Toxic mechanisms of microcystins in mammals

McLellan, Nicole L.; Manderville, Richard A.

doi:10.1039/c7tx00043j

Cited by 146 publications

(69 citation statements)

References 97 publications

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“…Depending on the MC congener, the dose, and the duration of exposure, MCs cause necrotic, apoptotic, or cell-proliferative changes [90,91]. Due to the high abundance of OATP1B1 and 1B3 in parenchymal hepatocytes, the high metabolic activity, and detoxifying function, toxic effects often manifest in the liver, even though the first site of action upon water-borne contaminants is probably mucosal epithelia of the GIT (Table 2).…”

Section: Microcystin Effectsmentioning

confidence: 99%

Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system

et al. 2019

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Background: Cyanobacterial blooms occur with increasing frequency in freshwater ecosystems, posing a hazard to human and environmental health. Exposure of human to cyanobacterial metabolites occurs mostly via accidental ingestion through contaminated drinking water or during recreational activities and, most frequently, results in gastrointestinal symptoms. Despite the clinical manifestation, cyanobacterial metabolites are rather investigated for their toxicity towards specific organs or tissues, especially hepato-, nephro-, and neurotoxicity, than for effects on the gastrointestinal tract and the associated lymphoid tissue. Main body: The aim of this review was to systematically summarize available literature on the effects on the gastrointestinal tract and the mucosal innate immune system and compile the data from both, in vitro and in vivo studies, focusing on human health-relevant models. Our systematic literature review revealed significant data gaps in the understanding on metabolites breaching the gastrointestinal barrier and the role of the immune system in the establishment of clinical symptoms. Microcystins and cylindrospermopsin were linked to gastrointestinal symptoms, immune system effects, or both. Furthermore, cyanobacterial bloom lipopolysaccharides, other less studied metabolites and their mixtures have been also implicated to have a role in gastrointestinal inflammation. Conclusion: The collected data indicate the need for a reassessment of potential enterotoxicity of microcystins and cylindrospermopsin. In addition, the carcinogenic potential of cyanotoxins, especially microcystins, has to be clarified, as an increasing amount of epidemiological studies show correlations between cyanobacterial blooms and gastrointestinal cancer incidence. Furthermore, other, often highly abundant bioactive metabolites such as aeruginosins, have to be toxicologically evaluated at distinct levels also accounting for (sub-)chronic exposure to low concentrations and in combination with naturally co-occurring metabolites, which can be expected in drinking water supplies.

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Section: Microcystin Effectsmentioning

confidence: 99%

Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system

et al. 2019

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“…Large MC doses lead to acute liver failure [7,9], but prolonged exposure to low levels of MCs may be more prevalent and pernicious. The effects of such exposure in humans are not well understood and are generally extrapolated from animal models [24][25][26][27][28]. Animal studies have found biomarkers of MC exposure in mouse serum [29] and rat urine [30] after intraperitoneal injection.…”

Section: Introductionmentioning

confidence: 99%

Development and Application of Extraction Methods for LC-MS Quantification of Microcystins in Liver Tissue

Baliu-Rodriguez

Kucheriavaia

Palagama

et al. 2020

Toxins

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A method was developed to extract and quantify microcystins (MCs) from mouse liver with limits of quantification (LOQs) lower than previously reported. MCs were extracted from 40-mg liver samples using 85:15 (v:v) CH3CN:H2O containing 200 mM ZnSO4 and 1% formic acid. Solid-phase extraction with a C18 cartridge was used for sample cleanup. MCs were detected and quantified using HPLC-orbitrap-MS with simultaneous MS/MS detection of the 135.08 m/z fragment from the conserved Adda amino acid for structural confirmation. The method was used to extract six MCs (MC-LR, MC-RR, MC-YR, MC-LA, MC-LF, and MC-LW) from spiked liver tissue and the MC-LR cysteine adduct (MC-LR-Cys) created by the glutathione detoxification pathway. Matrix-matched internal standard calibration curves were constructed for each MC (R2 ≥ 0.993), with LOQs between 0.25 ng per g of liver tissue (ng/g) and 0.75 ng/g for MC-LR, MC-RR, MC-YR, MC-LA, and MC-LR-Cys, and 2.5 ng/g for MC-LF and MC-LW. The protocol was applied to extract and quantify MC-LR and MC-LR-Cys from the liver of mice that had been gavaged with 50 µg or 100 µg of MC-LR per kg bodyweight and were euthanized 2 h, 4 h, or 48 h after final gavage. C57Bl/6J (wild type, control) and Leprdb/J (experiment) mice were used as a model to study non-alcoholic fatty liver disease. The Leprdb/J mice were relatively inefficient in metabolizing MC-LR into MC-LR-Cys, which is an important defense mechanism against MC-LR exposure. Trends were also observed as a function of MC-LR gavage amount and time between final MC-LR gavage and euthanasia/organ harvest.

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“…The gene cluster of the MC biosynthesis pathway in Microcystis consists of ten genes (mcyA-J, approximately 55 kb in length) [12,13]. With the establishment of a genetic basis of MCs biosynthesis, various molecular approaches have been subsequently developed for detecting and quantifying the potential of MC-producing cyanobacteria [14,15]. While the biosynthesis, identification, detection, and toxicity of MCs have been well understood [16], the biological and ecological functions of these metabolites still remain a subject of debate [17].…”

Section: Introductionmentioning

confidence: 99%

Programmed Cell Death-Like and Accompanying Release of Microcystin in Freshwater Bloom-Forming Cyanobacterium Microcystis: From Identification to Ecological Relevance

Rzymski

2019

Toxins

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Microcystis is the most common freshwater bloom-forming cyanobacterium. Its massive blooms not only adversely affect the functionality of aquatic ecosystems, but are also associated with the production of microcystins (MCs), a group of potent toxins that become a threat to public health when cell-bound MCs are significantly released from the dying Microcystis into the water column. Managing Microcystis blooms thus requires sufficient knowledge regarding both the cell death modes and the release of toxins. Recently, more and more studies have demonstrated the occurrence of programmed cell death-like (or apoptosis-like) events in laboratory and field samples of Microcystis. Apoptosis is a genetically controlled process that is essential for the development and survival of metazoa; however, it has been gradually realized to be an existing phenomenon playing important ecological roles in unicellular microorganisms. Here, we review the current progress and the existing knowledge gap regarding apoptosis-like death in Microcystis. Specifically, we focus first on the tools utilized to characterize the apoptosis-related biochemical and morphological features in Microcystis. We further outline various stressful stimuli that trigger the occurrence of apoptosis and discuss the potential mechanisms of apoptosis in Microcystis. We then propose a conceptual model to describe the functional coupling of apoptosis and MC in Microcystis. This model could be useful for understanding both roles of MC and apoptosis in this species. Lastly, we conclude the review by highlighting the current knowledge gap and considering the direction of future research. Overall, this review provides a recent update with respect to the knowledge of apoptosis in Microcystis and also offers a guide for future investigations of its ecology and survival strategies.

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Toxic mechanisms of microcystins in mammals

Cited by 146 publications

References 97 publications

Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system

Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system

Development and Application of Extraction Methods for LC-MS Quantification of Microcystins in Liver Tissue

Programmed Cell Death-Like and Accompanying Release of Microcystin in Freshwater Bloom-Forming Cyanobacterium Microcystis: From Identification to Ecological Relevance

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