Rat Tumour Histopathology Associated with Experimental Chronic Dietary Exposure to Ochratoxin A in Prediction of the Mycotoxin's Risk for Human Cancers.

Diana Herman,Peter Mantle

doi:10.3390/toxins13030205

Abstract

Mammalian animal toxicity of ochratoxin A (OTA) has focused largely in the past half-century on pigs because of initial recognition of it as a principal cause of intermittent growth suppression and renal disease caused by mouldy feed. Subsequent classical toxicology has used laboratory rodents because renal pathology in pigs raised questions concerning possible involvement in the human idiopathic bilateral renal atrophy of Balkan endemic nephropathy for which OTA was a focus of attention for human nephropathy through 1980s and into 2000s. Emphasis on human nephropathy has more recently concerned the plant metabolite aristolochic acid. Recognition that agricultural management can often minimise food and feed-stuff spoilage by OTA-producing Aspergilli and Penicillia has moderated some of the risks for animals. Legislation for human food safety combined with sophisticated analysis generally provides safety in the developed world. Chronic experimental exposure of male rats, in the absence of clinical dis-ease, specifically causes renal cancer. The possibility of this as a unique model for the human has generated considerable experimental evidence which may be more directly relevant for carcinogenesis in the complex kidney than that obtained from biochemical toxicities in vitro. Nevertheless, there does not appear to be any case of human renal or urinary tract cancer for which there is verified etiological proof for causation by OTA, contrary to much claim in the literature. To contribute to such debate, histopathology review of OTA/rat renal cancers, augmented where appropriate by immune profiles, has been completed for all remaining tumours in our research archive. Overall consistency of positivity for vimentin, is matched with occasional positives either for CD10 or the cytokeratin MNF 116. The current situation is discussed. Suggestion that OTA could cause human testicular cancer has also been challenged as unsupported by any experimental findings in rats, where the Leydig cell tumour immune profile does not match that of human germ cell neoplasms.

Highlights

Ochratoxin A (OTA) was discovered in South Africa in the early 1960s to explain the general toxicity of cultured Aspergillus ochraceus as a dietary additive for experimental rats
Histopathology and immune profiles of the present four rat renal tumours caused by chronic exposure to dietary OTA are complementary to our other similar tumours to which immunohistochemical profiles have recently been ascribed [9]
The latter have recently been shown to have an immune profile indistinguishable from urothelial tumours studied in Slovakia where the Balkan nephropathy has not been reported, thereby dis-associating OTA from urothelial tumours sometimes occurring in Balkan nephropathy cases

Summary

Introduction

Ochratoxin A (OTA) was discovered in South Africa in the early 1960s to explain the general toxicity of cultured Aspergillus ochraceus as a dietary additive for experimental rats. Seasonal opportunist moulding by a common Penicillium, and chromatographic recognition of OTA partly by its fluorescence under UV254 light, revealed another biosynthetic source of the mycotoxin in amounts subsequently demonstrated experimentally as a major cause of the disease in pigs. This had been expressed as reduced growth rate, low carcass weight and mottled and disproportionally enlarged kidneys, readily recognised at meat inspection and the carcass rejected [1]. Concern that traces of OTA in major cereal products such as pasta might pose a human health risk, and of potential economic threat to commercial images of the high-end commodities, stimulated extensive research into OTA toxicology. Worldwide food safety authorities (e.g., for Europe, Joint expert committee on food additives, International agency for research on cancer, European food standards agency) addressed potential health risks and formulated documents to guide regulatory legislations

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Discussion

Conclusion