In vitro and in silico evaluation of transactivation potencies of avian AHR1 and AHR2 by endogenous ligands: Implications for the physiological role of avian AHR2

Kim, In-Sung; Hwang, Ji-Hee; Hirano, Masashi; Iwata, Hisato; Kim, Eun Young

doi:10.1016/j.cbpc.2016.03.011

Cited by 12 publications

(7 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, there are fewer inter-species differences in AHR1 sensitivity to this endogenous ligand33, whereas there are large differences in responses to TCDD of the AHR1 among species2024. Our previous study also supported that there was no linkage between avian AHR1 genotypes and AHR1-mediated responses to FICZ34. This implies that the exposure to naturally occurring dioxins under various ecological conditions has exerted selection pressure on the AHR1 genotype with different dioxin sensitivity in the evolutionary process of avian species.…”

Section: Discussionsupporting

confidence: 57%

Ecological factors drive natural selection pressure of avian aryl hydrocarbon receptor 1 genotypes

Hwang

Park

Bak

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

The aryl hydrocarbon receptor (AHR) mediates dioxin toxicities. Several studies have suggested that two amino acid residues corresponding to the 324th and 380th positions in the ligand binding domain (LBD) of the chicken AHR1 (Ile_Ser as high sensitivity, Ile_Ala as moderate sensitivity, and Val_Ala as low sensitivity), could be an important factor determining dioxin sensitivity in avian species. Here, we analyzed the association between ecological factors and AHR1 LBD genotypes of 113 avian species. Cluster analyses showed that 2 major clusters and sub-clusters of the cluster 3 were associated with specific AHR1 genotypes depending on the food, habitat, and migration of the animal. The majority of the species with Ile_Ala type were the Passeriformes, which are omnivorous or herbivorous feeders in the terrestrial environment. The species with Val_Ala type was primarily composed of raptors and waterbirds, which have been exposed to naturally occurring dioxins. An in vitro reporter gene assay revealed that the sensitivity to a natural dioxin, 1,3,7-tribromodibenzo-p-dioxin was in the order of Ile_Ser > Ile_Ala > Val_Ala. These results suggest that ecological factors related to the exposure of natural dioxins contribute to natural selection of the avian AHR1 genotype, which consequently leads to different sensitivity to man-made dioxins.

show abstract

Section: Discussionsupporting

confidence: 57%

Ecological factors drive natural selection pressure of avian aryl hydrocarbon receptor 1 genotypes

Hwang

Park

Bak

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…KYNA is a direct agonist for GPR35 and reduces the intracellular Ca + , cAMP, AKT/ERK/p38 phosphorylation and elevated beta-catenin levels [57][58][59][60]. KYNA activates the dimerization of pro-transcription factor Ahr and its nuclear translocator (ARNT) to generate an active transcriptional complex, which regulates NFkB signaling pathways [61,62], and is an antagonist for neurotransmitter signaling as it can inhibit NMDA and AMPA receptors [63][64][65]. Therefore, the effect of KYNA on respective tissues is highly versatile depending on the receptor type expressed in the target tissue.…”

Section: Supplementary Materialsmentioning

confidence: 99%

KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease

Siddiqui

Bhattarai

Popova

et al. 2021

Cells

View full text Add to dashboard Cite

Neurogenesis decreases in Alzheimer’s disease (AD) patients, suggesting that restoring the normal neurogenic response could be a disease modifying intervention. To study the mechanisms of pathology-induced neuro-regeneration in vertebrate brains, zebrafish is an excellent model due to its extensive neural regeneration capacity. Here, we report that Kynurenic acid (KYNA), a metabolite of the amino acid tryptophan, negatively regulates neural stem cell (NSC) plasticity in adult zebrafish brain through its receptor, aryl hydrocarbon receptor 2 (Ahr2). The production of KYNA is suppressed after amyloid-toxicity through reduction of the levels of Kynurenine amino transferase 2 (KAT2), the key enzyme producing KYNA. NSC proliferation is enhanced by an antagonist for Ahr2 and is reduced with Ahr2 agonists or KYNA. A subset of Ahr2-expressing zebrafish NSCs do not express other regulatory receptors such as il4r or ngfra, indicating that ahr2-positive NSCs constitute a new subset of neural progenitors that are responsive to amyloid-toxicity. By performing transcriptome-wide association studies (TWAS) in three late onset Alzheimer disease (LOAD) brain autopsy cohorts, we also found that several genes that are components of KYNA metabolism or AHR signaling are differentially expressed in LOAD, suggesting a strong link between KYNA/Ahr2 signaling axis to neurogenesis in LOAD.

show abstract

“…FICZ is produced by photochemical reactions under ultraviolet and visible light (Fritsche et al, 2007;Wincent et al, 2009) or by enzymatic and oxidative pathways (Smirnova et al, 2016;Wincent et al, 2009), likely resulting in a systemic distribution of FICZ (Smirnova et al, 2016) to perform several essential functions especially in immunity (Rannug and Rannug, 2018). FICZ is able to activate AhR in various species such as fish (Jönsson et al, 2009), frog (Laub et al, 2010), and birds (Farmahin et al, 2014;Kim et al, 2016). However, little is known about its potency and mode of action compared to the widely studied AhR ligand TCDD.…”

Section: Cyp1a1)mentioning

confidence: 99%

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

Doan

Connolly

Igout

et al. 2020

Environmental Pollution

View full text Add to dashboard Cite

TCDD (2,3,7, 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 2Trp-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 10h post-exposure to complete disappearance after 24h. 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.

show abstract

In vitro and in silico evaluation of transactivation potencies of avian AHR1 and AHR2 by endogenous ligands: Implications for the physiological role of avian AHR2

Cited by 12 publications

References 47 publications

Ecological factors drive natural selection pressure of avian aryl hydrocarbon receptor 1 genotypes

Ecological factors drive natural selection pressure of avian aryl hydrocarbon receptor 1 genotypes

KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease

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

Contact Info

Product

Resources

About