Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation.
In mammals, the toxicity of halogenated aromatic hydrocarbons (HAH) correlates with their ability to activate the aryl hydrocarbon receptor (AHR). To test this correlation in an avian model, we selected six HAHs based on their affinity for the mammalian AHR, including: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PCDD); 2,3,7,8-tetrachlorodibenzofuran (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 cardiotoxicity, as measured by an increase in heart wet weight on incubation day 10 in the chick embryo (Gallus gallus) and formation of the avian AHR/ARNT/DNA binding complex in chicken hepatoma cells. Relative potency values (RPs) were calculated by dividing the TCDD EC(50) (AHR/ARNT/DNA binding) or ED(50) (15% increase in day-10 heart wet weight) by the HAH congeners EC(50) or ED(50), respectively. 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 outliers). 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 luciferase reporter assays and analysis of cytochrome P4501A1 protein levels. These results indicate that the ability of HAHs to activate the avian AHR signaling pathway, in general, correlates with their ability to mediate cardiotoxicity in the chick embryo.
Heid
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Department of Pharmacology, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
Walker
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MK
Swanson
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D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D001665:Binding Sites; D015153:Blotting, Western; D002460:Cell Line; D002642:Chick Embryo / Q000187:drug effects*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects* / Q000196:embryology; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008156:Luciferases / Q000032:analysis; D009024:Morphogenesis; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives* / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics; D013223:Statistics as Topic; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured
D001572:Benzofurans; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D008156:Luciferases; D019363:Cytochrome P-450 CYP1A1