title: Metabolomics Reveals that Aryl Hydrocarbon Receptor Activation by Environmental Chemicals Induces Systemic Metabolic Dysfunction in Mice.
abstract: Environmental exposure to dioxins and dioxin-like compounds poses a significant health risk for human health. Developing a better understanding of the mechanisms of toxicity through activation of the aryl hydrocarbon receptor (AHR) is likely to improve the reliability of risk assessment. In this study, the AHR-dependent metabolic response of mice exposed to 2,3,7,8-tetrachlorodibenzofuran (TCDF) was assessed using global (1)H nuclear magnetic resonance (NMR)-based metabolomics and targeted metabolite profiling of extracts obtained from serum and liver. (1)H NMR analyses revealed that TCDF exposure suppressed gluconeogenesis and glycogenolysis, stimulated lipogenesis, and triggered inflammatory gene expression in an Ahr-dependent manner. Targeted analyses using gas chromatography coupled with mass spectrometry showed TCDF treatment altered the ratio of unsaturated/saturated fatty acids. Consistent with this observation, an increase in hepatic expression of stearoyl coenzyme A desaturase 1 was observed. In addition, TCDF exposure resulted in inhibition of de novo fatty acid biosynthesis manifested by down-regulation of acetyl-CoA, malonyl-CoA, and palmitoyl-CoA metabolites and related mRNA levels. In contrast, no significant changes in the levels of glucose and lipid were observed in serum and liver obtained from Ahr-null mice following TCDF treatment, thus strongly supporting the important role of the AHR in mediating the metabolic effects seen following TCDF exposure.
authors.affiliation: †Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.|‡CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences (CAS), Wuhan 430071, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: §Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Hatzakis
authors.affiliation: †Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nichols
authors.affiliation: †Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
authors.forename: Ruixin
authors.initials: R
authors.lastname: Hao
authors.affiliation: †Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
authors.forename: Jared
authors.initials: J
authors.lastname: Correll
authors.affiliation: ⊥Metabolomics Facility, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Smith
authors.affiliation: †Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Chiaro
authors.affiliation: †Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
authors.affiliation: †Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Patterson
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D004147:Dioxins / Q000633:toxicity; D004785:Environmental Pollutants / Q000633:toxicity; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: D001572:Benzofurans; D004147:Dioxins; D004785:Environmental Pollutants; D005227:Fatty Acids; D018336:Receptors, Aryl Hydrocarbon; D005947:Glucose; C014211:2,3,7,8-tetrachlorodibenzofuran