Induction of oxidative stress and cancer

Induction of cellular oxidative stress, resulting from an increase in the production of oxygen and hydrogen radicals, and a depletion of cellular defense mechanisms such as glutathione, is a common following exposure to many mycotoxins (Surai and Dvorska, 2005). The pro-oxidant effect of mycotoxins is dose- and time-dependent and may go beyond glu-tathione depletion to include changes in the activity of glutathione peroxidase, catalase and superoxide dismutase. For example, glutathione depletion in the liver is one of the earliest signs of exposure to mycotoxins such as aflatoxins and ochratoxins, but the response is transient. After repetitive exposure to low amounts of mycotoxins, measurable glutathione levels increase again, as a sign of adaptation. Cellular oxidative stress and enhanced radical production cause lipid peroxidation and cellular necrosis. Many mycotoxins including the trichothecenes, aflatoxins and ochratoxins also affect the transport of tocopherol, carotino-ids and ascorbic acid (as mentioned above), which encourages lipid peroxidation, impairs vital cellular functions and induces cell necrosis and apoptosis. Particularly vulnerable cells are those with a high energy demand as well as rapidly proliferating cells, such as entero-cytes and cells of the immune system. The degree of oxidative stress is assumed to be one of the key factors contributing to the immunosuppressive effect of mycotoxins.

Reactive oxygen species also can interact with nuclear DNA to form 8-deoxyguanosine or 06-methylguanine, which are indicative of oxidative damage to DNA. Formation of 8-deoxyguanosine is associated with mutations resulting from G/T transitions, so reactive oxygen species may ultimately induce tumor formation. Therefore, oxidative DNA damage is considered a prominent non-genotoxic mechanism in determining the tissue specific risk of cancer development. This type of non-genotoxic mechanism has been proposed for ochratox-in A and fumonisin Bj, whereas aflatoxins can induce mutational events directly since its exo-epoxide can interact directly with DNA to form a stable adduct. Moreover, mutations in the tumor suppressor gene p53 have been observed following exposure to aflatoxins.

In farm animals, the induction of cancer by mycotoxins is rarely seen, with the exception of liver cancer induced in fish species by aflatoxins, as during the relatively short life span of these animals, neoplastic lesions are not of clinical importance.

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