API

Relationship: 16

Title

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Altered regulation, AHR nuclear translocator (ARNT)-dependent pathways leads to Altered, Cardiovascular development/function

Upstream event

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Altered regulation, AHR nuclear translocator (ARNT)-dependent pathways

Downstream event

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Altered, Cardiovascular development/function

Key Event Relationship Overview

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AOPs Referencing Relationship

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Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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How Does This Key Event Relationship Work

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Weight of Evidence

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Biological Plausibility

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Empirical Support for Linkage

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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[1][2]. 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[3]. 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[3].

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)[4]. 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[5].

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[3], which would explain some DLC-induced effects on vascular development in chicken embryos[6][2][5].

Uncertainties or Inconsistencies

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Quantitative Understanding of the Linkage

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Evidence Supporting Taxonomic Applicability

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References

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  1. 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.
  2. 2.0 2.1 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.
  3. 3.0 3.1 3.2 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.
  4. Full Reference?
  5. 5.0 5.1 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.
  6. 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.