In vitro differential responses of rat and human aryl hydrocarbon receptor to two distinct ligands and to different polyphenols

T Q Doan, L Connolly, A Igout, M Muller, M L Scippo

Research output: Contribution to journalArticle

Abstract

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and several other environment/food-borne toxic compounds induce their toxicity via the aryl hydrocarbon receptor (AhR). AhR is also modulated by various endogenous ligands e.g. highly potent tryptophan (Trp)-derivative FICZ (6-formylindolo[3,2-b]carbazole) and natural ligands abundant in the human diet e.g. polyphenols. Therefore, evaluating AhR species-specific responses is crucial for understanding AhR physiological functions, establishing risk assessments, and exploring the applicability of AhR mediators in drug and food industry towards human-based usages. We studied AhR transactivation of FICZ/TCDD in vitro in a time-dependent and species-specific manner using dioxin responsive luciferase reporter gene assays derived from rat (DR-H4IIE) and human (DR-HepG2) hepatoma cells. We observed for the first time that FICZ potency was similar in both cell lines and was 40 times higher than TCDD in DR-HepG2 cells. Depleting Trp-derivative endogenously produced ligands by using culture medium without Trp, resulted in 3-fold higher AhR activation upon adding FICZ in DR-H4IIE cells, in contrast to DR-HepG2 cells which revealed a fast degradation of FICZ induction from 10 h post-exposure to complete disappearance after 24 h. Seven polyphenols and a mixture thereof, chosen based on commercially recommended doses and adjusted to human realistic exposure, caused rat and human species-specific AhR responses. Two isoflavones (daidzein and genistein) induced rat AhR synergistic effects with FICZ and/or TCDD, while quercetin, chrysin, curcumin, resveratrol, and the mixture exerted a strong inhibitory effect on the human AhR. Strikingly, resveratrol and quercetin at their realistic nanomolar concentrations acted additively in the mixture to abolish human AhR activation induced by various TCDD concentrations. Taken together, these results illustrate the species-specific complexity of AhR transcriptional activities modulated by various ligands and highlight the need for studies of human-based approaches.

Original languageEnglish
Pages (from-to)114966
JournalEnvironmental pollution (Barking, Essex : 1987)
Volume265
Issue numberPt B
Early online date10 Jun 2020
DOIs
Publication statusEarly online date - 10 Jun 2020

Bibliographical note

Copyright © 2020 Elsevier Ltd. All rights reserved.

Fingerprint Dive into the research topics of 'In vitro differential responses of rat and human aryl hydrocarbon receptor to two distinct ligands and to different polyphenols'. Together they form a unique fingerprint.

  • Projects

    Cite this