Ochratoxin A: potential epigenetic mechanisms of toxicity and carcinogenicity.

Assessment of the significance to human health of ochratoxin A (OTA) in food is limited by a lack of human toxicity data. Therefore, OTA risk evaluation relies mainly on the use of animal data, with renal carcinogenicity in rat being considered as the pivotal effect. The elucidation of the mechanism of action would improve the use of the carcinogenicity data for risk assessment. Direct genotoxicity versus epigenetic mechanisms appears to be a key question. In this presentation, new biochemical and toxicogenomic results obtained in a recent European project (EU-Grant # QLK1-CT-2001-011614) will be summarized in the context of previously reported mechanisms of action including inhibition of protein synthesis, production of oxidative stress and alteration of cell signalling. Amongst others, the new data indicate that chronic administration of a carcinogenic dose of OTA affected cell-signalling pathways resulting in a significantly reduced renal antioxidant defence and increased oxidative DNA damage. These data confirm previous hypotheses involving oxidative stress as a possible key epigenetic mechanism of OTA toxicity and carcinogenicity.