Neurotoxic action of microcystin-LR is reflected in the transcriptional stress response of Caenorhabditis elegans

Saul, Nadine; Chakrabarti, Shumon; Stürzenbaum, Stephen R.; Menzel, Ralph; Steinberg, Christian E. W.

doi:10.1016/j.cbi.2014.09.007

Cited by 21 publications

(15 citation statements)

References 66 publications

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“…4 MC-LR has been shown to invoke multiorgan toxicity, such as neurotoxicity, kidney impairment, and liver toxicity. [5][6][7][8][9] Our previous studies identified that MC-LR could cause male reproductive toxicity, such as decline of serum testosterone, impaired spermatogenesis, inducing testicular inflammation and apoptosis of spermatogenic cells in vivo and in vitro. [10][11][12][13][14] In addition, epidemiological study revealed that MC-LR contamination of drinking water is positively associated with the incidence of some cancers, such as the colorectal cancer and primary liver cancer.…”

Section: Introductionmentioning

confidence: 99%

piRNA‐DQ722010 contributes to prostate hyperplasia of the male offspring mice after the maternal exposed to microcystin‐leucine arginine

et al. 2019

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Background: Microcystin-leucine arginine (MC-LR) could disrupt prostate development and cause prostate hyperplasia. But whether and how maternal and beforeweaning MC-LR exposure causes prostate hyperplasia in male offspring by changing expression profile of P-element-induced wimpy (PIWI)-interacting RNAs (piRNAs)have not yet been reported.Methods: From the 12th day in the embryonic period to the 21st day after offspring birth, three groups of pregnant mice that were randomly assigned were exposed to 0, 10, and 50 μg/L of MC-LR through drinking water followed by the analyses of their male offspring. Abortion rate and litter size of maternal mice were recorded. The prostate histopathology was observed. Differential expressed piRNAs of prostate were screened by piRNA microarray analysis. Murine prostate cancer cell line (RM-1) was used for further mechanism study. Luciferase report assay was used to determine the relationship between piRNA-DQ722010 and polypeptide 3 (Pik3r3). Results: The downregulated expression of piRNA-DQ722010 was the most significant in piRNA microarray analysis in 10 μg/L MC-LR treated group, while Pik3r3 was significantly upregulated, consistent with the results that a distinct prostatic epithelial hyperplasia was observed and phosphoinositide-3-kinase (PI3K)/ protien kinase B (AKT) signaling pathway was activated. Pik3r3 was verified as the target gene of piRNA-DQ722010. In addition, we found MC-LR decreased the expression of PIWI-like RNA-mediated gene silencing 2 (Piwil2) and 4 (Piwil4) both in vivo and in vitro, and both Piwil4 and Piwil2 could regulate the expression of DQ722010. Conclusion: MC-LR caused downregulation of piRNA-DQ722010 and PIWI proteins, while piRNA-DQ722010 downregulation promoted activation of PI3K/AKT signaling pathway inducing prostate hyperplasia by upregulating the expression of Pik3r3. In contrast, piRNA-DQ722010 downregulation may be attributed to PIWI proteins downregulation. The Prostate. 2019;79:798-812. wileyonlinelibrary.com/journal/pros 798 |

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Section: Introductionmentioning

confidence: 99%

piRNA‐DQ722010 contributes to prostate hyperplasia of the male offspring mice after the maternal exposed to microcystin‐leucine arginine

et al. 2019

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“…Since molecular background of MC-LR toxicity seems to be similar in different tissues, it was reasonable to assume that similar effects will emerge in the brain. MiRNA profiling of experimental stroke brains has shown alterations in many individual miRNAs, and bioinformatics tools revealed putative functional miRNA:mRNA pairs (Saul et al 2014 ). The observation that miRNA levels in the nervous system were changed by MC-LR (Saul et al 2014 ) prompted us to investigate the role of fish microRNAs in the context of brain-specific MC-LR toxicity.…”

Section: Introductionmentioning

confidence: 99%

“…MiRNA profiling of experimental stroke brains has shown alterations in many individual miRNAs, and bioinformatics tools revealed putative functional miRNA:mRNA pairs (Saul et al 2014 ). The observation that miRNA levels in the nervous system were changed by MC-LR (Saul et al 2014 ) prompted us to investigate the role of fish microRNAs in the context of brain-specific MC-LR toxicity. Moreover, recent studies have shown that disrupted expression of GFAP is associated with altered levels of miRNAs such as MiR125b (Pogue et al 2010 ) and MiR145 (Wang et al 2015 ).…”

Section: Introductionmentioning

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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“…Only a few analyses have been conducted on neurological effects, although the nervous system is one of the primary targets for environmental chemicals and pollutions [ 4 ]. This aspect is gaining increasing significance, since many invertebrates lack real livers and even well-known hepatotoxins display major adverse neurotoxic actions, as recently exemplified with microcystin-LR in Caenorhabditis elegans ( C. elegans ) [ 5 ]. One of the main reasons, why neurological examination is often omitted, is that standardized neurotoxicity screening methods devolved by the WHO and US EPA use vertebrates like rats or mice.…”

Section: Introductionmentioning

confidence: 99%

Natural Marine and Synthetic Xenobiotics Get on Nematode’s Nerves: Neuro-Stimulating and Neurotoxic Findings in Caenorhabditis elegans

Lieke

Steinberg

et al. 2015

Marine Drugs

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Marine algae release a plethora of organic halogenated compounds, many of them with unknown ecological impact if environmentally realistic concentrations are applied. One major compound is dibromoacetic acid (DBAA) which was tested for neurotoxicity in the invertebrate model organism Caenorhabditis elegans (C. elegans). This natural compound was compared with the widespread synthetic xenobiotic tetrabromobisphenol-A (TBBP-A) found in marine sediments and mussels. We found a neuro-stimulating effect for DBAA; this is contradictory to existing toxicological reports of mammals that applied comparatively high dosages. For TBBP-A, we found a hormetic concentration-effect relationship. As chemicals rarely occur isolated in the environment, a combination of both organobromines was also examined. Surprisingly, the presence of DBAA increased the toxicity of TBBP-A. Our results demonstrated that organohalogens have the potential to affect single organisms especially by altering the neurological processes, even with promoting effects on exposed organisms.

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Neurotoxic action of microcystin-LR is reflected in the transcriptional stress response of Caenorhabditis elegans

Cited by 21 publications

References 66 publications

piRNA‐DQ722010 contributes to prostate hyperplasia of the male offspring mice after the maternal exposed to microcystin‐leucine arginine

piRNA‐DQ722010 contributes to prostate hyperplasia of the male offspring mice after the maternal exposed to microcystin‐leucine arginine

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

Natural Marine and Synthetic Xenobiotics Get on Nematode’s Nerves: Neuro-Stimulating and Neurotoxic Findings in Caenorhabditis elegans

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