Abstract
Mycotoxins are toxic secondary metabolites produced by a range of fungi and are common contaminants of agricultural crops. These toxins are chemically diverse and structurally stable, enabling them to enter the food chain which can lead to numerous adverse health effects in animals and humans. Although mycotoxin exposure is associated with the development of several cancers, it has proved challenging to show a direct connection between exposure and oncogenic change. This study investigates the in vitro cytotoxicity, molecular mechanisms and secondary signalling responses associated with the exposure to three major mycotoxins, fumonisin B1 (FB1), deoxynivalenol (Don) and zearalenone (Zea). The cytotoxicity of FB1, Don and Zea were investigated in cultured HepG2 and Caco-2 cells using cell viability assays as well as flow cytometry. FB1 proved to be less cytotoxic than its counterparts, while Don and Zea demonstrated high cytotoxicity through an apoptotic mechanism. Expression profiles of 84 genes involved in mediating communication between tumour cells and the cellular mediators of inflammation as well as the innate immune system were also studied. The expression profiles associated with the different mycotoxins were further explored for functional networks, biological functions, canonical pathways, toxicological association as well as to predict network associations between the differentially expressed genes. RT-qPCR revealed the significant differential expression of 46 genes, including the expression of several genes strongly associated with cancer and aberrant inflammatory signalling, after mycotoxin exposure. Aberrant inflammatory signalling seems to be a credible contributing factor that initiates the malignant change observed in cells exposed to mycotoxins.
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Acknowledgments
The authors thank Prof. PJ Pretorius for his critical input, the National Research Foundation of South Africa (NRF) (85297) and Nestlè Nutrition Institute Africa (PO4546394578). Any opinion, findings and conclusions or recommendations expressed in this material are those of the authors, and therefore, the NRF does not accept any liability in regard thereto.
Authors’ contributions
Wentzel, J.F, Lombard, M.J, Du Plessis, L.H. and Zandberg, L. conceptualized the study. Wentzel, J.F and Zandberg, L. contributed equally to the study design, experimental work, data analyses and interpretation, as well as to drafting the manuscript. Lombard, M.J. and Du Plessis, L.H. critically reviewed the manuscript and approved the final draft.
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Wentzel, J.F., Lombard, M.J, Du Plessis, L.H, and Zandberg, L declare that they have no conflict of interest.
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Johannes F. Wentzel and Lizelle Zandberg have contributed equally to this work.
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Wentzel, J.F., Lombard, M.J., Du Plessis, L.H. et al. Evaluation of the cytotoxic properties, gene expression profiles and secondary signalling responses of cultured cells exposed to fumonisin B1, deoxynivalenol and zearalenone mycotoxins. Arch Toxicol 91, 2265–2282 (2017). https://doi.org/10.1007/s00204-016-1872-y
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DOI: https://doi.org/10.1007/s00204-016-1872-y