Ochratoxin A: The Continuing Enigma

Abstract

The mycotoxin ochratoxin A (OTA) has been linked to the genesis of several disease states in both animals and humans. It has been described as nephrotoxic, carcinogenic, teratogenic, immunotoxic, and hepatotoxic in laboratory and domestic animals, as well as being thought to be the probable causal agent in the development of nephropathies (Balkan Endemic Nephropathy, BEN and Chronic Interstitial Nephropathy, CIN) and urothelial tumors in humans. As a result, several international agencies are currently attempting to define safe legal limits for OTA concentration in foodstuffs (e.g., grain, meat, wine, and coffee), in processed foods, and in animal fodder. In order to achieve this goal, an accurate risk assessment of OTA toxicity including mechanistic and epidemiological studies must be carried out. Ochratoxin has been suggested by various researchers to mediate its toxic effects via induction of apoptosis, disruption of mitochondrial respiration and/or the cytoskeleton, or, indeed, via the generation of DNA adducts. Thus, it is still unclear if the predominant mechanism is of a genotoxic or an epigenetic nature. One aspect that is clear, however, is that the toxicity of OTA is subject to and characterized by large species-and sex-specific differences, as well as an apparently strict structure-activity relationship. These considerations could be crucial in the investigation of OTA-mediated toxicity. Furthermore, the use of appropriate in vivo and in vitro model systems appears to be vital in the generation of relevant experimental data. The intention of this review is to collate and discuss the currently available data on OTA-mediated toxicity with particular focus on their relevance for the in vivo situation, and also to suggest possible future strategies for unlocking the secrets of ochratoxin A.

Ochratoxin A: Potential epigenetic mechanisms of toxicity and carcinogenicity

“…As suggested above, in MDCK-C7 and OK cell cultures, OTA activated JNK and p38 pathways leading to apoptosis . In contrast, in other in vitro systems, OTA did not induce apoptosis or only at a very low rate (O'Brien and Dietrich 2005). Studies addressing the presence of apoptosis in OTA-treated animals provided some controversial data.…”

“…The literature on OTA and apoptosis is complex and inconsistent (O'Brien andDietrich 2005, Gekle et al 2005). Apoptosis refers to programmed cell death, an active process to be differentiated from necrosis.…”

“…In animal models, OTA was shown to produce a wide array of toxicological effects, including nephrotoxicity and nephrocarcinogenicity, neurotoxicity and immunotoxicity ( WHO 2001, O'Brien andDietrich 2005). From a risk assessment perspective, it has been assumed that the renal carcinogenicity in rats constituted the highest health concern and was therefore considered as the pivotal effect (WHO 2001).…”

Aristolochic acid and the etiology of endemic (Balkan) nephropathy

“…Considerable attention has been devoted to the hypothesis that a mycotoxin, ochratoxin A (OTA), is the environmental toxin responsible for EN (12,13,42). However, solid epidemiologic evidence supporting an association between OTA exposure and the prevalence of EN or upper urothelial cancer is lacking (43).…”

“…The potential involvement of environmental toxins, including mycotoxins, phytotoxins, heavy metals, viruses, and trace element deficiencies, has been widely explored (9)(10)(11), with ochratoxin A being a primary focus of EN research in recent years (12,13). Our investigations into this subject were prompted by the striking clinical and histopathologic similarities between EN and aristolochic acid nephropathy (AAN) (14,15).…”