engleski

Synergistic effect of three Nephrotoxic and Carcinogenic Mycotoxins (Citrinin, Fumonisin, Ochratoxin A) on Human Kidney cells Viability and Genotoxicity

The aim of this study was to determine the cytotoxic and genotoxic combined effects of three mycotoxins : citrinin CIT, ochratoxin A OTA and fumonisin FB. The studies were conducted (i) in cells culture and (ii) in vivo on rat or pig fed OTA and/or CIT ; and/or FB. The decrease of viability (measured by MTT test) of human kidney cells (HK2) induced by OTA is considerably enhanced by the simultaneous presence of CIT & FB. Expression of biotransformation enzymes (CYP, COX, LIPOX) in HK2 is differently modulated depending of the combination. Induction of COX2 and LIPOX by CIT increased genotoxicity of OTA measured by DNA adducts formation detected by P32 post-labeling. DNA adducts patterns of rat kidney after a 3-weeks feeding by either CIT alone or OTA alone or both together, are similar to those obtained on cell cultures. The main OTA DNA-adduct, found in human tumours, identified as C8 dG-OTA is increased by simultaneous presence of CIT and OTA. In the same way, in in vivo studies on rat and pig fed simultaneously by OT and FB in feed we observed increased OTA specific DNA adducts including C-C8dG OTA adduct and the both OTHQ related adduct. These specific adducts are found in human urothelial tumours, notably in Balkan regions. This data is particularly interesting as we previously shown that families suffering BEN eat food more frequently contaminated by OTA, CIT and FB. In blood cell and kidney of human and rat we isolated OTA and several OTA derivatives identified by HPLC ms/ms, including quinone OTA (OTHQ), GSH-OTA, GSH-OTHQ, DC-OTHQ. The data indicate clearly that exposure to low concentration of mycotoxin which is considered as safe when they are present together can lead to dramatic effect. Until now, regulation does not take into account co-contamination.

genotoxicty; DNA-adducts; endemic nephropathy; human kidney

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