title: Crosstalk between AhR and wnt/β-catenin signal pathways in the cardiac developmental toxicity of PM2.5 in zebrafish embryos.
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.
authors.affiliation: 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.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Suzhou Environmental Monitor Center, Key Laboratory of Atmospheric Combined Pollution Monitoring, Environmental Protection Department of Jiangsu Province, Suzhou, China.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Cong
authors.initials: C
authors.lastname: Yue
authors.affiliation: 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.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Tong
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000196:embryology; D006330:Heart Defects, Congenital / Q000209:etiology* / Q000235:genetics; D006339:Heart Rate / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D052638:Particulate Matter / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics; D000098907:R-Spondins
chemical_list: D000393:Air Pollutants; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D036341:Intercellular Signaling Peptides and Proteins; D052638:Particulate Matter; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D029961:Zebrafish Proteins; C000595220:Rspo2 protein, zebrafish; D000098907:R-Spondins
keywords: AhR; Cardiac development; PM2.5; Wnt; Zebrafish; β-catenin