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Research ArticleArticle

PBDEs and Gut Microbiome Modulate Metabolic Syndrome-Related Aqueous Metabolites in Mice

David K Scoville, Cindy Yanfei Li, Dongfang Wang, Joseph L Demspey, Daniel Raftery, Sridhar Mani, Haiwei Gu and Julia Yue Cui
Drug Metabolism and Disposition May 23, 2019, dmd.119.086538; DOI: https://doi.org/10.1124/dmd.119.086538
David K Scoville
1 University of Washington;
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Cindy Yanfei Li
1 University of Washington;
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Dongfang Wang
2 Peking University;
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Joseph L Demspey
1 University of Washington;
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Daniel Raftery
1 University of Washington;
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Sridhar Mani
3 Albert Einstein College of Medicine;
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Haiwei Gu
4 Arizona State University
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  • For correspondence: juliacui@uw.edu haiweigu@asu.edu
Julia Yue Cui
1 University of Washington;
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  • For correspondence: juliacui@uw.edu haiweigu@asu.edu
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Abstract

Polybrominated diphenyl ethers (PBDEs) are persistent environmental toxicants associated with increased risk for metabolic syndrome. Intermediary metabolism is influenced by the intestinal microbiome. To test the hypothesis that PBDEs reduce host-beneficial intermediary metabolites in an intestinal microbiome-dependent manner, nine-week old male conventional (CV) and germ-free (GF) C57BL/6 mice orally gavaged once daily with vehicle, BDE-47, or BDE-99 (100 µmol/kg) for four-days. Intestinal microbiome (16S rDNA sequencing), liver transcriptome (RNA-Seq), and intermediary metabolites in serum, liver, as well as small and large intestinal contents (SIC and LIC; LC-MS) were examined. Changes in intermediary metabolite abundances in serum, liver, and SIC, were observed under basal conditions (CV versus GF mice) and by PBDE exposure. PBDEs altered the largest number of metabolites in the LIC; most were regulated by PBDEs in GF conditions. Importantly, intestinal microbiome was necessary for PBDE-mediated decreases in branched chain and aromatic amino acid metabolites including 3-indolepropionic acid, a tryptophan metabolite recently shown to be protective against inflammation and diabetes. Gene-metabolite networks revealed a positive association between the hepatic glycan synthesis gene alpha-1,6-mannosyltransferase (Alg12) mRNA and mannose which are important for protein glycosylation. Glycome changes have been observed in patients with metabolic syndrome. In LIC of CV mice, 23 bacterial taxa were regulated by PBDEs. Correlations of certain taxa with distinct serum metabolites further highlight a modulatory role of the microbiome in mediating PBDE effects. In summary, PBDEs impact intermediary metabolism in an intestinal microbiome-dependent manner, suggesting that dysbiosis may contribute to PBDE-mediated toxicities including metabolic syndrome.

SIGNIFICANCE STATEMENT N/A

  • animal models
  • animal/nonclinical/preclinical
  • functional genomics/bioinformatics
  • metabolomics
  • microbiome
  • systems biology
  • toxicology
  • transcriptomics
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (1)
Drug Metabolism and Disposition
Vol. 49, Issue 1
1 Jan 2021
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Research ArticleArticle

PBDEs and Gut Microbiome Modulate Metabolic Syndrome-Related Aqueous Metabolites in Mice

David K Scoville, Cindy Yanfei Li, Dongfang Wang, Joseph L Demspey, Daniel Raftery, Sridhar Mani, Haiwei Gu and Julia Yue Cui
Drug Metabolism and Disposition May 23, 2019, dmd.119.086538; DOI: https://doi.org/10.1124/dmd.119.086538

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Research ArticleArticle

PBDEs and Gut Microbiome Modulate Metabolic Syndrome-Related Aqueous Metabolites in Mice

David K Scoville, Cindy Yanfei Li, Dongfang Wang, Joseph L Demspey, Daniel Raftery, Sridhar Mani, Haiwei Gu and Julia Yue Cui
Drug Metabolism and Disposition May 23, 2019, dmd.119.086538; DOI: https://doi.org/10.1124/dmd.119.086538
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