The mechanisms of ochratoxin A tumorigenicity
Ochratoxin A (OTA) is produced by several fungi of the Aspergillus flavus and Penicillium genera, including Aspergillus ochraceus. Human exposure occurs mainly through consumption of contaminated grain and pork products. In humans, exposure to ochratoxin A has been linked to Balkan endemic nephropathy (BEN), a chronic kidney disease associated with tumours of the renal system, and an increased incidence of urinary tract tumours. In animals, ochratoxin A is nephrotoxic and induces tumours in the kidney, but also in other organs of rodents. The project investigated mechanisms of ochratoxin A tumorigenicity and biomarkers of effects in animals in vivo and human tissues or appropriate cell systems. In this direction sophisticated analytical chemistry, modern molecular biology and molecular genetics are applied to a toxicological problem. Biomarkers of oxidative stress have been analysed, showing an induction of the inducible nitric oxide synthase (INOS). However, the stress-response was inconsistent with regard to the different parameters determined and a possible delay in the response in vivo is indicated. In addition, a major effect of ochratoxin A was observed on in vitro cultures on the basal expression of several genes regulated by the transcription factor Nrf2. The Nrf2 pathway has been reported to be responsible for the activation of several detoxifying phase II enzymes and antioxidant proteins. Experimental data showed that inhibition of the Nrf2 pathway in the kidney of rats treated chronically with ochratoxin A, resulted in a marked inhibition of the defence mechanism against oxidative stress. Consequently research data suggest that a reduction of the cellular defence against oxidative stress may be a plausible mechanism of OTA nephrocarcinogenicity. The project conclusions led to an improved understanding of mechanisms resulting in DNA-damage and their contribution to tumour induction by ochratoxin A. The results of this project may be used by EU regulatory and standardisation bodies, food authorities and industrial end-users for a science-based risk assessment for ochratoxin A.
