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Gremlin1 repression-mediated mitochondrial hyperfunction contributes to TCE-induced zebrafish cardiac defects

ABSTRACT: Gremlin1 repression-mediated mitochondrial hyperfunction contributes to TCE-induced zebrafish cardiac defects

PROVIDER: PRJNA1068954 | ENA |

REPOSITORIES: ENA

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Gremlin1 repression-mediated mitochondrial hyperfunction contributes to TCE-induced zebrafish cardiac defects

Project description:Trichloroethylene (TCE) is a ubiquitous pollutant with potential capacity to induce congenital heart disease (CHD). However, the mechanisms underlying TCE-induced CHD is largely unraveled. Herein, we found that early-stage exposure to TCE induced significant cardiac defects characterized by elongated SV-BV distance, thinned myocardium and attenuated contractility. Gremlin1 encoding gene, grem1a, was screened out as a putative target of TCE and was expressed in heart since its appearance. Further, grem1a knockdown in zebrafish induced phenotypes generally similar to that of TCE-treated group, accompanying with the disarrangement of myofibril structure. Single-cell RNA sequencing depicted that mitochondria respiration in grem1a-repressed cardiomyocytes were greatly enhanced, ultimately leading to an abnormal branch from normal developmental trajectory. Accordingly, the results from AC16 and human pluripotent stem cell-derived cardiomyocytes showed that GREM1 repression increased mitochondrial content, ATP production, mitochondrial reactive oxygen species and mitochondrial membrane potential, which probably disrupted the process of myofibril expansion. Altogether, these results suggested that TCE-induced gremlin1 repression could prematurely stimulate mitochondrial hyperfunction, thereby hamper cardiomyocyte development and cause cardiac defects in zebrafish embryos. This study provided a novel insight of gremlin1 in the associations between TCE exposure burden and CHD risk and a better understanding of the etiology of environmental stressor-caused CHD.

2025-07-09 | GSE254184 | GEO

Mitochondrial dysfunction, disruption of F-actin polymerization, and transcriptomic alterations in zebrafish larvae exposed to trichloroethylene

Project description:Trichloroethylene (TCE) is primarily used as an industrial degreasing agent and has been in use since the 1940s. TCE is released into the soil, surface, and groundwater. From an environmental and regulatory standpoint more than half of Superfund hazardous waste sites on the National Priority List are contaminated with TCE. Occupational exposure to TCE occurs primarily via inhalation, while environmental TCE exposure also occurs through ingestion of contaminated drinking water. Current literature links TCE exposure to various adverse health effects including cardiovascular toxicity. Current studies aiming to address developmental cardiovascular toxicity utilized rodent and avian models with the majority of studies using relatively higher parts per million (ppm; mg/L) doses. In this study to further investigate developmental cardiotoxicity of TCE, zebrafish embryos were treated with 0, 10, 100, or 500 parts per billion (ppb; μg/L) TCE during embryogenesis and/or through early larval stages. After the appropriate exposure period, angiogenesis, F-actin polymerization, and mitochondrial function were assessed. A significant dose response decrease in angiogenesis, F-actin polymerization, and mitochondrial function was observed. To further complement this data, a transcriptomic profile of zebrafish larvae was completed to identify gene alterations associated with the 10 ppb TCE exposure. Results from the transcriptomic data revealed that an embryonic TCE exposure caused significant changes in genes associated with cardiovascular disease, cancer, and organismal injury and abnormalities with a number of targets in the FAK signaling pathway. Overall, results from our study further support TCE as a developmental cardiovascular toxicant and continued priority for environmental regulation.

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Relieving Dyrk1a repression of MKL1 corrects developmental defects in infantile megakaryocytes

Project description:Relieving Dyrk1a repression of MKL1 corrects developmental defects in infantile megakaryocytes

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Relieving Dyrk1a repression of MKL1 corrects developmental defects in infantile megakaryocytes

Project description:Relieving Dyrk1a repression of MKL1 corrects developmental defects in infantile megakaryocytes

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AhR-mediated lipid peroxidation contributes to TCDD-induced cardiac injury in zebrafish

Project description:2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant. Previous reports revealed TCDD activating aryl hydrocarbon receptor (AhR) pathway and causing cardiac damage. However, the mechanism of AhR-induced cardiac defect in response to TCDD exposure remains unclear. In this study, we characterized the impacts of TCDD exposure on heart morphology and cardiac function in zebrafish. To investigate the differentially expressed genes under TCDD exposure, we collected the zebrafish larave heart from the control and TCDD treatment groups. We then performed gene expression profiling analysis using data obtained from RNA-seq. Transcriptomic profiling showed that, along with an upregulation of the AhR signaling pathway by TCDD, the expression of pro-ferroptosis genes was upregulated, while genes implicated in glutathione metabolism were downregulated. Consistently, lipid peroxidation, as indicated by malonaldehyde (MDA) production, increased in TCDD-exposed cardiac tissue. Accordingly, inhibiting lipid peroxidation with Liproxstatin-1 reversed the adverse cardiac effects under TCDD treatment. Together, our findings demonstrate that AhR-mediated lipid peroxidation contributes to the cardiac developmental defects of TCDD during zebrafish early development.

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Tafazzin-Deficient Zebrafish Display Mitochondrial Dysfunction and Metabolic Defects Without Myopathy

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Crol contributes to PRE-mediated repression and Polycomb group proteins recruitment in Drosophila

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Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Noninflammatory Hepatocellular Carcinoma

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Deletion of Pr72 causes cardiac developmental defects in Zebrafish.

Project description:The alpha regulator subunit B'' of protein phosphatase 2 (PPP2R3A), a regulatory subunit of protein phosphatase 2A (PP2A), was reported to present a special subcellular localization in cardiomyocytes and elevate in non-ischemia failing hearts. PPP2R3A has two transcriptions PR72 and PR130. PR72 acts as a negative regulator of the Wnt signaling cascade, while the Wnt signaling cascade plays a pivotal role in cardiac development. And PR130 was found to be involved in cardiac development of zebrafish in our previous study. Thus, to investigate the function of PR72 in heart, two stable pr72 knockout (KO) zebrafish lines were generated using Transcription Activator-Like Effector Nuclease (TALEN) technology. Homozygous pr72 KO fish struggled to survive to adulthood and exhibited cardiac developmental defects, including enlarged ventricular chambers, reduced cardiomyocytes and decreased cardiac function. And the defective sarcomere ultrastructure that affected mitochondria, I bands, Z lines, and intercalated disks was also observed. Furthermore, the abnormal heart looping was detected in mutants which could be rescued by injection with wild type pr72 mRNA. Additionally, it was found that Wnt effectors were elevated in mutants. Those indicated that deletion of pr72 in zebrafish interrupted cardiac development, probably through activation of the Wnt pathway.

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ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

Project description:ANP32B-mediated repression of p53 contributes to maintenance of normal and CML stem cells

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