PUBLICATION
Crosstalk between AhR and wnt/β-catenin signal pathways in the cardiac developmental toxicity of PM2.5 in zebrafish embryos
- Authors
- Zhang, H., Yao, Y., Chen, Y., Yue, C., Chen, J., Tong, J., Jiang, Y., Chen, T.
- ID
- ZDB-PUB-160525-10
- 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
- CTD
- 27216425
Citation
Zhang, H., Yao, Y., Chen, Y., Yue, C., Chen, J., Tong, J., Jiang, Y., Chen, T. (2016) Crosstalk between AhR and wnt/β-catenin signal pathways in the cardiac developmental toxicity of PM2.5 in zebrafish embryos. Toxicology. 355-356:31-8.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping