Molecular mechanism of ochratoxin A and ochratoxin A together with citrinin on human renal cells

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Ochratoxin A and citrinin are metabolites of mould fungi growing on food and feed. Often they are found together in foodstuff generating a risk due to co-exposure. We could show that exposure to OTA in the nanomolar range led to a marked increase of the RNA expression of WISP1 (Wnt1 signaling pathway protein 1). Besides WISP1 also the expression of other genes involved in fibrosis or inflammation was elevated. First experiments show that the OTA-upregulated WISP1-RNA does not code for a protein but can bind the anti-fibrotic miR-29b, thereby disturbing its regulatory function. This new alternative WISP1 transcript contains putative binding sites for other miRNAs also and their relatedness to OTA toxicity remains to be determined. Additionally, the importance of the other OTA-regulated genes remains to be deter-mined.OTB, an OTA analogon without the chloride moiety, has no effect on the alternative WISP1-RNA expression. Therefore, it is extremely tantalizing and mechanistically relevant to characterize the role of this and other functional groups of the OTA molecule. By exchanging the chloride against other halogens and the phenylalanine against other amino acids, we are able to determine the impact of these groups for cell survival, fibrotic events and gene expression.OTA and citrinin can be found together in foodstuff. Therefore, a mutual influence on cell fate is conceivable. The harmful effects of one substance (OTA or citrinin) alone may be aggravated by additional stress, as caused by e.g. increased radical formation. We are able to determine the effects of a co-exposure of OTA and citrinin or OTA and other endogenously generated stressors as increased radical formation by measuring cell survival, fibrotic alterations, or dysregulated gene expression in human renal cells in primary culture.In summary therefore, it is necessary to determine(i) the role of the WISP1-RNA (and the other OTA-regulated genes) as well as to identify miRNAs which may interfere in OTA toxicity,(ii) the importance of functional groups of the OTA molecule using OTA analoga and to determine(iii) the potential risk emanating from co-exposure to the two mycotoxins together with endogenously generated cell stress.These investigations will be done using human renal cells mostly in primary culture.