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

Abstract

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

Genetic Variation in AhR Gene Related to Dioxin Sensitivity in the Japanese Field Mouse, Apodemus speciosus

“…In congeneric mouse strains, C57/BL6 and DBA, the difference in sensitivity is due to a difference in ligand-binding affinity from the difference in the primary structures by only one amino acid substitution (Ema et al, 1994). Similar findings have been reported in 2 bird species, chicken and common tern (Karchner et al, 2006). Furthermore, deletion of 38 or 43 amino acids in the transactivation domain due to one base substitution in an intronic region resulted in different susceptibility to TCDD in congeneric rat strains (Pohjanvirta et al, 1998).…”

Molecular determinants of species-specific agonist and antagonist activity of a substituted flavone towards the aryl hydrocarbon receptor

“…Alanine mutants of the neighboring I319 and H320 also lost ligand responsiveness. The residue equivalent to murine I319 in the tern AhR is V325, which along with A381, accounted for the reduced TCDD binding affinity, reduced transactivation, and reduced sensitivity to HAH toxicity in terns compared to chickens, in which these residues are Ile and Ser respectively [24]. The I319 residue of mAhR is also one of four identified by Pandini et al [21] that have smaller side chains than the corresponding residues in the non-ligand-dependent PAS protein HIF-2α and which they conclude provide a larger "empty" space for ligand in the AhR.…”

When evolution is the solution to pollution: Key principles, and lessons from rapid repeated adaptation of killifish (Fundulus heteroclitus) populations

“…Among HAHs, ligand affinity is a good predictor of toxicity; compounds that bind with greatest affinity are the most potent at altering gene expression and causing toxic effects (Safe, 1994). Differences in AHR properties, including affinity for ligand binding, explain differences in sensitivity to DLCs in several vertebrate systems, including strains of rodents (Moffat, Roblin, Harper, Okey, & Pohjanvirta, 2007; Poland, Palen, & Glover, 1994), species of birds (Farmahin et al., 2013; Karchner, Franks, Kennedy, & Hahn, 2006), and populations of some fish (Atlantic tomcod) (Wirgin et al., 2011). (At the extreme end of this spectrum are invertebrates, which have AHR proteins that lack the ability to bind DLCs [Powell‐Coffman, Bradfield, & Wood, 1998; Butler, Kelley, Powell, Hahn, & Van Beneden, 2001] and also are largely insensitive to DLC toxicity [Hahn, 1998a]. )…”