ZFIN ID: ZDB-PUB-160525-10
Crosstalk between AhR and wnt/β-catenin signal pathways in the cardiac developmental toxicity of PM2.5 in zebrafish embryos
Zhang, H., Yao, Y., Chen, Y., Yue, C., Chen, J., Tong, J., Jiang, Y., Chen, T.
Date: 2016
Source: Toxicology   355-356: 31-8 (Journal)
Registered Authors:
Keywords: AhR, PM2.5, Wnt, cardiac development, zebrafish, β-catenin
MeSH Terms:
  • Air Pollutants/toxicity*
  • Animals
  • Cytochrome P-450 CYP1A1/genetics
  • Cytochrome P-450 CYP1B1/genetics
  • Gene Expression Regulation, Developmental/drug effects
  • Heart/drug effects
  • Heart/embryology
  • Heart Defects, Congenital/etiology*
  • Heart Defects, Congenital/genetics
  • Heart Rate/drug effects
  • Intercellular Signaling Peptides and Proteins/genetics
  • Particulate Matter/toxicity*
  • RNA, Messenger/metabolism
  • Receptors, Aryl Hydrocarbon/drug effects*
  • Receptors, Aryl Hydrocarbon/metabolism
  • Signal Transduction/drug effects
  • Wnt Signaling Pathway/drug effects*
  • Zebrafish/embryology
  • Zebrafish Proteins/genetics
PubMed: 27216425 Full text @ Toxicology
Recent studies have shown an association between congenital heart defects and air fine particle matter (PM2.5), but the molecular mechanisms remain elusive. It is well known that a number of organic compounds in PM2.5 can act as AhR agonists, and activation of AhR can antagonize Wnt/β-catenin signaling. Therefore, we hypothesized that PM2.5 could activate AhR and then repress the expression of wnt/β-catenin targeted genes essential for cardiogenesis, resulting in heart defects. To test this hypothesis, we investigated the effects of extractable organic matter (EOM) from PM2.5 on AhR and Wnt/β-catenin signal pathways in zebrafish embryos. We confirmed that EOM could cause malformations in the heart and decreased heart rate in zebrafish embryos at 72hpf, and found that the EOM-induced heart defects were rescued in embryos co-exposed with EOM plus AhR antagonist CH223191 or β-catenin agonist CHIR99021. We further found that EOM had increased the expression levels of AhR targeted genes (Cyp1a1, Cyp1b1 and Ahrra) and reduced the mRNA levels of β-catenin targeted genes (axin2, nkx2.5 and sox9b). The mRNA expression level of Rspo2, a β-catenin upstream gene, was also decreased in embryos exposed to EOM. Supplementation with CH223191 or CHIR99021 attenuated most of the EOM-induced expression changes of genes involved in both AhR and wnt/β-catenin signal pathways. However, the mRNA expression level of AhR inhibitor Ahrrb, which did not change by EOM treatment alone, was increased in embryos co-exposed to EOM plus CH223191 or CHIR99021. We conclude that the activation of AhR by EOM from PM2.5 might repress wnt/β-catenin signaling, leading to heart defects in zebrafish embryos. Furthermore, our results indicate that the cardiac developmental toxicity of PM2.5 might be prevented by targeting AhR or wnt/β-catenin signaling.