Rached Eva, Hard Gordon C, Blumbach Kai, Weber Klaus, Draheim Regina, Lutz Werner K, Ozden Sibel, Steger Ulrich, Dekant Wolfgang, Mally Angela
Department of Toxicology, University of Würzburg, Würzburg, Germany.
Toxicol Sci. 2007 Jun;97(2):288-98. doi: 10.1093/toxsci/kfm042. Epub 2007 Mar 6.
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.
赭曲霉毒素A（OTA）具有肾毒性，是一种强效的肾致癌物。雄性大鼠对OTA毒性最为敏感，长期给予OTA（70和210微克/千克体重）两年已显示可诱发近端肾小管直段上皮产生腺瘤和癌的高发生率。相比之下，给予较低剂量21微克/千克体重的处理并未导致肿瘤发生率增加，这表明OTA诱发肾肿瘤存在非线性剂量反应。由于OTA致癌的机制仍很大程度上未知，本研究旨在调查OTA的早期功能和病理影响，并确定肾细胞增殖的持续刺激是否起作用。雄性F344/N大鼠在国家毒理学计划（NTP）生物测定条件下接受OTA处理长达13周。使用溴脱氧尿苷掺入和免疫组织化学法测定肾皮质和外髓质外带（OSOM）中的细胞增殖。组织病理学检查显示，中、高剂量处理的动物肾脏出现改变，包括单细胞死亡以及直近端小管内明显的核肿大。给予70和210微克/千克体重剂量的OTA处理导致肾细胞增殖显著的剂量和时间依赖性增加，从髓放线延伸至OSOM。低剂量处理动物的肾脏或肝脏未观察到明显影响，肝脏不是OTA致癌的靶器官。本研究确定的无观察到有害作用水平为21微克/千克体重，这与NTP两年生物测定中未产生肾肿瘤的剂量相关。OTA诱导的细胞更新增强与肿瘤形成之间的明显相关性表明，细胞增殖的刺激可能在OTA致癌性中起重要作用，并为表观遗传的阈值机制提供了进一步证据。
