Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells

Wang, Xinjin; Yan, Mengling; Zhao, Lina; Wu, Qing; Wu, Chunhua; Chang, Xiuli; Zhou, Zhijun

doi:10.3390/ijms17122058

Cited by 19 publications

(13 citation statements)

References 51 publications

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“…miR-30d, which was downregulated upon exposure to COL and DOX in our study, was also downregulated in blood samples of acute ischemic stroke patients and in CSF samples of AD patients ( Brennan et al , 2019 ; Jiang et al , 2018 ). In vitro , exposure of methyl mercury to immortalized human neural progenitor cells resulted in downregulation of miR-30d upon neurotoxicant exposure, similar to what we observed in our study ( Wang et al , 2016 ). The proposed pathways of neurodegeneration associated with these 3 key downregulated miRNAs, miR-20a, -30b, and -30d, are shown in Figures 6A and 6B .…”

Section: Resultssupporting

confidence: 90%

“…miR-30d downregulated in CSF samples from AD patients ( Brennan et al , 2019 ), in methyl mercury-exposed immortalized human neural progenitor cells ( Wang et al , 2016 ), in brain tissue of a hypoxia ischemia rat model and cerebral I/R mouse model ( Jin et al , 2021 ; Zhao et al , 2017 ) and in peripheral blood samples from acute ischemic stroke patients ( Jiang et al , 2018 )…”

Section: Resultsmentioning

confidence: 99%

“…We specifically focused on secreted biomarkers in vitro, since secreted factors would be most likely to translate to detection of miRNAs in fluids (serum, CSF, and urine) of animals or humans. Additionally, these miRNAs were previously shown to be altered in a variety of nonclinical systems, such as human neuroblastoma and neural progenitor cells, and nonclinical species including mice and rats under neurotoxic conditions ( Aranha et al , 2010 ; Beveridge et al , 2009 ; Feng et al , 2020 ; Jeyaseelan et al , 2008 ; Jian et al , 2019 ; Jin et al , 2021 ; Liu et al , 2015 ; Shen et al , 2020 ; Song et al , 2019 ; Wang and Jia, 2021 ; Wang et al , 2016 , 2020 ; Wei et al , 2015 ; Yang et al , 2021 ; Zhang et al , 2014 ; Zhao et al , 2017 , 2021 ; Zhong et al , 2020 ). This suggests a strong translation of effect across species and increases our confidence that these notable miRNAs may be predictive biomarkers of chemical-induced neurodegeneration in nonclinical safety studies and in humans.…”

Section: Discussionmentioning

confidence: 99%

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Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons

You

Cohen

Pustovalova

et al. 2022

Toxicological Sciences

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Elucidation of predictive fluidic biochemical markers to detect and monitor chemical-induced neurodegeneration has been a major challenge due to a lack of understanding of molecular mechanisms driving altered neuronal morphology and function, as well as poor sensitivity in methods to quantify low-level biomarkers in bodily fluids. Here, we evaluated five neurotoxicants (acetaminophen [negative control], bisindolylmaleimide-1, colchicine, doxorubicin, paclitaxel, and rotenone) in human iPSC-derived neurons to profile secreted miRNAs at early and late stages of decline in neuronal cell morphology and viability. Based on evaluation of these morphological (neurite outgrowth parameters) and viability (ATP) changes, two concentrations of each chemical were selected for analysis in a human 754 miRNA panel: a low concentration with no/minimal effect on cell viability but a significant decrease in neurite outgrowth, and a high concentration with a significant decrease in both endpoints. A total of 39 miRNAs demonstrated significant changes (fold-change ≥1.5 or ≤ 0.67, p-value < 0.01) with at least one exposure. Further analyses of targets modulated by these miRNAs revealed 38 key mRNA targets with roles in neurological dysfunctions, and identified TGF-β signaling as a commonly enriched pathway. Of the 39 miRNAs, five miRNAs, three down-regulated (miR-20a, miR-30b, and miR-30d) and two up-regulated (miR-1243 and miR-1305), correlated well with morphological changes induced by multiple neurotoxicants and were notable based on their relationship to various neurodegenerative conditions and/or key pathways, such as TGF-β signaling. These data sets reveal miRNA candidates that warrant further evaluation as potential safety biomarkers of chemical-induced neurodegeneration.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons

You

Cohen

Pustovalova

et al. 2022

Toxicological Sciences

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“…MiR-761, miR-133a, miR-493-3p, and miR-130b negatively regulate mitochondrial biogenesis by directly targeting the inhibition of PGC-1α expression (Xu et al, 2015;Nie et al, 2016;Jiang et al, 2017;Lemecha et al, 2018). MiR-27b and miR-25 inhibit mitochondrial biogenesis by downregulating the expression of forkhead box J3 (Foxj3) and P53, respectively (Wang et al, 2016;Shen et al, 2016). Additionally, miR-144 and miR-142-3p promote mitochondrial biogenesis by targeting the rac family small gtpase 1(Rac1) to activate PGC-1α (Tao et al, 2020;Xia et al, 2020).…”

Section: Mitochondrial Biogenesismentioning

confidence: 99%

MicroRNAs Regulating Mitochondrial Function in Cardiac Diseases

et al. 2021

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Mitochondria are the key organelles that supply cellular energy. As the most active organ in the body, the energy required to maintain the mechanical function of the heart requires a high quantity of high-quality mitochondria in cardiomyocytes. MicroRNAs (miRNAs) are single-stranded noncoding RNAs, approximately 22 nt in length, which play key roles in mediating post-transcriptional gene silencing. Numerous studies have confirmed that miRNAs can participate in the occurrence and development of cardiac diseases by regulating mitochondrial function-related genes and signaling pathways. Therefore, elucidating the crosstalk that occurs between miRNAs and mitochondria is important for the prevention and treatment of cardiac diseases. In this review, we discuss the biogenesis of miRNAs, the miRNA-mediated regulation of major genes involved in the maintenance of mitochondrial function, and the effects of miRNAs on mitochondrial function in cardiac diseases in order to provide a theoretical basis for the clinical prevention and treatment of cardiac disease and the development of new drugs.

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“…miR-196b downregulates hox gene translation [17]. Intriguingly, exposed human neural progenitor cells exhibited decreased miR-1285, miR-25, and miR-30d expression [18]. These miRNAs target the tumor suppressor p53 [19][20][21].…”

Section: Epigenetic Modifications In Vitromentioning

confidence: 99%

Methylmercury Epigenetics

Culbreth

Aschner

2019

Toxics

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Methylmercury (MeHg) has conventionally been investigated for effects on nervous system development. As such, epigenetic modifications have become an attractive mechanistic target, and research on MeHg and epigenetics has rapidly expanded in the past decade. Although, these inquiries are a recent advance in the field, much has been learned in regards to MeHg-induced epigenetic modifications, particularly in the brain. In vitro and in vivo controlled exposure studies illustrate that MeHg effects microRNA (miRNA) expression, histone modifications, and DNA methylation both globally and at individual genes. Moreover, some effects are transgenerationally inherited, as organisms not directly exposed to MeHg exhibited biological and behavioral alterations. miRNA expression generally appears to be downregulated consequent to exposure. Further, global histone acetylation also seems to be reduced, persist at distinct gene promoters, and is contemporaneous with enhanced histone methylation. Moreover, global DNA methylation appears to decrease in brain-derived tissues, but not in the liver; however, selected individual genes in the brain are hypermethylated. Human epidemiological studies have also identified hypo- or hypermethylated individual genes, which correlated with MeHg exposure in distinct populations. Intriguingly, several observed epigenetic modifications can be correlated with known mechanisms of MeHg toxicity. Despite this knowledge, however, the functional consequences of these modifications are not entirely evident. Additional research will be necessary to fully comprehend MeHg-induced epigenetic modifications and the impact on the toxic response.

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Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells

Cited by 19 publications

References 51 publications

Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons

Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons

MicroRNAs Regulating Mitochondrial Function in Cardiac Diseases

Methylmercury Epigenetics

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