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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

Authors: Fader, Kelly A; Nault, Rance; Zhang, Chen; Kumagai, Kazuyoshi; Harkema, Jack R; Zacharewski, Timothy R

Published In Sci Rep, (2017 Jul 19)

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.

PubMed ID: 28725001 Exiting the NIEHS site

MeSH Terms: Animals; Bacteria/drug effects; Bacteria/genetics; Bacteria/metabolism*; Bile Acids and Salts/blood; Bile Acids and Salts/metabolism*; Cholesterol/metabolism; Enterohepatic Circulation/drug effects*; Feces/chemistry; Female; Genes, Bacterial; Homeostasis/drug effects*; Hydrophobic and Hydrophilic Interactions; Intestinal Absorption/drug effects; Liver/drug effects; Liver/metabolism; Male; Mice, Inbred C57BL; Polychlorinated Dibenzodioxins/toxicity*

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