Dioxin and AHR impairs mesoderm gene expression and cardiac differentiation in human embryonic stem cells

Fu, Hualing; Wang, Li; Wang, Jiajia; Bennett, Brian D.; Li, Jianliang; Zhao, Bin; Hu, Guang

doi:10.1016/j.scitotenv.2018.09.247

Cited by 36 publications

(13 citation statements)

References 61 publications

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“…Furthermore, the prototypical environmental AhR ligand, 3,4,7,8-tetrachlorodibenzo- p -dioxin (TCDD) has been reported to induce cardiomyopathies, cardiac lesions, arteritis, and atherosclerosis in rodents, and increase the risk of CVD in humans [83]. Recently it was also shown that TCDD inhibits cardiomyocyte differentiation from human embryonic stem cells via AhR-regulated mechanisms [90].…”

Section: Introductionmentioning

confidence: 99%

Potential role of polycyclic aromatic hydrocarbons as mediators of cardiovascular effects from combustion particles

et al. 2019

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Air pollution is the most important environmental risk factor for disease and premature death, and exposure to combustion particles from vehicles is a major contributor. Human epidemiological studies combined with experimental studies strongly suggest that exposure to combustion particles may enhance the risk of cardiovascular disease (CVD), including atherosclerosis, hypertension, thrombosis and myocardial infarction. In this review we hypothesize that adhered organic chemicals like polycyclic aromatic hydrocarbons (PAHs), contribute to development or exacerbation of CVD from combustion particles exposure. We summarize present knowledge from existing human epidemiological and clinical studies as well as experimental studies in animals and relevant in vitro studies. The available evidence suggests that organic compounds attached to these particles are significant triggers of CVD. Furthermore, their effects seem to be mediated at least in part by the aryl hydrocarbon receptor (AhR). The mechanisms include AhR-induced changes in gene expression as well as formation of reactive oxygen species (ROS) and/or reactive electrophilic metabolites. This is in accordance with a role of PAHs, as they seem to be the major chemical group on combustion particles, which bind AhR and/or is metabolically activated by CYP-enzymes. In some experimental models however, it seems as PAHs may induce an inflammatory atherosclerotic plaque phenotype irrespective of DNA- and/or AhR-ligand binding properties. Thus, various components and several signalling mechanisms/pathways are likely involved in CVD induced by combustion particles. We still need to expand our knowledge about the role of PAHs in CVD and in particular the relative importance of the different PAH species. This warrants further studies as enhanced knowledge on this issue may amend risk assessment of CVD caused by combustion particles and selection of efficient measures to reduce the health effects of particular matters (PM).

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Section: Introductionmentioning

confidence: 99%

Potential role of polycyclic aromatic hydrocarbons as mediators of cardiovascular effects from combustion particles

et al. 2019

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“…Accumulating evidence shows that AHR plays a central role in the development and function of the cardiovascular system in fish, mice, and humans. − Many studies have demonstrated that the activation of AHR could lead to the generation of reactive oxygen species (ROS) through the upregulation of cytochrome P450 enzymes (CYPs). , In the current study, an induced oxidative stress response, combined with an up-regulation of cyp1a1 mRNA expression specifically, suggests there is an AHR-mediated induction of ROS following PFOSA exposure. During early life stages of development, the heart is particularly sensitive to ROS-induced oxidative stress, with an excessive amount of ROS production capable of causing heart failure .…”

Section: Discussionmentioning

confidence: 59%

Perfluorooctane Sulfonamide (PFOSA) Induces Cardiotoxicity via Aryl Hydrocarbon Receptor Activation in Zebrafish

Chen

Zheng

Yang

et al. 2022

Environ. Sci. Technol.

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Perfluorooctane sulfonamide (PFOSA), a precursor of perfluorooctanesulfonate (PFOS), is widely used during industrial processes, though little is known about its toxicity, particularly to early life stage organisms that are generally sensitive to xenobiotic exposure. Here, following exposure to concentrations of 0.01, 0.1, 1, 10, and 100 μg/L PFOSA, transcriptional, morphological, physiological, and biochemical assays were used to evaluate the potential effects on aquatic organisms. The top Tox functions in exposed zebrafish were related to cardiac diseases predicted by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Ingenuity Pathway Analysis (IPA) analysis. Consistent with impacts predicted by transcriptional changes, abnormal cardiac morphology, disordered heartbeat signals, as well as reduced heart rate and cardiac output were observed following the exposure of 0.1, 1, 10, or 100 μg/L PFOSA. Furthermore, these PFOSA-induced cardiac effects were either prevented or alleviated by supplementation with an aryl hydrocarbon receptor (AHR) antagonist or ahr2-morpholino knock-down, uncovering a seminal role of AHR in PFOSA-induced cardiotoxicity. Our results provide the first evidence in fish that PFOSA can impair proper heart development and function and raises concern for PFOSA analogues in the natural environment.

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“…The AhR plays a critical role in cardiac development and function (Chen et al, 2022; Fu et al, 2019). Flumioxazin exposure induced significant up‐regulation of AhR pathway‐related genes ( ahr2, cyp1a1 , and cyp1b1 ).…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress contributes to flumioxazin-induced cardiotoxicity in zebrafish embryos

Ma,

Jiang,

Huang

et al. 2023

Environmental Toxicology and Chemistry

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Flumioxazin is a widely applicated herbicide in the control of aquatic plants. Current evidence suggested that flumioxazin could induce cardiac defects (ventricular septal defects) in vertebrates, but the underlining mechanisms remain unclear. Because of the inhibitory effect of flumioxazin on polyphenol oxidase (PPO), the assumption is made that flumioxazin‐induced cardiotoxicity is caused by oxidative stress. The results show that flumioxazin induced cardiac malformations and abnormal gene expression associated with cardiac development. Cardiac malformations include pericardium edema, cardiac linearization, elongated heart, cardiomegaly, cardiac wall hypocellularity, myocardial cell atrophy into granular, and a significant gap between the myocardial intima and the adventitia. An increase in oxidative stress and apoptosis was observed in the cardiac region of zebrafish after exposure to flumioxazin. Antioxidant astaxanthin reversed the cardiac malformations, excessive ROS production and expression of genes for cardiac developmental and apoptosis regulation induced by flumioxazin. In addition, flumioxazin also activated AHR signaling pathway genes (ahr2, cyp1a1, and cyp1b1) and increased porphyrins concentration. In conclusion, the results suggest that excessive ROS production, which could be mediated through AHR, led to apoptosis, contributing to the cardiotoxicity of flumioxazin in zebrafish embryos.

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Dioxin and AHR impairs mesoderm gene expression and cardiac differentiation in human embryonic stem cells

Cited by 36 publications

References 61 publications

Potential role of polycyclic aromatic hydrocarbons as mediators of cardiovascular effects from combustion particles

Potential role of polycyclic aromatic hydrocarbons as mediators of cardiovascular effects from combustion particles

Perfluorooctane Sulfonamide (PFOSA) Induces Cardiotoxicity via Aryl Hydrocarbon Receptor Activation in Zebrafish

Oxidative stress contributes to flumioxazin-induced cardiotoxicity in zebrafish embryos

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