Hepatic Microsomal Ethoxyresorufin O-Deethylase-Inducing Potency in Ovo and Cytosolic Ah Receptor Binding Affinity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Comparison of 4 Avian Species

Sanderson, J. Thomas; Bellward, Gail D.

doi:10.1006/taap.1995.1094

Cited by 65 publications

(62 citation statements)

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“…In contrast, several other avian species are 10-to 1,000-fold less sensitive than chickens to these effects (20)(21)(22)(23)(24). Although early biochemical studies suggested that differences in AHR properties may contribute to this differential sensitivity (25,26), the exact role of the AHR remains unclear. Understanding the mechanisms by which avian species differ in their sensitivity to dioxin-like compounds is important for risk assessment, particularly for species of fisheating birds that are highly exposed to these compounds in the wild (27).…”

mentioning

confidence: 89%

The molecular basis for differential dioxin sensitivity in birds: Role of the aryl hydrocarbon receptor

Karchner

Franks²,

Kennedy³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

196

223

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons (HAHs) are highly toxic to most vertebrate animals, but there are dramatic differences in sensitivity among species and strains. Aquatic birds including the common tern (Sterna hirundo) are highly exposed to HAHs in the environment, but are up to 250-fold less sensitive to these compounds than the typical avian model, the domestic chicken (Gallus gallus). The mechanism of HAH toxicity involves altered gene expression subsequent to activation of the aryl hydrocarbon receptor (AHR), a basic helix-loop-helix-PAS transcription factor. AHR polymorphisms underlie mouse strain differences in sensitivity to HAHs and polynuclear aromatic hydrocarbons, but the role of the AHR in species differences in HAH sensitivity is not well understood. Here, we show that although chicken and tern AHRs both exhibit specific binding of [ 3 H]TCDD, the tern AHR has a lower binding affinity and exhibits a reduced ability to support TCDD-dependent transactivation as compared to AHRs from chicken or mouse. We further show through use of chimeric AHR proteins and site-directed mutagenesis that the difference between the chicken and tern AHRs resides in the ligand-binding domain and that two amino acids (Val-325 and Ala-381) are responsible for the reduced activity of the tern AHR. Other avian species with reduced sensitivity to HAHs also possess these residues. These studies provide a molecular understanding of species differences in sensitivity to dioxinlike compounds and suggest an approach to using the AHR as a marker of dioxin susceptibility in wildlife.basic helix-loop-helix-PAS ͉ comparative toxicology ͉ mechanisms ͉ risk assessment ͉ susceptibility

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mentioning

confidence: 89%

The molecular basis for differential dioxin sensitivity in birds: Role of the aryl hydrocarbon receptor

Karchner

Franks²,

Kennedy³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

196

223

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“…These species include domestic chicken, duck, domestic goose, turkey, pheasant, gull, common tern, double-crested cormorant, and American kestrel (64)(65)(66)(67)(68). As with fish and mammals, Ah receptor-mediated CYPlA1 induction has been found in a large number of avian species, clearly indicating an Ah receptor responsiveness in this taxa.…”

Section: Tefs For Birdsmentioning

confidence: 99%

Toxic Equivalency Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans and Wildlife

Berg¹,

Birnbaum²,

Bosveld³

et al. 1998

Environmental Health Perspectives

567

852

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“…Nevertheless, significant species-, strain-, tissue-, and developmental stage-specific differences are common features in TCDD responsiveness (Ema et al, 1994;Dohr et al, 1995;Sanderson and Bellward, 1995;Garrison et al, 1996;Kikuchi et al, 1996). For example, in response to acute TCDD toxicity, the difference in LD 50 between guinea pig, the most sensitive species, and mouse is 100-fold; for hamster, the most resistant species, it is as high as 1000-fold (Birnbaum, 1994).…”

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confidence: 99%

Species-Specific Transcriptional Activity of Synthetic Flavonoids in Guinea Pig and Mouse Cells as a Result of Differential Activation of the Aryl Hydrocarbon Receptor to Interact with Dioxin-Responsive Elements

Zhou

Henry²,

Palermo³

et al. 2003

Mol Pharmacol

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To investigate possible species-specificity of aryl hydrocarbon receptor (AhR)-mediated signal transduction pathways, activities of 2,3,7,8-tetrochlorodibenzo-p-dioxin (TCDD) and six synthetic flavonoids were evaluated in mouse hepatoma and guinea pig adenocarcinoma cells transfected with an AhR-responsive luciferase reporter. Rank order potency in these two cell lines was similar for the ability of these flavonoids to antagonize TCDDinduced reporter gene expression. However, in the presence of flavone alone, a species-specific difference in agonist activity was observed. In guinea pig cells, several flavonoids demonstrated agonist activity up to 50% of the maximum TCDD response. In mouse cells, however, no significant agonist activity was observed at the same concentrations based on luciferase enzyme activity, protein expression, and mRNA analysis. Moreover, competitive ligand-binding assays, using [ 3 H]TCDD in cytosolic fractions, demonstrated that 3Ј-methoxy-4Ј-nitroflavone had a similar IC 50 in both recombinant cell lines, suggesting that the flavone has similar binding affinity to receptors from both species. However, electrophoretic mobility shift assay using the cytosolic fractions demonstrated that this flavone elicited binding to the DRE by guinea pig but not mouse AhR complex. The dependence of the AhR in this differential interaction was further demonstrated using in vitro synthesized guinea pig and mouse Ah receptors and mouse Arnt. Together, these data suggest that the differential agonist/antagonist activity of these flavone derivatives is caused by the efficacy of these flavonoids in eliciting an AhR conformation that recognizes regulatory response elements in a species-specific manner.The aryl hydrocarbon receptor (AhR), a member of the basic helix-loop-helix protein superfamily, is a ligand-activated transcription factor (Swanson and Bradfield, 1993;Schmidt and Bradfield, 1996). Ligand-free AhR resides in the cytosol as a complex associated with the 90-kDa heat shock protein and several other proteins (Kazlauskas et al., 1999;Whitlock, 1999). Ligand-elicited activation [e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)] promotes the receptor to undergo a series of processes involving dissociation from cytosolic chaperones, translocation to the nucleus, association with the AhR nuclear translocation partner (Arnt), recognition of the dioxin responsive element (DRE), and modification of gene transcription (Denison et al., 1989;Dong et al., 1996).Among a variety of species, the AhR possesses similar physiochemical properties, and the interaction between TCDD-bound AhR and DRE has been demonstrated to be highly conserved for AhR-mediated signal transduction (Bank et al., 1992). Nevertheless, significant species-, strain-, tissue-, and developmental stage-specific differences are common features in TCDD responsiveness (Ema et al., 1994;Dohr et al

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Hepatic Microsomal Ethoxyresorufin O-Deethylase-Inducing Potency in Ovo and Cytosolic Ah Receptor Binding Affinity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Comparison of 4 Avian Species

Cited by 65 publications

References 0 publications

The molecular basis for differential dioxin sensitivity in birds: Role of the aryl hydrocarbon receptor

The molecular basis for differential dioxin sensitivity in birds: Role of the aryl hydrocarbon receptor

Toxic Equivalency Factors (TEFs) for PCBs, PCDDs, PCDFs for Humans and Wildlife

Species-Specific Transcriptional Activity of Synthetic Flavonoids in Guinea Pig and Mouse Cells as a Result of Differential Activation of the Aryl Hydrocarbon Receptor to Interact with Dioxin-Responsive Elements

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