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Cytotoxic and inflammatory effects of individual and combined exposure of HepG2 cells to zearalenone and its metabolites

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Abstract

Zearalenone (ZEA), a mycotoxin produced by several Fusarium spp., is most commonly found as a contaminant in stored grain. ZEA derivatives (α-zearalenol (α-ZOL), β-zearalenol (β-ZOL)) can also be produced by Fusarium spp. in corn stems infected by fungi in the field. Also, following oral exposure, zearalenone is metabolized in various tissues, particularly in the liver, the major metabolites being α-ZOL and β-ZOL. The co-exposure of cells to mixture of a combination of mycotoxins may cause an increase of toxicity produced by these mycotoxins. In this in vitro study, we investigated the combined effects of ZEA, α-ZOL, β-ZOL in binary mixtures on the viability and inflammatory response of human liver cancer cell line (HepG2). Cell viability was assessed after 72 h using a neutral red assay. Effect of the toxins and their binary combinations on the expression of genes involved in inflammation (IL-1β, TNF-α, and IL-8) were assessed through qPCR. Our viability data showed that irrespective of the toxin combinations, the toxins have synergistic effect. ZEA + α-ZOL and ZEA + β-ZOL mixtures have induced a slight to high antagonistic response on inflammatory cytokines at low concentrations that have turned into strong synergism for high concentrations. α-ZOL + β-ZOL showed antagonistic effects on inflammation for IL-1β and TNF-α, but act synergic for IL-8 at high toxin concentrations. This study clearly shows that co-contamination of food and feed with ZEA metabolites should be taken into consideration, as the co-exposure to mycotoxins might result in stronger adverse effect than resulted from the exposure to individual toxin.

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Funding

The experimental work of this study was supported by funds from the National Research Project 8PCCDI0473-PC1. The publication was supported by funds from the National Research Development Project Projects to finance excellence (PFE)-17/2018–2020 granted by the Romanian Ministry of Research and Innovation.

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  1. Laboratory of Animal Biology, National Institute for Research and Development for Biology and Animal Nutrition, Calea Bucuresti No. 1, 077015, Balotesti, Ilfov, Romania

    D. E. Marin, G. C. Pistol, C. V. Bulgaru & I. Taranu

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  1. D. E. Marin
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  2. G. C. Pistol
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  3. C. V. Bulgaru
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  4. I. Taranu
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DME and IT conceived and designed the research. DME conducted the cell culture experiments. GCP and CVB performed the RT-PCR analyses. DME analyzed the data and wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to D. E. Marin.

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Marin, D.E., Pistol, G.C., Bulgaru, C.V. et al. Cytotoxic and inflammatory effects of individual and combined exposure of HepG2 cells to zearalenone and its metabolites. Naunyn-Schmiedeberg's Arch Pharmacol 392, 937–947 (2019). https://doi.org/10.1007/s00210-019-01644-z

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