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Human Pluripotent Stem Cell Based Developmental Toxicity Assays for Chemical Safety Screening and Systems Biology Data Generation
Published on: June 17, 2015
Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic
Xinjin Wang1, Mengling Yan2, Lina Zhao3
1School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China. fjwangxinjin@163.com.
Abstract:
Mitochondria are essential organelles and important targets for environmental pollutants. The detection of mitochondrial biogenesis and generation of reactive oxygen species (ROS) and p53 levels following low-dose methylmercury (MeHg) exposure could expand our understanding of underlying mechanisms. Here, the sensitivity of immortalized human neural progenitor cells (ihNPCs) upon exposure to MeHg was investigated. We found that MeHg altered cell viability and the number of 5-ethynyl-2'-deoxyuridine (EdU)-positive cells. We also observed that low-dose MeHg exposure increased the mRNA expression of cell cycle regulators. We observed that MeHg induced ROS production in a dose-dependent manner. In addition, mRNA levels of peroxisome-proliferator-activated receptor gammacoactivator-1α (PGC-1α), mitochondrial transcription factor A (TFAM) and p53-controlled ribonucleotide reductase (p53R2) were significantly elevated, which were correlated with the increase of mitochondrial DNA (mtDNA) copy number at a concentration as low as 10 nM. Moreover, we examined the expression of microRNAs (miRNAs) known as regulatory miRNAs of p53 (i.e., miR-30d, miR-1285, miR-25). We found that the expression of these miRNAs was significantly downregulated upon MeHg treatment. Furthermore, the overexpression of miR-25 resulted in significantly reducted p53 protein levels and decreased mRNA expression of genes involved in mitochondrial biogenesis regulation. Taken together, these results demonstrated that MeHg could induce developmental neurotoxicity in ihNPCs through altering mitochondrial functions and the expression of miRNA.
Insights
Methylmercury (MeHg) exposure harms neural progenitor cells by disrupting mitochondrial function and altering microRNA (miRNA) expression. This study reveals MeHg
Area of Science:
- Environmental toxicology
- Neuroscience
- Mitochondrial biology
Background:
- Mitochondria are vital organelles susceptible to environmental pollutants.
- Methylmercury (MeHg) is a neurotoxicant whose low-dose effects on mitochondrial function and neurodevelopment require further investigation.
- Understanding MeHg's impact on mitochondrial biogenesis, reactive oxygen species (ROS) generation, and p53 pathways is crucial for assessing developmental neurotoxicity.
Purpose of the Study:
- To investigate the sensitivity of immortalized human neural progenitor cells (ihNPCs) to methylmercury (MeHg) exposure.
- To elucidate the mechanisms by which low-dose MeHg affects mitochondrial biogenesis, ROS production, and miRNA regulation in ihNPCs.
- To determine the role of specific microRNAs (miRNAs) in mediating MeHg-induced neurotoxicity.
Main Methods:
- Exposure of ihNPCs to varying concentrations of MeHg.
- Assessment of cell viability and proliferation using EdU incorporation.
- Quantification of ROS production, mRNA expression of key genes (e.g., PGC-1α, TFAM, p53R2), mtDNA copy number, and miRNA levels (miR-30d, miR-1285, miR-25).
- Functional analysis of miRNA effects through overexpression studies.
Main Results:
- MeHg exposure significantly altered ihNPC viability and proliferation.
- Low-dose MeHg induced ROS production and increased mRNA levels of mitochondrial biogenesis regulators (PGC-1α, TFAM, p53R2) and mtDNA copy number.
- MeHg treatment downregulated specific miRNAs (miR-30d, miR-1285, miR-25), and miR-25 overexpression reduced p53 protein levels and mitochondrial biogenesis gene expression.
Conclusions:
- Methylmercury induces developmental neurotoxicity in human neural progenitor cells by impairing mitochondrial function.
- MeHg disrupts mitochondrial biogenesis and increases oxidative stress via dose-dependent ROS production.
- Downregulation of specific miRNAs, particularly miR-25, plays a critical role in mediating MeHg's effects on p53 levels and mitochondrial regulation.
