Interactions between TCDD and hypoxia signalling pathways in zebrafish: hypoxia decreases responses to TCDD in zebrafish embryos

Prasch, A.L., Andreasen, E.A., Peterson, R.E., and Heideman, W.
Toxicological sciences : an official journal of the Society of Toxicology   78(1): 68-77 (Journal)
Registered Authors
Andreasen, Eric A., Heideman, Warren, Peterson, Richard E., Prasch, Amy
AHR2, ARNT2, CYP1A, TCDD, hypoxia, zebrafish, embryo, development, toxicity, edema, cardiovascular
MeSH Terms
  • Animals
  • Blotting, Northern
  • Cytochrome P-450 Enzyme System/biosynthesis
  • Cytochrome P-450 Enzyme System/genetics
  • Dose-Response Relationship, Drug
  • Embryo, Nonmammalian/physiology*
  • Environmental Pollutants/pharmacology*
  • Fertilization
  • Hypoxia/physiopathology*
  • Kinetics
  • Larva
  • Receptor Cross-Talk/physiology
  • Receptors, Aryl Hydrocarbon/physiology
  • Signal Transduction/drug effects*
  • Teratogens/toxicity
  • Water
  • Zebrafish/physiology*
14691204 Full text @ Toxicol. Sci.
The aryl hydrocarbon receptor (AHR) interacts with the aryl hydrocarbon receptor nuclear translocator (ARNT) to form a heterodimer which binds to promoters in target genes to alter transcription in response to xenobiotics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The ARNT protein also forms heterodimers with other proteins such as HIF-1alpha and HIF-2alpha to alter gene expression in response to low oxygen conditions. Because ARNT is shared between multiple signalling pathways it is possible that activation of one ARNT-requiring pathway could inhibit the activation of other pathways that depend on ARNT. One hypothesis to explain TCDD toxicity in early life stage fish is that TCDD activation of zfAHR2 sequesters zfARNT2 away from the hypoxia signaling pathway. To test this hypothesis we measured the ability of TCDD to prevent induction of heme oxygenase by hypoxia (40% saturation), as well as the ability of hypoxia to increase the sensitivity of zebrafish to the effects of TCDD during the first week of life. As a further test of the model we examined mutant zebrafish which lack zfARNT2 for phenotypes that resemble the effects of TCDD exposure. Our results demonstrate that sequestration of zfARNT2 is not causing TCDD toxicity. TCDD did not inhibit hypoxia induction of heme oxygenase, hypoxia and TCDD exposures were not additive in causing developmental toxicity, and mutant embryos that lack zfARNT2 do not develop defects mimicking TCDD toxicity. However, our results demonstrate some level of cross-talk between the two pathways in the zebrafish embryo. Hypoxia decreased TCDD induction of zfCYP1A mRNA, and decreased the potency of TCDD in causing edema. It is not clear whether this is mediated through competition for ARNT, or through other mechanisms.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes