2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis: Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism

Kelly A. Fader, Rance Nault, Chen Zhang, Kazuyoshi Kumagai, Jack R. Harkema, Timothy R. Zacharewski

Research output: Contribution to journalArticle

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Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which elicits hepatotoxicity through activation of the aryl hydrocarbon receptor (AhR). Male C57BL/6 mice orally gavaged with TCDD (0.01-30 μg/kg) every 4 days for 28 days exhibited bile duct proliferation and pericholangitis. Mass spectrometry analysis detected a 4.6-fold increase in total hepatic bile acid levels, despite the coordinated repression of genes involved in cholesterol and primary bile acid biosynthesis including Cyp7a1. Specifically, TCDD elicited a >200-fold increase in taurolithocholic acid (TLCA), a potent G protein-coupled bile acid receptor 1 (GPBAR1) agonist associated with bile duct proliferation. Increased levels of microbial bile acid metabolism loci (bsh, baiCD) are consistent with accumulation of TLCA and other secondary bile acids. Fecal bile acids decreased 2.8-fold, suggesting enhanced intestinal reabsorption due to induction of ileal transporters (Slc10a2, Slc51a) and increases in whole gut transit time and intestinal permeability. Moreover, serum bile acids were increased 45.4-fold, consistent with blood-to-hepatocyte transporter repression (Slco1a1, Slc10a1, Slco2b1, Slco1b2, Slco1a4) and hepatocyte-to-blood transporter induction (Abcc4, Abcc3). These results suggest that systemic alterations in enterohepatic circulation, as well as host and microbiota bile acid metabolism, favor bile acid accumulation that contributes to AhR-mediated hepatotoxicity.

Original languageEnglish (US)
Article number5927
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

Profile

Enterohepatic Circulation
Tetrachlorodibenzodioxin
Bile Acids and Salts
Homeostasis
Taurolithocholic Acid
Aryl Hydrocarbon Receptors
Bile Ducts
Hepatocytes
Microbiota
Inbred C57BL Mouse
GTP-Binding Proteins
Permeability
Mass Spectrometry
Cholesterol
Liver
Serum
Genes
Intestinal Reabsorption

ASJC Scopus subject areas

  • General

Cite this

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis : Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism. / Fader, Kelly A.; Nault, Rance; Zhang, Chen; Kumagai, Kazuyoshi; Harkema, Jack R.; Zacharewski, Timothy R.

In: Scientific Reports, Vol. 7, No. 1, 5927, 01.12.2017.

Research output: Contribution to journalArticle

Fader, Kelly A.; Nault, Rance; Zhang, Chen; Kumagai, Kazuyoshi; Harkema, Jack R.; Zacharewski, Timothy R. / 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis : Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism.

In: Scientific Reports, Vol. 7, No. 1, 5927, 01.12.2017.

Research output: Contribution to journalArticle

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abstract = "2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which elicits hepatotoxicity through activation of the aryl hydrocarbon receptor (AhR). Male C57BL/6 mice orally gavaged with TCDD (0.01-30 μg/kg) every 4 days for 28 days exhibited bile duct proliferation and pericholangitis. Mass spectrometry analysis detected a 4.6-fold increase in total hepatic bile acid levels, despite the coordinated repression of genes involved in cholesterol and primary bile acid biosynthesis including Cyp7a1. Specifically, TCDD elicited a >200-fold increase in taurolithocholic acid (TLCA), a potent G protein-coupled bile acid receptor 1 (GPBAR1) agonist associated with bile duct proliferation. Increased levels of microbial bile acid metabolism loci (bsh, baiCD) are consistent with accumulation of TLCA and other secondary bile acids. Fecal bile acids decreased 2.8-fold, suggesting enhanced intestinal reabsorption due to induction of ileal transporters (Slc10a2, Slc51a) and increases in whole gut transit time and intestinal permeability. Moreover, serum bile acids were increased 45.4-fold, consistent with blood-to-hepatocyte transporter repression (Slco1a1, Slc10a1, Slco2b1, Slco1b2, Slco1a4) and hepatocyte-to-blood transporter induction (Abcc4, Abcc3). These results suggest that systemic alterations in enterohepatic circulation, as well as host and microbiota bile acid metabolism, favor bile acid accumulation that contributes to AhR-mediated hepatotoxicity.",
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