Sensitivity of avian species to the aryl hydrocarbon receptor ligand 6-formylindolo [3,2-b] carbazole (FICZ)

Farmahin, Reza; Crump, Doug; Kennedy, Sean W.

doi:10.1016/j.cbi.2014.07.009

Cited by 21 publications

(23 citation statements)

References 43 publications

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“…Although mammalian and axolotl AHRs exhibit dramatic differences in sensitivity to transactivation by TCDD, the EC 50 values for the candidate endogenous ligand FICZ are much more similar. This observation mimics those made previously for frog 26, 57 and bird 65 AHRs. This differential ligand response is consistent with recent mutagenesis and functional activity studies demonstrating that FICZ can bind within the LBD of the mouse AHR in a fashion different than that of TCDD and related HAHs 78 .…”

Section: Discussionsupporting

confidence: 91%

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An Aryl Hydrocarbon Receptor from the Salamander Ambystoma mexicanum Exhibits Low Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Shoots

Fraccalvieri

Franks

et al. 2015

Environ. Sci. Technol.

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Structural features of the aryl hydrocarbon receptor (AHR) can underlie species- and population-specific differences in its affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These differences often explain variations in TCDD toxicity. Frogs are relatively insensitive to dioxin, and Xenopus AHRs bind TCDD with low affinity. Weak TCDD binding results from the combination of three residues in the ligand-binding domain: A354 and A370, and N325. Here we sought to determine whether this mechanism of weak TCDD binding is shared by other amphibian AHRs. We isolated an AHR cDNA from the Mexican axolotl (Ambystoma mexicanum). The encoded polypeptide contains identical residues at positions that confer low TCDD affinity to X. laevis AHRs (A364, A380, and N335), and homology modeling predicts they protrude into the binding cavity. Axolotl AHR bound one-tenth the TCDD of mouse AHR in velocity sedimentation analysis, and in transactivation assays, the EC50 for TCDD was 23 nM, similar to X. laevis AHR1β (27 nM) and greater than AHR containing the mouse ligand-binding domain (0.08 nM). Sequence, modeled structure, and function indicate that axolotl AHR binds TCDD weakly, predicting that A. mexicanum lacks sensitivity to TCDD toxicity. We hypothesize that this characteristic of axolotl and Xenopus AHRs arose in a common ancestor of the Caudata and Anura.

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Section: Discussionsupporting

confidence: 91%

“…The EC 50 for transactivation of axolotl AHR by FICZ, a candidate endogenous agonist 57, 58 , was also greater than that of the chimeric AHR (Figure 5, Table 1), although as observed previously for the X. laevis 26, 57 and bird 65 AHRs, the difference is much less pronounced, about 45-fold following 3 h exposure.…”

Section: Resultssupporting

confidence: 77%

An Aryl Hydrocarbon Receptor from the Salamander Ambystoma mexicanum Exhibits Low Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Shoots

Fraccalvieri

Franks

et al. 2015

Environ. Sci. Technol.

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“…Recent studies have shown that transactivation potencies of FICZ are greater than TCDD regardless of the avian AHR1 genotype2033. 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.…”

Section: Discussionsupporting

confidence: 76%

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

Hwang

Park

Bak

et al. 2016

Sci Rep

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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.

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“…The ability of FICZ to activate AHR signaling appears to be evolutionarily conserved. FICZ has been shown to bind and activate AHRs in different vertebrate species in addition to human, including mouse, African clawed frog ( Xenopus laevis ), zebrafish ( Danio rerio ) and several avian species [16-20]. Furthermore, recent studies suggest that FICZ-AHR and TCDD-AHR interactions are distinct.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, recent studies suggest that FICZ-AHR and TCDD-AHR interactions are distinct. For example, avian species known to differ in response to TCDD show no significant differences in sensitivity to FICZ [20], and FICZ differs from TCDD in its ability to bind AHR variants with certain mutated amino acids in the ligand-binding domain [21]. Such results emphasize the robustness of the FICZ-AHR interaction and further suggest that FICZ could have a role as an important natural signaling molecule.…”

Section: Introductionmentioning

confidence: 99%

Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner

Wincent

Kubota

Timme‐Laragy

et al. 2016

Biochemical Pharmacology

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6-Formylindolo[3,2-b]carbazole (FICZ) is a potent aryl hydrocarbon receptor (AHR) agonist that is efficiently metabolized by AHR-regulated cytochrome P4501 enzymes. FICZ is a proposed physiological AHR ligand that induces its own degradation as part of a regulatory negative feedback loop. In vitro studies in cells show that CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. We used zebrafish (Danio rerio) embryos to investigate the in vivo effects of FICZ when CYP1A is knocked down or inhibited. Embryos were injected with morpholino antisense oligonucleotides targeting CYP1A (CYP1A-MO), Ahr2, or a combination of both. FICZ exposure of non-injected embryos or embryos injected with control morpholino had little effect. In CYP1A-MO-injected embryos, however, FICZ dramatically increased mortality, incidence and severity of pericardial edema and circulation failure, reduced hatching frequency, blocked swim bladder inflation, and strongly potentiated expression of Ahr2-regulated genes. These effects were substantially reduced in embryos with a combined knockdown of Ahr2 and CYP1A, indicating that the toxicity was mediated at least partly by Ahr2. Co-exposure to the CYP1 inhibitor alpha-naphtoflavone and FICZ had similar effects as the combination of CYP1A-MO and FICZ. HPLC analysis of FICZ-exposed embryos showed increased levels of FICZ after concomitant CYP1A-MO injection or αNF co-exposure. Together, these results show that a functioning CYP1/AHR feedback loop is crucial for regulation of AHR signaling by a potential physiological ligand in vivo and further highlights the role of CYP1 enzymes in regulating biological effects of FICZ.

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Sensitivity of avian species to the aryl hydrocarbon receptor ligand 6-formylindolo [3,2-b] carbazole (FICZ)

Cited by 21 publications

References 43 publications

An Aryl Hydrocarbon Receptor from the Salamander Ambystoma mexicanum Exhibits Low Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

An Aryl Hydrocarbon Receptor from the Salamander Ambystoma mexicanum Exhibits Low Sensitivity to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

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

Biological effects of 6-formylindolo[3,2-b]carbazole (FICZ) in vivo are enhanced by loss of CYP1A function in an Ahr2-dependent manner

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