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Microcystin-LR-Triggered Neuronal Toxicity in Whitefish Does Not Involve MiR124-3p.

ABSTRACT: Microcystin-LR (MC-LR) is a potent hepatotoxin that has also been pointed out of causing neurotoxicity, but the exact mechanisms of action still remain ambiguous and need to be elucidated. Data from studies on mammals show that pathology of astrocyte cells points to perturbations of microRNA signaling. Glial fibrillary acidic protein (GFAP), a neuronal cell/astrocyte-specific protein, and a microRNA-124-3p (MiR124-3p) are among putative triggers and regulators of neuronal cell/astrocyte reactivity. In the present study on whitefish (Coregonus lavaretus), we found that gfap mRNA contains a putative target site for MIR124-3p, to potentially affect its expression changes. qPCR expression study of gfap:MiR124-3p pair in the midbrain of juvenile whitefish, during 28 days of exposure to a repeated subacute dose of MC-LR (100 ?g kg-1 body mass), showed marginally significant up-regulation of gfap only on the 7th day of exposure period which suggests neuronal toxicity. During the whole exposure period, neither midbrain nor blood plasma levels of MiR124-3p were changed. Furthermore, double luciferase gene reporter assay confirmed the lack of MiR124-3p involvement in mediating control over gfap mRNA expression. These data show that, although MC-LR may trigger neuronal toxicity in whitefish, this does not involve MiR124-3p in response to the treatment.

SUBMITTER: Florczyk M

PROVIDER: S-EPMC6313356 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Microcystin-LR-Triggered Neuronal Toxicity in Whitefish Does Not Involve MiR124-3p.

Florczyk Maciej M Brzuzan Paweł P Łakomiak Alicja A Jakimiuk Ewa E Woźny Maciej M

Neurotoxicity research 20180607 1

Microcystin-LR (MC-LR) is a potent hepatotoxin that has also been pointed out of causing neurotoxicity, but the exact mechanisms of action still remain ambiguous and need to be elucidated. Data from studies on mammals show that pathology of astrocyte cells points to perturbations of microRNA signaling. Glial fibrillary acidic protein (GFAP), a neuronal cell/astrocyte-specific protein, and a microRNA-124-3p (MiR124-3p) are among putative triggers and regulators of neuronal cell/astrocyte reactivi ...[more]

PMID: 29882005

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Project description:Molecular analyses show that challenging fish with microcystin-LR (MC-LR) causes perturbations of microRNA (miRNA) signaling. However, the significance and scope of these alterations is currently unknown. To address this issue, we studied miRNA gene expression in the liver of juvenile whitefish, C. lavaretus, during 28 days of exposure to a subacute dose of MC-LR (100 μg·kg-1 body mass). Using genomic resources of Atlantic salmon (AGKD03), the mature miRNA library of Atlantic salmon (miRBase-21) and bioinformatics tools (sRNAbench), we discovered and annotated a total of 377 distinct mature miRNAs belonging to 93 families of evolutionary conserved miRNAs, as well as 24 novel mature miRNA candidates that were mapped to 14 distinct S. salar miRNA precursors. miRNA-Seq transcriptome profiling of liver tissues revealed differential miRNA expression in control and treated fish at 14 days (73 miRNAs were modulated) and at 28 days (83 miRNAs) of the treatment, subsequently validated by qPCR for nine selected differentially expressed miRNAs. Additional qPCR study confirmed the miRNA-Seq data and revealed consistent, aberrant miRNAs expression profile in the later phase of MC-LR hepatotoxicity (7-28 d). Functional annotation analysis revealed that the aberrantly expressed miRNAs have target genes involved in cytoskeletal remodeling, cell metabolism, cell cycle regulation and apoptosis; dysregulation of these processes in liver cells leads to cirrhosis and hepatocellular carcinoma in humans. To enable deeper insight into the molecular responses of liver cells in fish exposed to MC-LR, we expanded the miRNAome analysis by inclusion of miRNA variants (isomiRs) profiles, and we showed that the isomiR profiles of liver specific MiR122, and a few other miRNAs, correlated with MC-LR treatment. Given the importance of isomiRs for disease biology in mammals, we believe that further research focused on the miRNA isoforms will bring us closer to better understanding the molecular mechanisms of MC-LR hepatotoxicity.

Dataset Information

Microcystin-LR-Triggered Neuronal Toxicity in Whitefish Does Not Involve MiR124-3p.

Publications

Microcystin-LR-Triggered Neuronal Toxicity in Whitefish Does Not Involve MiR124-3p.

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