Correlation between TCDD acute toxicity and aryl hydrocarbon receptor structure for different mammals

The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity has large species differences, and TCDD exerts its toxicity by binding into aryl hydrocarbon receptor (AHR). In this study, we applied bioinformatics approaches to quantitatively analyze the correlation between TCDD acute toxicity and AHRs. Seven mammalian AHRs were chosen as target receptors. Low conserved functional domains of AHRs were identified and quantitatively characterized. Linear regression was applied to determine the relationships of different mammalian AHRs and TCDD LD50 values. The results indicated that ligand binding domain and glutamine-rich domain of mammalian AHRs showed a low degree of conservation. Based on previous literatures, the number of glutamine residues (NOQ) and binding free energy with TCDD were applied to quantitatively represent the differences of glutamine-rich domain and ligand binding domain, respectively. Then, regression equations between studied mammalian AHR structures and TCDD LD50 were constructed, and high linear correlation was found (R2=0.986). This study indicated that mammalian differences of TCDD acute toxicity might be partly determined by the differences of glutamine-rich domain and ligand binding domain of AHR, which provides a potential insight to analyze the species differences of TCDD toxicity.

► Seven mammal aryl hydrocarbon receptors (AHRs) were compared.
► Glutamine-rich and ligand binding domains show a low degree of conservation.
► Number of glutamine residues was used to represent glutamine-rich domain.
► Binding free energy with TCDD was used to represent ligand binding domain.
► High linear correlation was found between TCDD LD50 and both domains of mammal AHRs.