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

Scott E. Heid, Mary K. Walker, Hollie I. Swanson

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

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 EC50 (AHR/ARNT/DNA binding) or ED50 (15% increase in day-10 heart wet weight) by the HAH congeners EC50 or ED50, 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.

Original languageEnglish
Pages (from-to)187-196
Number of pages10
JournalToxicological Sciences
Volume61
Issue number1
DOIs
StatePublished - 2001

Keywords

  • Aryl hydrocarbon receptor
  • Cardiac malformations
  • Chick embryo
  • Halogenated aromatic hydrocarbons
  • TCDD

ASJC Scopus subject areas

  • Toxicology

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