ZFIN ID: ZDB-PUB-190326-12
ahr2, but not ahr1a or ahr1b, is required for craniofacial and fin development and TCDD-dependent cardiotoxicity in zebrafish
Souder, J.P., Gorelick, D.A.
Date: 2019
Source: Toxicological sciences : an official journal of the Society of Toxicology   170(1): 25-44 (Journal)
Registered Authors: Gorelick, Daniel, Souder, Jaclyn P.
Keywords: none
MeSH Terms:
  • Animal Fins/drug effects
  • Animal Fins/growth & development*
  • Animals
  • Cardiotoxicity/etiology*
  • Cardiotoxicity/genetics
  • Cardiotoxicity/metabolism
  • Craniofacial Abnormalities/genetics*
  • Craniofacial Abnormalities/metabolism
  • Embryo, Nonmammalian
  • Female
  • Male
  • Polychlorinated Dibenzodioxins/toxicity*
  • Receptors, Aryl Hydrocarbon/metabolism*
  • Receptors, Estrogen/antagonists & inhibitors
  • Receptors, Estrogen/metabolism
  • Skull/drug effects
  • Skull/growth & development*
  • Skull/metabolism
  • Water Pollutants, Chemical/toxicity
  • Zebrafish
  • Zebrafish Proteins/metabolism*
PubMed: 30907958 Full text @ Toxicol. Sci.
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ABSTRACT
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that binds environmental toxicants and regulates gene expression. AHR also regulates developmental processes, like craniofacial development and hematopoiesis, in the absence of environmental exposures. Zebrafish have three paralogues of AHR: ahr1a, ahr1b and ahr2. Adult zebrafish with mutations in ahr2 exhibited craniofacial and fin defects. However, the degree to which ahr1a and ahr1b influence ahr2 signaling and contribute to fin and craniofacial development are not known. We compared morphology of adult ahr2 mutants and ahr1a;ahr1b single and double mutant zebrafish. We found that ahr1a;ahr1b single and double mutants were morphologically normal while ahr2 mutant zebrafish demonstrated fin and craniofacial malformations. At 5 days post fertilization, both ahr1a;ahr1b and ahr2 mutant larvae were normal, suggesting that adult phenotypes are due to defects in maturation or maintenance. Next, we analyzed the function of zebrafish AHRs activated by environmental ligands. The prototypical AHR ligand, TCDD, induces toxicity in humans and rodents via AHR and causes cardiotoxicity in zebrafish embryos. It has been shown that embryos with mutations in ahr2 are resistant to TCDD toxicity, yet it is unclear whether ahr1 receptors are required. Further, though AHR was shown to interact with estrogen receptor alpha following TCDD treatment, it is not known whether this interaction is constitutive or context-dependent. To determine whether estrogen receptors are constitutive cofactors for AHR signaling, we used genetic and pharmacologic techniques to analyze TCDD-dependent toxicity in estrogen receptor and ahr mutant embryos. We found that embryos with mutations in ahr1a;ahr1b or estrogen receptor genes are susceptible to TCDD toxicity while ahr2 mutant embryos are TCDD-resistant. Moreover, pharmacologic blockade of nuclear estrogen receptors failed to prevent TCDD toxicity. These findings suggest that ahr1 genes do not have overlapping functions with ahr2 in fin and craniofacial development or TCDD-dependent toxicity, and that estrogen receptors are not constitutive partners of ahr2.
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