Aryl hydrocarbon receptor (AhR) mediated short-term effects of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) on bile acid homeostasis in mice

Abstract

The effects of the most potent aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on bile acid (BA) homeostasis was examined in male and female wild-type and AhR-null mice shortly after 4-day exposure, rather than at a later time when secondary non-AhR dependent effects are more likely to occur. TCDD had similar effects on BA homeostasis in male and female mice. TCDD decreased the concentration of total-(Σ) BAs in liver by approximately 50% (all major BA categories except for the non-6,12-OH BAs), without decreasing the expression of the rate limiting BA synthetic enzyme (Cyp7a1) or altering the major BA regulatory pathways (FXR) in liver and intestine. Even though the Σ-BAs in liver were markedly decreased, the Σ-BAs excreted into bile were not altered. TCDD decreased the relative amount of 12-OH BAs (TCA, TDCA, CA, DCA) in bile and increased the biliary excretion of TCDCA and its metabolites (TαMCA, TUDCA); this was likely due to the decreased Cyp8b1 (12α-hydroxylase) in liver. The concentration of Σ-BAs in serum was not altered by TCDD, indicating that serum BAs do not reflect BA status in liver. However, proportions of individual BAs in serum reflected the decreased expression of Cyp8b1. All these TCDD-induced changes in BA homeostasis were absent in AhR-null mice. In summary, through the AhR, TCDD markedly decreases BA concentrations in liver and reduces the 12α-hydroxylation of BAs without altering Cyp7a1 and FXR signaling. The TCDD-induced decrease in Σ-BAs in liver did not result in a decrease in biliary excretion or serum concentrations of Σ-BAs.

Environmental Chemical Contribution to the Modulation of Bile Acid Homeostasis and Farnesoid X Receptor Signaling

“…Furthermore, TCDD increased fecal levels of bsh and the bile acid-inducible (Bai) operon, suggesting there was increased gut microbiota deconjugation and dehydroxylation activity, which is consistent with the accumulation of TLCA and other secondary BAs (Fader et al, 2017). A similar disruption on BA homeostasis in male and female mice by TCDD was observed when it was administered to wild-type (WT) and AHR-null mice at 37 mg/kg for 5 days (Csanaky et al, 2018). In WT mice, TCDD decreased the concentration of total hepatic BAs without decreasing Cyp7a1 expression and altering the FXR-gut-liver axis (Csanaky et al, 2018).…”

“…A similar disruption on BA homeostasis in male and female mice by TCDD was observed when it was administered to wild-type (WT) and AHR-null mice at 37 mg/kg for 5 days (Csanaky et al, 2018). In WT mice, TCDD decreased the concentration of total hepatic BAs without decreasing Cyp7a1 expression and altering the FXR-gut-liver axis (Csanaky et al, 2018). The amount of 12-OH BAs, including TCA, TDCA, CA and DCA in bile and its metabolites in the liver, T-αMCA, TUDCA, were decreased upon exposure to TCDD (Csanaky et al, 2018).…”

“…In WT mice, TCDD decreased the concentration of total hepatic BAs without decreasing Cyp7a1 expression and altering the FXR-gut-liver axis (Csanaky et al, 2018). The amount of 12-OH BAs, including TCA, TDCA, CA and DCA in bile and its metabolites in the liver, T-αMCA, TUDCA, were decreased upon exposure to TCDD (Csanaky et al, 2018). The observed decreases in 12-OH BAs are possibly due to the decrease in Cyp8b1 mRNA expression in the liver.…”

Pharmacological Activation of PXR and CAR Downregulates Distinct Bile Acid-Metabolizing Intestinal Bacteria and Alters Bile Acid Homeostasis

“…This study provides evidence of the effect of pharmacological activation of the host xenobiotic sensing nuclear receptors PXR and CAR on the gut microbiome composition and functions with a primary focus on bile acid homeostasis. Prior to our work, Dr Curtis Klaassen's laboratory has systematically characterized the effect of pharmacological activation of PXR, aryl hydrocarbon receptor (AhR), and peroxisome proliferatoractivated receptor a (PPARa) on bile acid homeostasis and the regulation of host bile acid processing genes in CV mice (Csanaky et al, 2018;Lickteig et al, 2016;Zhang et al, 2017Zhang et al, , 2018. As a follow-up, this study adds the knowledge to this field by (1) examining the effect of pharmacological activation of PXR and CAR in both CV and GF mice; and (2) unveiling the regulation of gut microbiota by these receptors.…”

In Vitro Human Cell–Based Experimental Models for the Evaluation of Enteric Metabolism and Drug Interaction Potential of Drugs and Natural Products

“…6. Aryl hydrocarbon receptor (AhR): AhR, originally discovered in the liver, is also found in extrahepatic tissues, including the intestine, with ligands including the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (Csanaky et al, 2018) as well as dietary components such as tryptophan metabolites (Manzella et al, 2018). Besides the regulation of CYP1A expression (Do et al, 2012), AhR is now known to play an important role in immune modulation (Li et al, 2016;Ehrlich et al, 2017;Metidji et al, 2018) and the maintenance of barrier functions (Liu et al, 2018) in the intestine.…”