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A Quantitative HILIC–MS/MS Assay of the Metabolic Response of Huh-7 Cells Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
CAS Key Laboratory of Magnetic Resonance in Biological Systems, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences (CAS), Wuhan 430071, China
Huck Institute of the Life Sciences, University Park, PA 16802, USA
Author to whom correspondence should be addressed.
Metabolites 2019, 9(6), 118;
Received: 30 May 2019 / Revised: 11 June 2019 / Accepted: 13 June 2019 / Published: 20 June 2019
A hydrophilic interaction liquid chromatography (HILIC)–ultra high-pressure liquid chromatography (UHPLC) coupled with tandem mass spectrometry (MS/MS) method was developed and applied to profile metabolite changes in human Huh-7 cells exposed to the potent aryl hydrocarbon receptor (AHR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Comparisons of sensitivity (limit of detection as low as 0.01 µM) and reproducibility (84% of compounds had an interday relative standard deviation (RSD) less than 10.0%; 83% of compounds had an intraday RSD less than 15.0%) were assessed for all the metabolites. The exposure of Huh-7 cells to the hepatotoxic carcinogen TCDD at low doses (1 nM and 10 nM for 4 h and 24 h, respectively) was reflected by the disturbance of amino acid metabolism, energy metabolism (glycolysis, TCA cycle), and nucleic acid metabolism. TCDD caused a significant decrease in amino acids such as serine, alanine, and proline while promoting an increase in arginine levels with 24 h treatment. Energy metabolism intermediates such as phosphoenolpyruvate and acetyl–CoA and nucleosides such as UMP, XMP, and CMP were also markedly decreased. These results support the application of HILIC–UHPLC–MS/MS for robust and reliable analysis of the cellular response to environmentally relevant toxicants at lower doses. View Full-Text
Keywords: polar metabolites; HILIC–UHPLC–MS/MS; targeted metabolomics; TCDD polar metabolites; HILIC–UHPLC–MS/MS; targeted metabolomics; TCDD
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Liu, Q.; Cai, J.; Nichols, R.G.; Tian, Y.; Zhang, J.; Smith, P.B.; Wang, Y.; Yan, C.; Patterson, A.D. A Quantitative HILIC–MS/MS Assay of the Metabolic Response of Huh-7 Cells Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin. Metabolites 2019, 9, 118.

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