engleski

Deleterious effects of combined mycotoxins

Ochratoxin A (OTA), citrinin (CTN) and beauvericin (BEA) are common contaminants of foods and feeds. OTA co-occurred with CTN or BEA in maize from the endemic nephropathy (EN) region in Croatia, Serbia and Bulgaria. Both OTA and CTN are nephrotoxic mycotoxins with potential carcinogenic action. Their cytotoxic and genotoxic effects were determined in cell lines of human and animal origin. BEA forms complexes with essential cations or cation selective channels in biological membranes leading to disturbance of ion homeostasis which might contribute to cytotoxicity and/or genotoxicity. This presentation gives an overview on interactions of OTA with CTN and BEA in porcine kidney epithelial cells (PK15) as experimental model. BEA (IC50=5.00.6 μM) is 3 times more toxic than OTA (IC50=14.02.4 μM), and 15 times more toxic than CTN (IC50=73.5±1.0 μM). Co-treatment with OTA+CTN and OTA+BEA caused additive and synergistic cytotoxicity. All three mycotoxins applied at subcytotoxic concentrations induced DNA damage in PK15 cells (measured by micronucelus and/or by comet assay), while combinations OTA+CTN and OTA+BEA produced dominant additive genotoxic effect. OTA genotoxicity may have a direct (DNA adduct formation) and indirect (oxidative DNA damage) mechanisms of action. The mechanism of BEA-induced DNA damage may be associated with the hexadepsipeptide structure of BEA e.g. fenilalanine in the BEA structure are positively charged and could interfere with negatively charged phosphate groups in the DNA strand, influencing DNA migration. On the other hand, BEA as well as OTA could cause indirect DNA damage through oxidative stress. The third possible scenario might involve BEA-increased intracellular calcium levels, which might influence endonuclease activity leading to DNA strand breaks. Disturbance of Ca2+ homeostasis caused by single and combined OTA and CTN plays a significant role in cell genotoxicity and death. Both mycotoxins induced dose-depended increase in cytosolic calcium level (assessed with Fura-2 AM) but combined treatment did not provoke additional increase in calcium signal. Co-exposure of cells to calcium chelator BAPTA-AM significantly reduced apoptosis and/or micronuclei formation evoked by single and combined OTA+CTN. In conclusion, simultaneous exposure to these toxins through contaminated food could lead to creation of apoptosis resistant cells, which could transform into cancer cells.

Ochratoxin A; beauvericin; citrinin; kidney cells; mycotoxin interactions

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