A Pilot Study of Nuclear Instability in Archived Renal and Upper Urinary Tract Tumours with Putative Ochratoxin Aetiology

Mantle, Peter G.; Amerasinghe, Cyrille; Brown, Amy L.; Herman, Diana; Horn, Thomas; Krogh, Thøger Persson; Odell, Edward; Rosenbaum, Tomas; Tatu, Calin A.

doi:10.3390/toxins2030326

Cited by 5 publications

(11 citation statements)

References 28 publications

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“…Further, a predictive animal-model role for the rat in human RCC aetiology seems at present insecure. Notably in the particular case of the late Palle Krogh, whose premature demise from a metastasising RCC might have come from professional experimental exposure to OTA for several years, the primary renal tumour was diploid [21] in marked histopathological contrast with the aneuploidy of OTA/rat carcinomas [22]. This makes an aetiological connection between experimental rat and natural human difficult for OTA, particularly since experiment needs a vastly greater dosage of the mycotoxin than is naturally available.…”

Section: Discussionmentioning

confidence: 99%

“…; similar to that for case 5 above), and is considered together with metastases that are also from archived paraffin-embedded tissues. Renal tumours in cases 2, 3 and 6 had already been designated deoxyribonucleic acid (DNA) aneuploid [21] (in which, specifically for case 6 here, see Table 1, rat 5, Figure 1L and Figure 2E). The extensive renal distortion/destruction by most of these tumours has precluded exclusion of their origin from transitional cell epithelia of the renal pelvis until the present study.…”

Section: Methodsmentioning

confidence: 99%

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Immunohistochemical Analysis of Rat Renal Tumours Caused by Ochratoxin A

Herman¹,

Mantle

2017

Toxins

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Immunohistochemical Analysis of Rat Renal Tumours Caused by Ochratoxin A

Herman¹,

Mantle

2017

Toxins

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“…A section of a Danish renal cell carcinoma (diploid) [9] also gave a negative response, as did a Romanian human angiosarcoma. Reciprocal analysis of the angiosarcoma of rat case 4 in Romania showed that the tissue did not express the human proteins CD31, CD34 or D2-40.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly archived human tumour tissues were from Denmark (a metastasising renal cell carcinoma [9]) and Romania (County Hospital, Timisoara; four transitional cell carcinomas from cases of Balkan endemic nephropathy [9]); details of their histopathology and DNA ploidy distribution have also been published [9]. A Romanian human angiosarcoma was also used.…”

Section: Methodsmentioning

confidence: 99%

Comparative Immunohistochemical Analysis of Ochratoxin A Tumourigenesis in Rats and Urinary Tract Carcinoma in Humans; Mechanistic Significance of p-S6 Ribosomal Protein Expression

Gazinska

Herman²,

Gillett

et al. 2012

Toxins

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Ochratoxin A (OTA) is considered to be a possible human urinary tract carcinogen, based largely on a rat model, but no molecular genetic changes in the rat carcinomas have yet been defined. The phosphorylated-S6 ribosomal protein is a marker indicating activity of the mammalian target of rapamycin, which is a serine/threonine kinase with a key role in protein biosynthesis, cell proliferation, transcription, cellular metabolism and apoptosis, while being functionally deregulated in cancer. To assess p-S6 expression we performed immunohistochemistry on formalin-fixed and paraffin-embedded tumours and normal tissues. Marked intensity of p-S6 expression was observed in highly proliferative regions of rat renal carcinomas and a rare angiosarcoma, all of which were attributed to prolonged exposure to dietary OTA. Only very small OTA-generated renal adenomas were negative for p-S6. Examples of rat subcutaneous fibrosarcoma and testicular seminoma, as well as of normal renal tissue, showed no or very weak positive staining. In contrast to the animal model, human renal cell carcinoma, upper urinary tract transitional cell carcinoma from cases of Balkan endemic nephropathy, and a human angiosarcoma were negative for p-S6. The combined findings are reminiscent of constitutive changes in the rat tuberous sclerosis gene complex in the Eker strain correlated with renal neoplasms, Therefore rat renal carcinogenesis caused by OTA does not obviously mimic human urinary tract tumourigenesis.

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“…A very recent publication (45) reports enhanced AA-DNA adduct formation by OTA in rats, with indirect implication for ideas about OTA in BEN tumourigenesis. This had already been recognised generically (46) for OTA on account of common complex aneuploidy in rat renal/OTA tumours and Romanian BEN urothelial tumours. However, it is important to remember that, although mis-repair of adducts can be a route to cancer, occurrence only indicates exposure, and exposure is an important dimension of satisfying Koch's postulates in epidemiology.…”

Section: Aa/dna Adductsmentioning

confidence: 87%

Is Aristolochic Acid Really the Cause of the Balkan Endemic Nephropathy?

Mantle

Herman

Tatu

2016

jcbmr

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In recent years, aristolochic acid has been promoted vigorously as the causal agent of the Balkan endemic nephropathy because of similarities to some other nephropathies, association with DNA adducts and a perception of human exposure via bread. Critical evaluation of the literature exposes flaws in these aspects, and there has been consistent failure of experimental toxicology to mimic either the slow silent bilateral atrophy of the Balkan disease or the transitional cell carcinomas in the upper urothelium. It seems yet premature to promote the curious Balkan disease as aristolochic acid nephropathy without the epidemiological rigour necessary in biomedical research.

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A Pilot Study of Nuclear Instability in Archived Renal and Upper Urinary Tract Tumours with Putative Ochratoxin Aetiology

Cited by 5 publications

References 28 publications

Immunohistochemical Analysis of Rat Renal Tumours Caused by Ochratoxin A

Immunohistochemical Analysis of Rat Renal Tumours Caused by Ochratoxin A

Comparative Immunohistochemical Analysis of Ochratoxin A Tumourigenesis in Rats and Urinary Tract Carcinoma in Humans; Mechanistic Significance of p-S6 Ribosomal Protein Expression

Is Aristolochic Acid Really the Cause of the Balkan Endemic Nephropathy?

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