Upstream eventAltered regulation, AHR nuclear translocator (ARNT)-dependent pathways
Altered, Cardiovascular development/function
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Evidence Supporting this KER
Include consideration of temporal concordance here
Another proposed mechanism for the observed effects of DLCs on heart development is that sustained AHR/ARNT dimerization induced by DLCs may sequester ARNT from its other dimerization partners at inappropriate times during embryonic cardiomorphogenesis, disrupting ARNT-dependent cellular functions. Co-treatment of a human hepatoma cell line with CoCl2 or desferrioxamine, which are known to induce hypoxia-like responses, and TCDD resulted in inhibited HIF-1 mediated gene expression in a luciferase reporter gene assay system. HIF-1 binding to DNA was increased by desferrioxamine in Hepa 1 cells, however pre-incubation of cells with TCDD prior to desferrioxamine treatment significantly reduced DNA binding activity to HIF-1.
Exposure to TCDD reduces myocardial hypoxia, VEGF expression and endothelial cell responsiveness to angiogenic stimuli in the chicken embryo (Ivnitski-Steele et al., 2004; 2005). A dose-dependent decrease in nuclear-localized HIF-1α and overall levels of HIF-1α signaling was observed in chicken embryos exposed to TCDD. Embryos exposed to TCDD also experienced increased mortality, hemorrhaging and coronary anomalies. These results support the hypothesis that TCDD-induced AHR activation competes with HIF-1α for ARNT, which prevents nuclear translocation of the HIF-1 complex and results in abnormal coronary vasculature development.
These studies indicate that the effects of DLCs can be explained by crosstalk between the AHR and hypoxia pathways involving ARNT. Sequestration of ARNT from HIF-1α may impair hypoxia-stimulated coronary angiogenesis through inhibition of VEGF expression, which would explain some DLC-induced effects on vascular development in chicken embryos.
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Heid, S. E., Walker, M. K., and Swanson, H. I. (2001). Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation. Toxicol.Sci 61, 187-196.
- Walker, M. K., Pollenz, R. S., and Smith, S. M. (1997). Expression of the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator during chick cardiogenesis is consistent with 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced heart defects. Toxicol.Appl.Pharmacol. 143, 407-419.
- Nie, M., Blankenship, A. L., and Giesy, J. P. (2001). Interactions between aryl hydrocarbon receptor (AhR) and hypoxia signaling pathways. Environ.Toxicol.Pharmacol. 10, 17-27.
- Full Reference?
- Wikenheiser, J., Karunamuni, G., Sloter, E., Walker, M. K., Roy, D., Wilson, D. L., and Watanabe, M. (2012). Altering HIF-1alpha Through 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Exposure Affects Coronary Vessel Development. Cardiovasc.Toxicol.
- Walker, M. K., and Catron, T. F. (2000). Characterization of cardiotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chemicals during early chick embryo development. Toxicol.Appl.Pharmacol. 167, 210-221.