Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation

In mammals, the toxicity of halogenated aromatic hydrocarbons (HAH) correla tes with their ability to activate the aryl hydrocarbon receptor (AKR). To test this correlation in an avian model, we selected six HAHs based on thei r affinity for the mammalian AHR, including: 2,3,7,8-tetrachlorodibenzo-p-d ioxin (TCDD); 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PCDD); 2,3,7,8-tetrach lorodibenzofuran (TCDF); 2,3,4,7,8 -pentachlorodibenzofuran (PCDF); 3,3',4, 4'-tetrachlorobiphenyl (PCB 77); and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153). We determined the ability of these compounds to induce cardiotoxicit y, as measured by an increase in heart wet weight on incubation day 10 in t he chick embryo (Gallus gallus) and formation of the avian AHR/ARNT/DNA bin ding complex in chicken hepatoma cells. Relative potency values (RBs) were calculated by dividing the TCDD EC50 (AHR/ARNT/DNA binding) or ED50 (15% in crease in day-10 heart wet weight) by the HAH congeners EC50 or ED50, respe ctively. The rank order of potencies for inducing cardiotoxicity were TCDD > PCDD = PCDF = TCDF > PCDF > PCB77, PCB 153, no effect. The RP values for inducing AHR/ARNT DNA binding were then correlated with those for inducing cardiotoxicity (the RP values of PCDD were determined to be statistical out liers). This correlation was found to be highly significant (r = 0.94, p = 0.017). The ability of PCDD to act as an AHR agonist was verified using luc iferase reporter assays and analysis of cytochrome P4501A1 protein levels. These results indicate that the ability of HAHs to activate the avian AHR s ignaling pathway, in general, correlates with their ability to mediate card iotoxicity in the chick embryo.