title: Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells.
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.
authors.affiliation: School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China. fjwangxinjin@163.com.
authors.forename: Xinjin
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China. 13211020073@fudan.edu.cn.
authors.forename: Mengling
authors.initials: M
authors.lastname: Yan
authors.affiliation: School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China. 14211020022@fudan.edu.cn.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.affiliation: School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China. qingwu@fudan.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wu
authors.affiliation: School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China. chwu@shmu.edu.cn.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Wu
authors.affiliation: School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China. xlchang@fudan.edu.cn.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Chang
authors.affiliation: School of Public Health and Key Laboratory of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China. zjzhou@fudan.edu.cn.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008767:Methylmercury Compounds / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; C543351:MIRN25 microRNA, human; D008767:Methylmercury Compounds; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases
keywords: developmental neurotoxicity; methylmercury; microRNA; mitochondria biogenesis