of female mice gavaged with TCDD every 4 days for 28 days

Publications

Pyruvate Kinase Isoform Switching and Hepatic Metabolic Reprogramming by the Environmental Contaminant 2,3,7,8-Tetrachlorodibenzo-p-Dioxin.

Similar Datasets

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