1. Academic Validation
  2. Crosstalk between AhR and wnt/β-catenin signal pathways in the cardiac developmental toxicity of PM2.5 in zebrafish embryos

Crosstalk between AhR and wnt/β-catenin signal pathways in the cardiac developmental toxicity of PM2.5 in zebrafish embryos

  • Toxicology. 2016 Apr 29;355-356:31-8. doi: 10.1016/j.tox.2016.05.014.
Hang Zhang 1 Yugang Yao 2 Yang Chen 3 Cong Yue 1 Jiahong Chen 1 Jian Tong 1 Yan Jiang 4 Tao Chen 5
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
  • 2 Suzhou Environmental Monitor Center, Key Laboratory of Atmospheric Combined Pollution Monitoring, Environmental Protection Department of Jiangsu Province, Suzhou, China.
  • 3 Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, China.
  • 4 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China; Department of Physiology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, China. Electronic address: yjiang@suda.edu.cn.
  • 5 Department of Toxicology, School of Public Health, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China. Electronic address: tchen@suda.edu.cn.
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.

Keywords

AhR; Cardiac development; PM2.5; Wnt; Zebrafish; β-catenin.

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