Ochratoxin A: 13-Week Oral Toxicity and Cell Proliferation in Male F344/N Rats

Abstract

Ochratoxin A (OTA) is nephrotoxic and a potent renal carcinogen. Male rats are most susceptible to OTA toxicity, and chronic administration of OTA (70 and 210 microg/kg bw) for 2 years has been shown to induce high incidences of adenomas and carcinomas arising from the straight segment of the proximal tubule epithelium. In contrast, treatment with a lower dose of 21 microg/kg bw did not result in increased tumor rates, suggesting a nonlinear dose response for renal tumor formation by OTA. Since the mechanism of OTA carcinogenicity is still largely unknown, this study was conducted to investigate early functional and pathological effects of OTA and to determine if sustained stimulation of renal cell proliferation plays a role. Male F344/N rats were treated with OTA for up to 13 weeks under conditions of the National Toxicology Program (NTP) bioassay. Cell proliferation in the renal cortex and outer stripe of the outer medulla (OSOM) was determined using bromodeoxyuridine incorporation and immunohistochemistry. Histopathological examination showed renal alterations in mid- and high-dose-treated animals involving single-cell death and prominent nuclear enlargement within the straight proximal tubules. Treatment with OTA at doses of 70 and 210 microg/kg bw led to a marked dose- and time-dependent increase in renal cell proliferation, extending from the medullary rays into the OSOM. No effects were evident in kidneys of low-dose-treated animals or in the liver, which is not a target for OTA carcinogenicity. A no observed effect level in this study was established at 21 microg/kg bw, correlating with the dose in the NTP 2-year bioassay that did not produce renal tumors. The apparent correlation between enhanced cell turnover and tumor formation induced by OTA indicates that stimulation of cell proliferation may play an important role in OTA carcinogenicity and provides further evidence for an epigenetic, thresholded mechanism.

Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies

“…S2). These results are consistent with a previous toxicity study of orally administering OTA for 13 weeks 5 .…”

“…In addition, the differences of the serum biochemical indexes at 13 weeks were higher in high-dose (compared to control) livers than medium-dose (compared to control) livers. Medial-dose OTA does not have impact on the serum chemical or histopathological indexes, which is consistent with OTA studies [4][5][6] . Nonetheless, the derivatives found in the liver indicates that OTA must be metabolized in order to act as a carcinogen 26 .…”

Molecular Characterization of Preneoplastic Lesions Provides Insight on the Development of Renal Tumors

“…Comparable findings were described in F344 rats treated with the same dose regimen, 28,29,40 thus confirming comparable sensitivity of Eker rats to OTA nephrotoxicity.…”

Ochratoxin A kinetics: A review of analytical methods and studies in rat model

“…The main difference between Zepnik et al (2003) and the aforementioned studies is that an acidification step was not used in the extraction method (see "Analytical techniques for ochratoxin A toxicokinetic studies" section). However, when the same analytical method was applied in samples from repeated dose studies (Mally et al, 2005;Rached et al, 2007), similar levels of OTA were found between both organs. The authors explained the similar concentration between both organs at higher doses as being due to an effect of redistribution and deposition of OTA in all lipid-rich organs.…”