Journal article
Gut Microbiome Critically Impacts PCB-induced Changes in Metabolic Fingerprints and the Hepatic Transcriptome in Mice
Toxicological sciences, Vol.177(1), pp.168-187
09/01/2020
DOI: 10.1093/toxsci/kfaa090
PMID: 32544245
Abstract
Abstract
Polychlorinated biphenyls (PCBs) are ubiquitously detected and have been linked to metabolic diseases. Gut microbiome is recognized as a critical regulator of disease susceptibility; however, little is known how PCBs and gut microbiome interact to modulate hepatic xenobiotic and intermediary metabolism. We hypothesized the gut microbiome regulates PCB-mediated changes in the metabolic fingerprints and hepatic transcriptome. Ninety-day-old female conventional and germ-free mice were orally exposed to the Fox River Mixture (synthetic PCB mixture, 6 or 30 mg/kg) or corn oil (vehicle control, 10 ml/kg), once daily for 3 consecutive days. RNA-seq was conducted in liver, and endogenous metabolites were measured in liver and serum by LC-MS. Prototypical target genes of aryl hydrocarbon receptor, pregnane X receptor, and constitutive androstane receptor were more readily upregulated by PCBs in conventional conditions, indicating PCBs, to the hepatic transcriptome, act partly through the gut microbiome. In a gut microbiome-dependent manner, xenobiotic, and steroid metabolism pathways were upregulated, whereas response to misfolded proteins-related pathways was downregulated by PCBs. At the high PCB dose, NADP, and arginine appear to interact with drug-metabolizing enzymes (ie, Cyp1–3 family), which are highly correlated with Ruminiclostridium and Roseburia, providing a novel explanation of gut-liver interaction from PCB-exposure. Utilizing the Library of Integrated Network-based Cellular Signatures L1000 database, therapeutics targeting anti-inflammatory and endoplasmic reticulum stress pathways are predicted to be remedies that can mitigate PCB toxicity. Our findings demonstrate that habitation of the gut microbiota drives PCB-mediated hepatic responses. Our study adds knowledge of physiological response differences from PCB exposure and considerations for further investigations for gut microbiome-dependent therapeutics.
Details
- Title: Subtitle
- Gut Microbiome Critically Impacts PCB-induced Changes in Metabolic Fingerprints and the Hepatic Transcriptome in Mice
- Creators
- Joe Jongpyo Lim - Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195Xueshu Li - Department of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa 52242; andHans-Joachim Lehmler - Department of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa 52242; andDongfang Wang - Arizona Metabolomics Laboratory, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Scottsdale, Arizona 85259Haiwei Gu - Arizona Metabolomics Laboratory, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Scottsdale, Arizona 85259Julia Yue Cui - Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195
- Resource Type
- Journal article
- Publication Details
- Toxicological sciences, Vol.177(1), pp.168-187
- DOI
- 10.1093/toxsci/kfaa090
- PMID
- 32544245
- NLM abbreviation
- Toxicol Sci
- ISSN
- 1096-6080
- eISSN
- 1096-0929
- Publisher
- Oxford University Press
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 ES025708, R01 ES030197, R01 GM111381, R01 ES031098, T32 ES007032, ES013661, ES005605; name: University of Washington Center for Exposures, Diseases, Genomics, and Environment, award: NIH P30 ES0007033
- Language
- English
- Date published
- 09/01/2020
- Academic Unit
- Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
- Record Identifier
- 9984066102602771
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