Analysis of Individual and Combined Effects of Ochratoxin  A and Zearalenone on HepG2 and KK-1 Cells with Mathematical Models

Li, Yuzhe; Zhang, Boyang; He, Xiaoyun; Cheng, Wen‐Hsing; Xu, Wentao; Luo, Yunbo; Liang, Rui; Luo, Hanpeng; Huang, Kunlun

doi:10.3390/toxins6041177

Cited by 51 publications

(42 citation statements)

References 53 publications

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“…These data suggest that cellular oxidative stress plays a critical role in the observed apoptosis. In previous studies, similar results were observed in HepG2 and porcine IPEC-J2 cells as ZEN generated ROS, reduced antioxidant enzyme activities, and induced cell death in vitro [24][25][26].…”

Section: Discussionsupporting

confidence: 82%

Zearalenone Induces Endoplasmic Reticulum Stress and Modulates the Expression of Phase I/II Enzymes in Human Liver Cells

Yoon

Lee²,

Seok

et al. 2019

Toxins

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Zearalenone (ZEN) is a mycotoxin produced by Fusarium species; however, its mechanisms of action in human livers have not been fully elucidated. Thus, we investigated the toxic mechanisms of ZEN in human liver cells. HepG2 cells were treated with ZEN (0–40 μg/mL) for up to 24 h. A significant decrease in cell viability was observed after treatment with 20 and 40 μg/mL of ZEN, including a significant increase in apoptosis and reactive oxygen species production. ZEN increased GRP78 and CHOP, and eIF2α phosphorylation, indicating ER stress; elevated transcription of the autophagy-associated genes, beclin1 and LC3, and translation of LC3; and increased phase I metabolism by increasing PXR and CYP3A4. The protein expression level of CYP3A4 was higher with ZEN treatment up to 20 μg/mL, but remained at the control level after treatment with 40 μg/mL ZEN. In phase II metabolism, Nrf2 activation and UGT1A expression were increased with ZEN treatment up to 20 μg/mL. Treating cells with an ER stress inhibitor alleviated ZEN-induced cell death and autophagy, and inhibited the expression of phase I/II enzymes. Overall, high ZEN concentrations can modulate the expression of phase I/II enzymes via ER stress and reduced protein levels in human liver cells.

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Section: Discussionsupporting

confidence: 82%

Zearalenone Induces Endoplasmic Reticulum Stress and Modulates the Expression of Phase I/II Enzymes in Human Liver Cells

Yoon

Lee²,

Seok

et al. 2019

Toxins

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“…The MDR and TI values indicated slight synergistic and antagonistic interactions among the components of the chemical mixtures. Nevertheless, the values are within 0.5 -2.0 range, thus the mixtures are said to be additive (Petersen & Tollefsen, 2011;Li et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Toxicity of Quaternary Mixtures of Phenolic Compounds and Formulated Glyphosate to Microbial Community of River Water

Nweke

Ike

Ibegbulem

2024

Ecotoxicol. Environ. Contam.

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The toxicity of mixtures of formulated glyphosate, phenol, 4-chlorophenol and 2,4-dichlorophenol to river water microbial community was investigated using non specific dehydrogenase activity as endpoint. The microbial community was exposed to individual toxicant and quaternary mixture ratios at concentrations ranging from 50 mg L -1 to 3000 mg L -1 over 24 h. The ecological doses (EC 50 ) as estimated from logistic or hormesis dose-effect models were 1317.946 ± 51.460 mg L -1 , 1046.414 ± 65.534 mg L -1 , 85.080 ± 4.468 mg L -1 and 60.897 ± 5.199 mg L -1 for formulated glyphosate, phenol, 4-chlorophenol and 2,4-dichlorophenol respectively. The toxicity and interaction of the mixtures were evaluated using concentration addition and toxic index models. The model deviation ratios (MDR) ranged from 0.553 ± 0.024 to 1.096 ± 0.021 while the toxic index (TI) varied between 0.912 ± 0.017 and 1.810 ± 0.078. However, the MDR and TI for all mixtures lie between 0.5 and 2.0. Thus, the joint action of the mixtures were considered additive.

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“…This does not seem to be correct according to the dose-response curves for OTA (E (1.60 µM of OTA) ≈ 30%) and ZEN (E (23.68 µM of ZEN) ≈ 50%) presented in aforementioned article [44], which raises the question: can the observed synergies be trusted at all? Even though this model is mathematically valid, due to the excessive number of assumptions that need to be fulfilled, this model probably remains inapplicable for assessing combinations of mycotoxins [43].…”

Section: Loewe's Additivity Lawmentioning

confidence: 95%

“…Finding two mycotoxins in a combination that fulfils all of these assumptions seems somewhat impossible. For example, apart from the Bliss independence criterion, Li et al [44] also used this method (as a concentration addition model) to assess the nature of interaction between OTA and ZEN. Since their dose-effect curves did not meet all of the assumptions, it is easy to see that Equation 4, on which Loewe's additivity law is based, does not hold true when we assign the values EC 10 (OTA) = 0.8 µM and EC 10 (ZEN) = 11.84 µM [44], and try to apply the main principles of dose equivalence and sham combination of this model (Equations 7and 8…”

Section: Loewe's Additivity Lawmentioning

confidence: 99%

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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Analysis of Individual and Combined Effects of Ochratoxin A and Zearalenone on HepG2 and KK-1 Cells with Mathematical Models

Cited by 51 publications

References 53 publications

Zearalenone Induces Endoplasmic Reticulum Stress and Modulates the Expression of Phase I/II Enzymes in Human Liver Cells

Zearalenone Induces Endoplasmic Reticulum Stress and Modulates the Expression of Phase I/II Enzymes in Human Liver Cells

Toxicity of Quaternary Mixtures of Phenolic Compounds and Formulated Glyphosate to Microbial Community of River Water

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

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