Functional, Biochemical, and Pathological Effects of Repeated Oral Administration of Ochratoxin A to Rats

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• 作者：Angela Mally ; Wolfgang Vö ; lkel ; Alexander Amberg ; Michael Kurz ; Paul Wanek ; Erwin Eder ; Gordon Hard ; and Wolfgang Dekant
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：August 2005
• 年：2005
• 卷：18
• 期：8
• 页码：1242 - 1252
• 全文大小：513K
• 年卷期：v.18,no.8(August 2005)
• ISSN：1520-5010

文摘

Ochratoxin A (OTA), a mycotoxin produced by several fungi of Aspergillus and Penicilliumspecies, may contaminate agricultural products, resulting in chronic human exposure. In rats,OTA is a potent nephrotoxin, and repeated administration of OTA for 2 years to rats in dosesup to 0.21 mg/kg of body wt resulted in high incidences of renal tumors arising from theproximal tubular epithelial cells. The mechanism of tumor formation by OTA in the kidney isnot well-defined, and controversial results regarding mode of action have been published. Theaim of this study was to characterize dose-dependent changes induced by OTA by applicationof clinical chemistry, biochemical markers, and toxicokinetics for a better conclusion on modesof action. Administration of OTA (0, 0.25, 0.5, 1, and 2 mg/kg of body wt) to male F344 rats(n = 3 per group) by oral gavage for 2 weeks resulted in a dose-dependent increase in OTAplasma concentrations and concentrations of OTA in both liver and kidney. Although oxidativestress has been implicated in OTA carcinogenicity, treatment with OTA did not induce overtlipid peroxidation or an increase in 8-oxo-7,8-dihydro-2'deoxyguanosine (8-OH-dG) in kidney.In the kidney, OTA-induced pathology was present at all dose levels administered, with aclear increase in severity related to dose. Pathology was restricted to the outer stripe of theouter medulla and consisted of disorganization of the tubule arrangement, frequent apoptoticcells, and abnormally enlarged nuclei scattered through the S3 tubules. Consistent with thehistopathology, a dose-dependent increase in the expression of proliferating cell nuclear antigen(PCNA), indicative of cell proliferation, was observed in kidneys, but not in livers of treatedanimals. The most prominent change in the composition of urine induced by OTA analyzed by¹H NMR and principal component analysis consisted of a major increase in the excretion oftrimethylamine N-oxide. However, typical changes observed with other proximal tubular toxinssuch as increased excretion of glucose were not observed at any of the doses administered.Similarly, treatment with OTA had no clear effects on clinical chemical parameters indicativeof nephrotoxicity, although urinary volume was increased at the higher-dose groups. Takentogether, the uncommon changes induced by OTA suggest that a unique mechanism may beinvolved in OTA nephrotoxicity and carcinogenicity.