Intraperitoneal exposure of whitefish to microcystin-LR induces rapid liver injury followed by regeneration and resilience to subsequent exposures

Woźny, Maciej; Lewczuk, Bogdan; Ziółkowska, Natalia; Gomułka, Piotr; Dobosz, Stefan; Łakomiak, Alicja; Florczyk, Maciej; Brzuzan, Paweł

doi:10.1016/j.taap.2016.10.014

Cited by 17 publications

(19 citation statements)

References 70 publications

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“…Additionally, our results show that DE PCT/3'UTR pairs at 6 and 9d of the exposure are similar in terms of function and direction of expression changes (Additional File 6). The observed changes in the liver transcriptome between the 1st and the 6th or 9th day of exposure may support our previous nding that challenging white sh with MC-LR results in severe liver damage, which is followed by resilience to further exposures to the toxin, allowing for regeneration of the damaged organ [14]. It should be investigated whether this apparent shift in the transcriptome pro le re ects remodeling of liver cell processes for repair of the tissue.…”

Section: Discussionsupporting

confidence: 81%

“…Successful applications of RNA-Seq technology for resolving problems pertinent to sh biology and immunology prompted us to use RNA based methods to investigate patterns of MC-LR-induced liver injury in a teleost sh, the white sh (Coregonus lavaretus). Our previous results showed that repeated exposure of white sh to MC-LR results in severe liver damage, followed by an unexpected resilience to further exposures to the toxin and regeneration of the damaged liver structure [14]. We showed that in these adaptations, MC-LR regulates several hepatic miRNA signaling pathways and alters the expression pro les of miRNAs over the short-term [15] and long-term [16], suggesting extensive transcriptome rebuilding during these processes.…”

Section: Introductionmentioning

confidence: 74%

“…The dose of MC-LR (100 μg•kg -1 of body mass) and the treatment periods (1, 6, and 9 days) were based on our previous studies on molecular and physiological responses of white sh to this toxin [14,16,21]. MC-LR (purity ≥ 95%; HPLC) was obtained from Enzo Life Sciences (Enzo Biochem, Inc.; USA) and dissolved in phosphate buffer saline (PBS) as a solvent vehicle.…”

Section: Fish Maintenance and Exposurementioning

confidence: 99%

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De novo profiling of long non-coding RNAs involved in MC-LR–induced liver injury in whitefish: discovery and perspectives

Florczyk

Brzuzan

Woźny

2020

Preprint

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BackgroundMicrocystin-LR (MC-LR) is a potent hepatotoxin for which a substantial gap in knowledge persists regarding the underlying molecular mechanisms of liver toxicity and injury. Although long non-coding RNAs (lncRNAs) have been extensively studied in model organisms, and their roles have been identified in various cellular processes including participation in regulation of gene expression together with microRNAs, our knowledge concerning the role of lncRNAs in liver injury is limited even in mammals. Given that lncRNAs show low levels of sequence conservation, their role becomes even more unclear in non-model organisms without an annotated genome, like whitefish (Coregonus lavaretus). The objective of this study was to discover and profile aberrantly expressed polyadenylated lncRNAs that are involved in MC-LR–induced liver injury in whitefish.ResultsUsing polyA-enriched RNA-Seq data, we de novo assembled a high quality whitefish liver transcriptome. This enabled us to find 94 differentially expressed (DE) putative evolutionary-conserved lncRNAs (orthologous to known lncRNAs in other species), such as MALAT1, HOTTIP, HOTAIR or HULC and 4,429 DE putative novel whitefish lncRNAs, which differed from annotated protein-coding transcripts (PCTs) in terms of minimum free energy, GC base-pair content and length. Additionally, we identified DE non-coding transcripts that might be 3’ autonomous untranslated regions of mRNAs (3’UTRs). We found that, in response to MC-LR treatment, these potential 3’UTRs could either be coexpressed with PCTs from the same mRNA, or the 3’UTRs were upregulated while the corresponding PCTs were downregulated, suggesting 3’UTR-dependent gene regulation.ConclusionsTo our knowledge this is the first report on aberrantly expressed lncRNAs in MC-LR–induced liver injury in whitefish. We found both evolutionary conserved lncRNAs as well as novel whitefish lncRNAs that could serve as biomarkers of severe and chronic liver injury. The lncRNA sequence data files and raw sequence files are available in the Dryad Digital Repository and the NCBI Sequence Read Archive, respectively.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 74%

Section: Fish Maintenance and Exposurementioning

confidence: 99%

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De novo profiling of long non-coding RNAs involved in MC-LR–induced liver injury in whitefish: discovery and perspectives

Florczyk

Brzuzan

Woźny

2020

Preprint

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“…Reactive astrocytes not only secrete inflammatory mediators and chemokines that contribute to inflammation-mediated CNS damage (Meeuwsen et al 2003 ) but also produce inflammatory cytokines and chemokines that contribute to reparative processes in the early stages of neuroinflammation (Sharma et al 2007 ). Similarly, in the liver of whitefish exposed to MC-LR, numerous macrophages were present on the 7th day of the exposure period, indicating that cell debris from cell damage were being removed and that liver regeneration was beginning (Woźny et al 2016 ). Activated macrophages produce cytokines, such as TNF-a, which is mainly involved in the systemic inflammation response, but also in apoptosis, cell proliferation, and cell differentiation (Hehlgans and Pfeffer 2005 ).…”

Section: Discussionmentioning

confidence: 99%

“…After acclimatization, the fish were deprived of food for 2 days, then anesthetized by immersion in etomidate solution prior to injection. The MC-LR dosage was selected based on our earlier studies in whitefish (Brzuzan et al 2016 ; Woźny et al 2016 ). Chemical standard of MC-LR (purity ≥ 95%; HPLC) was obtained from Enzo Life Sciences (Enzo Biochem, Inc.) and dissolved in saline solution (0.8% NaCl) as a vehicle solvent.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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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 μg kg 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.

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Biotransformations, Antioxidant System Responses, and Histopathological Indexes in the Liver of Fish Exposed to Cyanobacterial Extract

Paulino

Tavares

Terezan

et al. 2020

Enviro Toxic and Chemistry

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Radiocystis fernandoi, a microcystin (MC) producer, has been common in cyanobacterial blooms in tropical regions. Microcystin is a hepatotoxin that causes tissue damage and even death in animals, including humans; its detoxification process may involve biotransformation and activation of the antioxidant defense system. We evaluated the detoxification pathway, examined the antioxidant defense system responses, and determined the alterations and the organ histopathological indexes in the liver of the tropical fish Hoplias malabaricus after acute and subchronic intraperitoneal exposure to microcystin. The crude microcystin extract of R. fernandoi had predominantly MC‐RR and MC‐YR. The detoxification process was activated by increasing ethoxyresorufin‐O‐deethylase activity, whereas glutathione S‐transferase was inhibited. The activity of the antioxidant defense enzymes superoxide dismutase (SOD) and glutathione peroxidase decreased after acute exposure; the SOD–catalase system and the glutathione level increased after subchronic exposure. The carbonyl protein level, lipid peroxidation (LPO), and DNA damage were unchanged after acute exposure, whereas protein carbonyl was unchanged, LPO decreased, and DNA damage increased after subchronic exposure. Histopathological alteration indexes differed between acute and subchronic exposure, but the histopathological organ indexes indicate liver dysfunction in both exposure periods. We conclude that MC‐RR and MC‐YR induce different liver responses depending on the time of exposure, and the antioxidant defense responses after subchronic exposure may help to partially restore the liver function. Environ Toxicol Chem 2020;39:1041–1051. © 2020 SETAC

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Intraperitoneal exposure of whitefish to microcystin-LR induces rapid liver injury followed by regeneration and resilience to subsequent exposures

Cited by 17 publications

References 70 publications

De novo profiling of long non-coding RNAs involved in MC-LR–induced liver injury in whitefish: discovery and perspectives

De novo profiling of long non-coding RNAs involved in MC-LR–induced liver injury in whitefish: discovery and perspectives

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

Biotransformations, Antioxidant System Responses, and Histopathological Indexes in the Liver of Fish Exposed to Cyanobacterial Extract

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