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Title: Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers

Abstract

The gut microbiome is a novel frontier in xenobiotic metabolism. Polybrominated diphenyl ethers (PBDEs), especially BDE-47 and BDE-99, are among the most abundant and persistent environmental contaminants that produce a variety of toxicities. Little is known about how the gut microbiome affects the hepatic metabolism of PBDEs and the PBDE-mediated regulation of drug-processing genes (DPGs) in vivo. The goal of this study was to determine the role of gut microbiome in modulating the hepatic biotransformation of PBDEs. Nine-week-old male C57BL/6J conventional (CV) or germ free (GF) mice were treated with vehicle, BDE-47 or BDE-99 (100 μmol/kg) for four days. Following BDE-47 treatment, GF mice had higher level of 5-OH-BDE-47 but lower levels of 4 other metabolites in liver than CV mice; whereas following BDE-99 treatment, GF mice had lower levels of 4 minor metabolites in liver than CV mice. RNA- Seq demonstrated that the hepatic expression of DPGs was regulated by both PBDEs and enterotypes. Under basal condition, the lack of gut microbiome up-regulated the Cyp2c subfamily but down-regulated the Cyp3a subfamily. Following PBDE exposure, certain DPGs were differentially regulated by PBDEs in a gut microbiome-dependent manner. Interestingly, the lack of gut microbiome augmented PBDE-mediated up- regulation of many DPGs,more » such as Cyp1a2 and Cyp3a11 in mouse liver, which was further confirmed by targeted metabolomics. The lack of gut microbiome also augmented the Cyp3a enzyme activity in liver. In conclusion, our study has unveiled a novel interaction between gut microbiome and the hepatic biotransformation of PBDEs.« less

Authors:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1406719
Report Number(s):
PNNL-SA-129301
Journal ID: ISSN 0090-9556; 400480000
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Drug Metabolism and Disposition; Journal Volume: 45; Journal Issue: 11
Country of Publication:
United States
Language:
English

Citation Formats

Li, Cindy Yanfei, Lee, Soowan, Cade, Sara, Kuo, Li-Jung, Schultz, Irvin R., Bhatt, Deepak K., Prasad, Bhagwat, Bammler, Theo K., and Cui, Julia Yue. Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers. United States: N. p., 2017. Web. doi:10.1124/dmd.117.077024.
Li, Cindy Yanfei, Lee, Soowan, Cade, Sara, Kuo, Li-Jung, Schultz, Irvin R., Bhatt, Deepak K., Prasad, Bhagwat, Bammler, Theo K., & Cui, Julia Yue. Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers. United States. doi:10.1124/dmd.117.077024.
Li, Cindy Yanfei, Lee, Soowan, Cade, Sara, Kuo, Li-Jung, Schultz, Irvin R., Bhatt, Deepak K., Prasad, Bhagwat, Bammler, Theo K., and Cui, Julia Yue. Fri . "Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers". United States. doi:10.1124/dmd.117.077024.
@article{osti_1406719,
title = {Novel Interactions between Gut Microbiome and Host Drug-Processing Genes Modify the Hepatic Metabolism of the Environmental Chemicals Polybrominated Diphenyl Ethers},
author = {Li, Cindy Yanfei and Lee, Soowan and Cade, Sara and Kuo, Li-Jung and Schultz, Irvin R. and Bhatt, Deepak K. and Prasad, Bhagwat and Bammler, Theo K. and Cui, Julia Yue},
abstractNote = {The gut microbiome is a novel frontier in xenobiotic metabolism. Polybrominated diphenyl ethers (PBDEs), especially BDE-47 and BDE-99, are among the most abundant and persistent environmental contaminants that produce a variety of toxicities. Little is known about how the gut microbiome affects the hepatic metabolism of PBDEs and the PBDE-mediated regulation of drug-processing genes (DPGs) in vivo. The goal of this study was to determine the role of gut microbiome in modulating the hepatic biotransformation of PBDEs. Nine-week-old male C57BL/6J conventional (CV) or germ free (GF) mice were treated with vehicle, BDE-47 or BDE-99 (100 μmol/kg) for four days. Following BDE-47 treatment, GF mice had higher level of 5-OH-BDE-47 but lower levels of 4 other metabolites in liver than CV mice; whereas following BDE-99 treatment, GF mice had lower levels of 4 minor metabolites in liver than CV mice. RNA- Seq demonstrated that the hepatic expression of DPGs was regulated by both PBDEs and enterotypes. Under basal condition, the lack of gut microbiome up-regulated the Cyp2c subfamily but down-regulated the Cyp3a subfamily. Following PBDE exposure, certain DPGs were differentially regulated by PBDEs in a gut microbiome-dependent manner. Interestingly, the lack of gut microbiome augmented PBDE-mediated up- regulation of many DPGs, such as Cyp1a2 and Cyp3a11 in mouse liver, which was further confirmed by targeted metabolomics. The lack of gut microbiome also augmented the Cyp3a enzyme activity in liver. In conclusion, our study has unveiled a novel interaction between gut microbiome and the hepatic biotransformation of PBDEs.},
doi = {10.1124/dmd.117.077024},
journal = {Drug Metabolism and Disposition},
number = 11,
volume = 45,
place = {United States},
year = {Fri Sep 01 00:00:00 EDT 2017},
month = {Fri Sep 01 00:00:00 EDT 2017}
}