Immunohistochemical Analysis of Rat Renal Tumours Caused by Ochratoxin A

Abstract

Experimental renal cancer caused by ochratoxin A (OTA) in rats was first defined in the US National Toxicology Program (1989) and raised questions about any aetiological role in human urinary tract tumours. A review of histopathology in several rat kidney tumours from dietary OTA in recently described London studies, augmented by clinical immunohistochemistry for the first time for this mycotoxin, establishes their renal tubular cell origin. It had been assumed that the toxin might cause the human urothelial tumours associated with Balkan endemic nephropathy, but the present study could not support this. Comparison with a similar review of a metastasising renal tumour from a female rat of the NTP study consistently shows the kidney as the primary carcinogenic site for OTA. Morphological heterogeneity of these kidney tumours as epithelioid and/or sarcomatoid is revealed. Leiomyosarcoma was also diagnosed, and rhabdomyosarcoma differentiation was observed in the exceptionally aggressive NTP female tumour. The present pilot study involving immunohistochemistry indicates need for wider review of archived tumours for experimental evidence before formulating any epidemiological basis from a rat model for OTA’s relevance to idiopathic human renal cell carcinoma. Although the NTP study concluded that females are less sensitive to OTA than males, some female tumours still had heterogeneous morphology.

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

“…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 combined profiles in ten cases dis-associate the rat tumours from implying a model for an etiological role of OTA for the renal pelvic tumours sometimes associated with the Balkan endemic nephropathy.…”

“…Critical histology review of some OTA/rat renal tumours has been described [ 9 ], including exploratory application for the first time of clinical immunohistochemistry where most tumours showed a range of positive responses to the clinical immuno-stains. Although designed for human histopathological diagnosis some immuno-stains helpfully showed cross-reactivity to rats.…”

Histopathological review of renal pelvic tumours of Balkan nephropathy cases from Southern Serbia

“…From the nearly 60 years of history above it could be expected that most of the renal pelvis tumours sourced for the present study in the context of BEN could be linked aetiologically to that renal disease, but not necessary all. We have recent experience in applying clinical immunohistochemistry (IHC) to review of experimental cancers in rats given protracted or lifetime exposure to ochratoxin A [12,13]. Refinement of histopathology, of value in offering new understanding of the origin and context of cancers, contrasts with literature illustration of BEN-associated tumours [14,15] partly due to risks of postmortem tissue changes in subjects who most likely die at home.…”

Immunohistochemical Review of Leydig Cell Lesions in Ochratoxin A-Treated Fischer Rats and Controls

“…However, although the authors correctly noted the common embryology of the kidneys and testes from the mesonephros, this tissue also gives rise to the ovaries. Notably, primary ovary tumours were specifically absent from all control and OTA-treated female rats in the two-year NTP study [2]; in only one case did an ovary tumour occur, and this was attributed to metastasis from a kidney carcinoma, as has since been confirmed immunohistochemically [14].…”

“…Following recent application of clinical immunohistochemistry to rat renal tumours caused by OTA exposure in a pilot study [14], we have here explored histopathology in testicular lesions from the same and experimentally associated animals recruited from several lifetime rat studies [4,5,7]. The objective has been to assess whether chronic OTA exposure had made even subtle changes to the testicular lesion phenotype, which appears to be a normal outcome of ageing in some laboratory rat strains, including the Fischer rats used extensively for many years in NTP studies.…”