Rat Kidney Cancers Determined by Dietary Ochratoxin A in the First Year of Life

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Peter Mantle


Balkan endemic nephropathy, karyomegaly, latency, leukaemia, renal cell carcinoma, urothelial cancer


An experiment to explore renal carcinogenic efficacy of male rat exposure to dietary ochratoxin A (OTA) only in the first year of life has been made in comparison to lifetime exposure. Ten months exposure to OTA at 300 μg/kg b.w. was sufficient to cause high incidence of tumours which became apparent clinically after a latency of up to a year. As a putative model for human kidney cancer, the study shows a silent organ-specific carcinogenic effect through protracted exposure up to middle age and focused probably on very few nephrons. So far, tumourigenesis has not been recognised until in the last quarter of natural rat life, but for OTA, rat renal carcinogenesis requires both long exposure and only during the first year of normal longevity. The present findings offer an experimental framework within which systematic histopathology during tumourigenesis might show whether findings of mechanistic studies in key focal neoplasms can reasonably be applied to OTA as a putative renal carcinogen for idiopathic kidney cancer in humans. Already, the rat tumours mimic those occurring spontaneously in the Eker rat, and there is disparity between the large necessary OTA exposure in the rat and the trace amounts of OTA consumed by humans. In all such complex considerations it is important to adhere rigorously to established principles of disease epidemiology.

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1. Boorman GA. Toxicology and carcinogenesis studies of ochratoxin A (CAS No. 303-47-9) in F344/N rats (gavage studies). National Toxicology Program. Technical Report 358.
2. Waddell WJ. Critique of dose response in carcinogenesis. Hum Exp Toxicol. 2006;25:413–66.
3. Mantle P, Kulinskaya E, Nestler S. Renal tumourigenesis in male rats in response to chronic dietary ochratoxin A. Fd add Contam. 2005;22 Suppl 1:58–64.
4. Mally A, Volkel W, Amberg A, Kurz M, Wanek P, Eder E, et al. Functional, biochemical, and pathological effects of repeated oral administration of ochratoxin A to rats. Chem Res Toxicol. 2005;18:1242–52.
5. Mally A, Keim-Heusler H, Amberg A, Kurz M, Zepnik H, Mantle P, et al. Biotransformation and nephrotoxicity of ochratoxin B in rats. Toxicol Appl Pharmacol. 2004;206:43–53.
6. Mantle P, Kulinskaya E. Lifetime, low-dose ochratoxin A dietary study on renal carcinogenesis in Male Fischer rats. Fd Add Contam Part A. 2010;27:1566–73. http://dx.doi.org/10.1080/19440049.2010.502302
7. Harris JP, Mantle PG. Biosynthesis of ochratoxin A by Aspergillus ochraceus. Phytochemistry. 2001;58:709–16.
8. Molony WC, Boschetti AE, King VP. Spontaneous leukemia in Fischer rats. Cancer Res. 1970;30:41–3.
9. EFSA. Opinion of the scientific panel on contaminants in the food chain on a request from the Commission related to ochratoxin A in food. EFSA J. 2006;365:1–56.
10. Mantle PG. Interpretation of the pharmacokinetics of ochratoxin A in blood plasma of rats, during and after acute or chronic ingestion. Fd Chem Toxicol. 2008;46:1808–16. http://dx.doi.org/10.1016/j.fct.2008.01.020
11. Mantle PG. Minimum tolerable exposure period and maximum threshold dietary intake of ochratoxin A for causing renal cancer in male Dark Agouti rats. Fd Chem Toxicol. 2009;47:2419–24. http://dx.doi.org/10.1016/j.fct.2009.05.043
12. Mantle PG, Nicholls AW, Shockcor JP. 1H NMR spectroscopy-based metabolomic assessment of uremic toxicity, with toxicological outcomes, in male rats following an acute, mid-life insult from ochratoxin A. Toxins 2011;3:504–19. http://dx.doi.org/10.3390/toxins3060504
13. Mantle PG, Nolan CC. Pathological outcomes in kidney and brain in male Fischer rats given dietary ochratoxin A, commencing at one year of age. Toxins. 2010;2:1100–10. http://dx.doi.org/10.3390/toxins2051100
14. Mantle PG, Nagy JM. Binding of ochratoxin A to a urinary globulin: a new concept to account for gender difference in rat nephrocarcinogenic responses. Int J Mol Sci. 2008;9:719–35.
15. Mantle PG, McHugh KM, Fincham JE. Contrasting nephropathic responses to oral administration of extract of cultured Penicillium polonicum in rat and primate. Toxins. 2010;2:2083–97. http://dx.doi.org/10.3390/toxins2082083.
16. Brown AL, Odell EW, Mantle PG. DNA ploidy distribution in renal tumours induced in male rats by dietary ochratoxin A. Exp Toxicol Pathol. 2007;59:85–95.
17. Nestler S. Experimental renal ochratoxicosis; a molecular and pathological study in the rat. Ph.D. thesis, University of London, 2007.
18. Mantle PG, Miljkovic A, Udupa V, Dobrota M. Does apoptosis cause renal atrophy in Balkan endemic nephropathy? Lancet. 1998;352:1118–9.
19. Gazinska P, Herman D, Gillett C, Pinder S, Mantle P. Comparative immunohistochemical analysis of ochratoxin A tumourigenesis in rats and urinary tract carcinoma in humans; mechanistic significance of p-S6 ribosomal protein expression. Toxins. 2012;4:643–62. http://dx.doi.org/10.3390/toxins4090643
20. Malir F, Ostry V, Pfohl-Leszkowicz A, Malir J, Toman J. Ochratoxin A: 50 years of research. Toxins. 2016;8:E191. http://dx.doi.org/10.3390/toxins8070191
21. Koch R. Untersuchungen über Bakterien: V. Die Ätiologie der MilzbrandKrankheit, begründet auf die Entwicklungsgeschichte des Bacillus anthracis. Cohns Beitrage zur Biologie der Pflanzen. 1876;2:277–310.
22. Hill AB. The environment and disease: association or causation? 1965. J R Soc Med. 2015;108:32–7.