Hepatotoxicity of fusariotoxins, alone and in combination, towards the HepaRG human hepatocyte cell line

Smith, Marie-Caroline; Hymery, Nolwenn; Troadec, Samuel; Pawtowski, Audrey; Coton, Emmanuel; Madec, Stéphanie

doi:10.1016/j.fct.2017.09.022

Cited by 35 publications

(13 citation statements)

References 59 publications

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“…The cell line is regarded as a superior surrogate in vitro model for assessing drug-induced hepatotoxicity since this cell line expresses high levels of various CYPs, such as detoxification enzymes (CYP3A4) and drug-metabolizing enzyme (CYP4F3B). It also possesses both the metabolic performance of primary human hepatocytes and the growth capacity of a hepatic cell line [ 26 , 27 ]. In this study, we elucidated the cytotoxicity of rhein in HepaRG cells in vitro.…”

Section: Introductionmentioning

confidence: 99%

Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway

You

Dong

Yin

et al. 2018

IJMS

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Rhein, a naturally occurring active anthraquinone found abundantly in various medicinal and nutritional herbs, possesses a wide spectrum of pharmacological effects. Furthermore, previous studies have reported that rhein could induce hepatotoxicity in rats. However, its cytotoxicity and potential molecular mechanisms remain unclear. Therefore, the present study aimed to investigate the cytotoxicity of rhein on HepaRG cells and the underlying mechanisms of its cytotoxicity. Our results demonstrate, by 3-(4,5-dimethyl thiazol-2-yl-)-2,5-diphenyl tetrazolium bromide (MTT) and Annexin V-fluoresce isothiocyanate (FITC)/propidium iodide (PI) double-staining assays, that rhein significantly inhibited cell viability and induced apoptosis in HepaRG cells. Moreover, rhein treatment resulted in the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and S phase cell cycle arrest. The results of Western blotting showed that rhein treatment resulted in a significant increase in the protein levels of Fas, p53, p21, Bax, cleaved caspases-3, -8, -9, and poly(ADP-ribose)polymerase (PARP). The protein expression of Bcl-2, cyclin A, and cyclin-dependent kinase 2 (CDK 2) was decreased. In conclusion, these results suggest that rhein treatment could inhibit cell viability of HepaRG cells and induce cell death through cell cycle arrest in the S phase and activation of Fas- and mitochondrial-mediated pathways of apoptosis. These findings emphasize the need to assess the risk of exposure for humans to rhein.

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Section: Introductionmentioning

confidence: 99%

Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway

You

Dong

Yin

et al. 2018

IJMS

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“…Several of the recent studies listed in Table 1 simultaneously used different mathematical models, e.g., response additivity and Bliss independence criterion [38,39] or Bliss independence and Loewe additivity [40] or Chou-Talalay method [39,41]. As expected, these studies obtained different conclusions on mycotoxin interactions depending on the mathematical models that have been applied.…”

Section: Bliss Independence Criterionmentioning

confidence: 79%

“…As expected, these studies obtained different conclusions on mycotoxin interactions depending on the mathematical models that have been applied. For example, Smit et al [39] obtained a synergism of DON + ZEN at low and medium concentrations by both response additivity and Bliss independence model; while at high concentrations in combinations, an additive effect was obtained with Bliss independence model and antagonism by response additivity.…”

Section: Bliss Independence Criterionmentioning

confidence: 99%

“…Similarly to Loewe's additivity model, the isobologram can be constructed. The Chou-Talalay model combined with an isobologram has been applied in the majority of the recently published studies [39,[51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] listed in Table 2. Its great advantage is the recent development of a method for the estimation of confidence intervals for the combination index which enables the application of statistics [66].…”

Section: Chou and Talalay's Median Effect Approachmentioning

confidence: 99%

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Assessing the Effect of Mycotoxin Combinations: Which Mathematical Model Is (the Most) Appropriate?

Kifer

Jakšić

Klarić

2020

Toxins

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In the past decades, many studies have examined the nature of the interaction between mycotoxins in biological models classifying interaction effects as antagonisms, additive effects, or synergisms based on a comparison of the observed effect with the expected effect of combination. Among several described mathematical models, the arithmetic definition of additivity and factorial analysis of variance were the most commonly used in mycotoxicology. These models are incorrectly based on the assumption that mycotoxin dose-effect curves are linear. More appropriate mathematical models for assessing mycotoxin interactions include Bliss independence, Loewe’s additivity law, combination index, and isobologram analysis, Chou-Talalays median-effect approach, response surface, code for the identification of synergism numerically efficient (CISNE) and MixLow method. However, it seems that neither model is ideal. This review discusses the advantages and disadvantages of these mathematical models.

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“…With a primary focus on combinations of mycotoxins with comparably high prevalence but different modes of action (e.g., DON and ZEN), a vast number of different mycotoxin combinations have already been tested in vitro. The majority of these studies investigated primarily cytotoxic effects and/or related readouts in different cell models (e.g., Ren et al 2017 ; Smith et al 2017a , b , 2018 ; Wang et al 2014 ; Zhang et al 2018 ; Zhou et al 2017 ). Based on these studies, it appears that the impact of the combination of DON and ZEN varies substantially depending on the ratio of test compounds applied, the concentration range, and the cell model, ranging from antagonistic to additive and even synergistic effects.…”

Section: Current Status Of Combinatory Effects Of Zen and Its Modifiementioning

confidence: 99%

A critical evaluation of health risk assessment of modified mycotoxins with a special focus on zearalenone

et al. 2018

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A comprehensive definition introducing the term "modified mycotoxins" to encompass all possible forms in which mycotoxins and their modifications can occur was recently proposed and has rapidly gained wide acceptance within the scientific community. It is becoming increasingly evident that exposure to such modified mycotoxins due to their presence in food and feed has the potential to pose a substantial additional risk to human and animal health. Zearalenone (ZEN) is a well-characterized Fusarium toxin. Considering the diversity of modified forms of ZEN occurring in food and feed, the toxicologically relevant endocrine activity of many of these metabolites, and the fact that modified forms add to a dietary exposure which approaches the tolerable daily intake by free ZEN alone, modified forms of ZEN present an ideal case study for critical evaluation of modified mycotoxins in food safety. Following a summary of recent scientific opinions of EFSA dealing with health risk assessment of ZEN alone or in combination with its modified forms, uncertainties and data gaps are highlighted. Issues essential for evaluation and prioritization of modified mycotoxins in health risk assessment are identified and discussed, including opportunities to improve exposure assessment using biomonitoring data. Further issues such as future consideration of combinatory effects of the parent toxin with its modified forms and also other compounds co-occurring in food and feed are addressed. With a particular focus on ZEN, the most pressing challenges associated with health risk assessment of modified mycotoxins are identified and recommendations for further research to fill data gaps and reduce uncertainties are made.

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Hepatotoxicity of fusariotoxins, alone and in combination, towards the HepaRG human hepatocyte cell line

Cited by 35 publications

References 59 publications

Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway

Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway

Assessing the Effect of Mycotoxin Combinations: Which Mathematical Model Is (the Most) Appropriate?

A critical evaluation of health risk assessment of modified mycotoxins with a special focus on zearalenone

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