Genotoxic potential of the binary mixture of cyanotoxins microcystin-LR and cylindrospermopsin

Hercog, Klara; Maisanaba, Sara; Filipič, Metka; Jos, Ángeles; Cameán, Ana M.; Žegura, Bojana

doi:10.1016/j.chemosphere.2017.09.075

Cited by 35 publications

(54 citation statements)

References 65 publications

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“…The same was observed with the CHEK1 gene, the protein product of which is a checkpoint kinase that is activated in response to DNA damage and can thereafter modulate the activity of a number of proteins, including P53, providing a link between DNA damage and P53 checkpoint activity [88]. The results observed in single compound exposure groups are in agreement with previous reports, showing no deregulation of these genes by CYN or BPs in HepG2 cells [25,27,46], and the tested binary mixtures did not induce any different deregulation patterns from single compounds. .…”

Section: Dna Damage Response Genessupporting

confidence: 90%

“…Furthermore, BPA and BPF have been reported to be oxidized to reactive intermediates as well [70,71], which have been reported to form DNA adducts [51,72,73]. In line with our results, CYN was previously shown to up-regulate CYP1A1, and other CYP isoforms (CYP1B1 and CYP1A2) in HepG2 cells [18,[25][26][27] and human peripheral blood lymphocytes (HPBLs) [26]. Recently, the up-regulation of the expression of CYP1A1 was reported following the exposure to BPs (BPA, BPS, BPF, and BPAF) in HepG2 cells [46] and the up-regulation of CYP1A1 on the protein level following exposure to BPA in human placental JEG-3 choriocarcinoma cells was reported [74].…”

Section: Dna Damage Response Genessupporting

confidence: 89%

“…The expression of the tumor-suppressor gene, TP53, was not significantly altered by BPs exposure, whereas it was slightly (<1.5-fold) down-regulated by CYN and the CYN/BPs combinations. Previous studies on the expression of the TP53 gene reported that CYN [18,25,27] and BPs [46] did not influence TP53 expression in HepG2 cells. Our results indicate that the combined exposure to CYN/BPs does not affect the expression of this gene differently than exposure to CYN as a single compound.…”

Section: Dna Damage Response Genesmentioning

confidence: 80%

“…The influence of single compounds and CYN/BPs combinations on HepG2 cell viability was evaluated with the tetrazolium-based MTS assay. The concentrations of CYN (0.5 µg/ml) and BPs (10 µg/ml) were chosen based on previous findings on the genotoxic effects of CYN [25,27,28] and BPs [46] in HepG2 cells, also considering reported environmental concentrations and the significant daily uptake rate through dietary ingestion in the case of BPA. Although these concentrations are still higher than those reported in the environment and are not expected to be directly relevant for human exposure, they serve the aim of this study, which was to identify the possible DNA damaging effects (induction of DNA DSBs) and potential mechanisms of action of non-cytotoxic concentrations of CYN/BPs binary mixtures.…”

Section: The Influence Of Cyn Bps and Their Combinations On Cell VImentioning

confidence: 99%

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Plastics in Cyanobacterial Blooms—Genotoxic Effects of Binary Mixtures of Cylindrospermopsin and Bisphenols in HepG2 Cells

Hercog

Štern

Maisanaba

et al. 2020

Toxins

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Ever-expanding environmental pollution is causing a rise in cyanobacterial blooms and the accumulation of plastics in water bodies. Consequently, exposure to mixtures of cyanotoxins and plastic-related contaminants such as bisphenols (BPs) is of increasing concern. The present study describes genotoxic effects induced by co-exposure to one of the emerging cyanotoxins—cylindrospermopsin (CYN)—(0.5 µg/mL) and BPs (bisphenol A (BPA), S (BPS), and F (BPF); (10 µg/mL)) in HepG2 cells after 24 and 72 h of exposure. The cytotoxicity was evaluated with an MTS assay and genotoxicity was assessed through the measurement of the induction of DNA double strand breaks (DSB) with the γH2AX assay. The deregulation of selected genes (xenobiotic metabolic enzyme genes, DNA damage, and oxidative response genes) was assessed using qPCR. The results showed a moderate reduction of cell viability and induction of DSBs after 72 h of exposure to the CYN/BPs mixtures and CYN alone. None of the BPs alone reduced cell viability or induced DSBs. No significant difference was observed between CYN and CYN/BPs exposed cells, except with CYN/BPA, where the antagonistic activity of BPA against CYN was indicated. The deregulation of some of the tested genes (CYP1A1, CDKN1A, GADD45A, and GCLC) was more pronounced after exposure to the CYN/BPs mixtures compared to single compounds, suggesting additive or synergistic action. The present study confirms the importance of co-exposure studies, as our results show pollutant mixtures to induce effects different from those confirmed for single compounds.

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Section: Dna Damage Response Genessupporting

confidence: 90%

Section: Dna Damage Response Genessupporting

confidence: 89%

Section: Dna Damage Response Genesmentioning

confidence: 80%

Section: The Influence Of Cyn Bps and Their Combinations On Cell VImentioning

confidence: 99%

See 2 more Smart Citations

Plastics in Cyanobacterial Blooms—Genotoxic Effects of Binary Mixtures of Cylindrospermopsin and Bisphenols in HepG2 Cells

Hercog

Štern

Maisanaba

et al. 2020

Toxins

Self Cite

View full text Add to dashboard Cite

show abstract

“…With regard to in vitro studies, various assays have been performed ( Table 5 ) [ 26 , 27 , 28 , 35 , 53 , 60 , 63 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ], mainly in mammalian systems, which demonstrated the pro-genotoxic activity of CYN.…”

Section: Toxicity Mechanismsmentioning

confidence: 99%

In Vitro Toxicological Assessment of Cylindrospermopsin: A Review

Pichardo

Cameán

Jos

2017

Toxins

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Cylindrospermopsin (CYN) is a cyanobacterial toxin that is gaining importance, owing to its increasing expansion worldwide and the increased frequency of its blooms. CYN mainly targets the liver, but also involves other organs. Various mechanisms have been associated with its toxicity, such as protein synthesis inhibition, oxidative stress, etc. However, its toxic effects are not yet fully elucidated and additional data for hazard characterization purposes are required. In this regard, in vitro methods can play an important role, owing to their advantages in comparison to in vivo trials. The aim of this work was to compile and evaluate the in vitro data dealing with CYN available in the scientific literature, focusing on its toxicokinetics and its main toxicity mechanisms. This analysis would be useful to identify research needs and data gaps in order to complete knowledge about the toxicity profile of CYN. For example, it has been shown that research on various aspects, such as new emerging toxicity effects, the toxicity of analogs, or the potential interaction of CYN with other cyanotoxins, among others, is still very scarce. New in vitro studies are therefore welcome.

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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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Genotoxic potential of the binary mixture of cyanotoxins microcystin-LR and cylindrospermopsin

Cited by 35 publications

References 65 publications

Plastics in Cyanobacterial Blooms—Genotoxic Effects of Binary Mixtures of Cylindrospermopsin and Bisphenols in HepG2 Cells

Plastics in Cyanobacterial Blooms—Genotoxic Effects of Binary Mixtures of Cylindrospermopsin and Bisphenols in HepG2 Cells

In Vitro Toxicological Assessment of Cylindrospermopsin: A Review

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

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