Low concentrations of cylindrospermopsin induce increases of reactive oxygen species levels, metabolism and proliferation in human hepatoma cells (HepG2)

Liebel, Samuel; Ribeiro, Ciro Alberto de Oliveira; Magalhães, Valéria Freitas de; Silva, Rodrigo de Cássio da; Rossi, Stéfani Cibele; Randi, Marco Antônio Ferreira; Neto, Francisco Filipak

doi:10.1016/j.tiv.2014.12.022

Cited by 30 publications

(28 citation statements)

References 50 publications

(52 reference statements)

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“…However, these results could not be compared to those described in the present paper, since the authors did not indicate the CYN content in the different cyanobacterial extracts. Other authors have not found CYN effects on the HepG2 cell line, although the CYN‐extract concentrations were much lower than those used in the present paper (0.01–0.1 μg/mL CYN) …”

Section: Discussioncontrasting

confidence: 67%

Cytotoxic and morphological effects of microcystin‐LR, cylindrospermopsin, and their combinations on the human hepatic cell line HepG2

Gutiérrez-Praena

Guzmán-Guillén

Pichardo

et al. 2018

Environmental Toxicology

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Cylindrospermopsin (CYN) and Microcystin-LR (MC-LR) are toxins produced by different cyanobacterial species, which are found mainly in freshwater reservoirs. Both of them can induce, separately, toxic effects in humans and wildlife. However, little is known about the toxic effects of the combined exposure, which could likely happen, taking into account the concomitant occurrence of the producers. As both cyanotoxins are well known to induce hepatic damage, the human hepatocellular HepG2 cell line was selected for the present study. Thus, the cytotoxicity of both pure cyanotoxins alone (0-5 μg/mL CYN and 0-120 μg/mL MC-LR) and in combination for 24 and 48 h was assayed, as long as the cytotoxicity of extracts from CYN-producing and nonproducing cyanobacterial species. The potential interaction of the combination was evaluated by the isobologram or Chou-Talalay's method, which provides a combination index as a quantitative measure of the two cyanotoxins interaction's degree. Moreover, a morphological study of the individual pure toxins and their combinations was also performed. Results showed that CYN was the most toxic pure cyanotoxin, being the mean effective concentrations obtained ≈4 and 90 μg/mL for CYN and MC-LR, respectively after 24 h. However, the simultaneous exposure showed an antagonistic effect. Morphologically, autophagy, at low concentrations, and apoptosis, at high concentrations were observed, with affectation of the rough endoplasmic reticulum and mitochondria. These effects were more pronounced with the combination. Therefore, it is important to assess the toxicological profile of cyanotoxins combinations in order to perform more realistic risk evaluations.

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Section: Discussioncontrasting

confidence: 67%

Cytotoxic and morphological effects of microcystin‐LR, cylindrospermopsin, and their combinations on the human hepatic cell line HepG2

Gutiérrez-Praena

Guzmán-Guillén

Pichardo

et al. 2018

Environmental Toxicology

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“…CYN toxicity was reported to be attenuated by different inhibitors of cytochrome P450 (CYP450) in vivo [122], as well as in the cultured cells in vitro [121,[123][124][125][126][127]. Induction of CYP450 activity also increased CYN toxicity in hepatic cell lines [121,126,128]. Thus, it has been proposed that CYP450 activity is responsible for CYN bioactivation, increasing especially CYN-induced acute cytotoxicity, oxidative stress, and genotoxicity, while inhibition of protein synthesis appeared to be unaffected and attributed to the parental compound [121,125].…”

Section: Cylindrospermopsin Effectsmentioning

confidence: 99%

“…Thus, the exact role of CYP450 in CYN toxicity is not completely clear and should be investigated in the future [120]. Phase II detoxification of CYN is supposedly mediated via glutathione conjugation and excretion in the liver and kidney [5,120,124,127,128]. These detoxifying and excreting organs are also the most sensitive tissues (NOAEL = 30 µg/kg/day; in mice) and the major recipients of CYN toxicity, but adverse effects on the stomach, the small intestine, and on white blood cells have also been reported [131][132][133].…”

Section: Cylindrospermopsin 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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“…Cyanotoxin diminishes lipid peroxidation in cells that have not been previously induced by phenobarbital exposure for 12 h and elevates it in phenobarbitalinduced cells exposed to the highest CYN concentration (10 μg/L). Lipid peroxidation increases in both cell types after 24 h exposure, only at 10 μg/L CYN [112], demonstrating that the toxicity of low concentrations of CYN (<10 μg/L) is limited in human hepatoma cells. HepG2 cells are more sensitive compared to intestinal cells, while Caco-2 cells are even less sensitive.…”

Section: Anticancer Properties Of Cylindrospermopsinmentioning

confidence: 91%

Mechanisms of Cyanotoxin Toxicity—Carcinogenicity, Anticancer Potential, and Clinical Toxicology

Vankova¹,

Pasheva²,

Kiselova-Kaneva³

et al. 2021

Medical Toxicology

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Cyanoprokaryotes are distributed worldwide and they produce various bioactive compounds, including cyanotoxins. The major route of human exposure to cyanotoxins is the oral intake by using contaminated drinking water, by incidental intake of contaminated water during recreational and professional activities, and by consuming contaminated food or dietary supplements prepared from cyanobacteria. The prolonged chronic exposure to low concentrations of cyanotoxins provokes cell damage and may increase the risk for cancer development. Due to the variety of cyanotoxin chemical structures, different mechanisms of their toxic effects are known. At the same time, some of the natural compounds produced by cyanoprokaryotes have anticancer potential and are promising sources for the development of novel drugs. This chapter is dedicated to the target mechanisms behind the effects of the widely distributed cyanotoxins with an impact on human health, microcystins, nodularins, and cylindrospermopsin.

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Low concentrations of cylindrospermopsin induce increases of reactive oxygen species levels, metabolism and proliferation in human hepatoma cells (HepG2)

Cited by 30 publications

References 50 publications

Cytotoxic and morphological effects of microcystin‐LR, cylindrospermopsin, and their combinations on the human hepatic cell line HepG2

Cytotoxic and morphological effects of microcystin‐LR, cylindrospermopsin, and their combinations on the human hepatic cell line HepG2

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

Mechanisms of Cyanotoxin Toxicity—Carcinogenicity, Anticancer Potential, and Clinical Toxicology

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