Estrogen receptor “hijacking” by dioxin-like AhR-agonists in fish – “A rule or an exception”

Friday seminar by Augustine Arukwe

Abstract

The estrogenic and xenobiotic biotransformation gene expressions are receptor-mediated processes that are ligand structure-dependent interactions with estrogen-receptor (ER) and aryl hydrocarbon receptor (AhR), probably involving all subtypes and other co-factors. AhR agonists are known to have anti-estrogenic properties. It was previously proposed that the anti-estrogenicity of AhR agonists is mediated through crosstalk between the ER and AhR (probably involving several subtypes). In salmonid, this crosstalk is bidirectional and can be observed as alterations in gene and protein expression patterns. We reported previously that PCB congener 77, an AhR agonist with known anti-estrogenic activities, produced increases and decreases of in vivo ER-mediated nonylphenol (NP: an estrogen mimic) induced gene and protein expression patterns in Atlantic salmon and that these responses were dependent on PCB congener 77 and NP dose ratios and sequential order of exposure and interestingly influenced by seasonal changes. As a consequence, we suggested that these crosstalks represent exceptions rather than the rule for molecular and/or physiological mechanisms of action. In recent studies, we showed that the strong AhR and dioxin-like PCB congeners 126 and 77 produced estrogenic responses (ER-hijacking) in salmon hepatocytes. ER-hijacking is a phenomenon that was recently described in mammalian system occurring when the AhR-Arnt (AhR nuclear translocator) complex binds directly to the ER and induces transcription of ER controlled genes. Our mechanistic studies using inhibitors for the ER (ICI), AhR (3',4'-dimethoxyflavone: 3',4'-DMF) and protein (cyclohexamide) showed that ER-hijacking phenomenon in salmon in vitro system involve both receptor activation and receptor protein stability. These recent findings strongly indicate that ER-hijacking is part of our newly postulated complex interactions between the ER and AhR in fish. We believe that these results, especially the estrogenic actions of PCB126 and 77, despite being novel, is assisting to further unravelling of the mechanisms involved in ER-AhR crosstalks that is being pursued in our laboratory.

Augustine Arukwe
Section for Biotechnology, Molecular and Environmental Biology, Department of Biology, NTNU,
Høgskoleringen 5, 7491 Trondheim, NORWAY

Published Feb. 3, 2012 1:40 PM - Last modified Mar. 8, 2021 10:15 AM