Mally Angela, Völkel Wolfgang, Amberg Alexander, Kurz Michael, Wanek Paul, Eder Erwin, Hard Gordon, Dekant Wolfgang
Department of Toxicology, University of Würzburg, Germany.
Chem Res Toxicol. 2005 Aug;18(8):1242-52. doi: 10.1021/tx049651p.
Ochratoxin A (OTA), a mycotoxin produced by several fungi of Aspergillus and Penicillium species, 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 doses up to 0.21 mg/kg of body wt resulted in high incidences of renal tumors arising from the proximal tubular epithelial cells. The mechanism of tumor formation by OTA in the kidney is not well-defined, and controversial results regarding mode of action have been published. The aim of this study was to characterize dose-dependent changes induced by OTA by application of clinical chemistry, biochemical markers, and toxicokinetics for a better conclusion on modes of 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 OTA plasma concentrations and concentrations of OTA in both liver and kidney. Although oxidative stress has been implicated in OTA carcinogenicity, treatment with OTA did not induce overt lipid 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 a clear increase in severity related to dose. Pathology was restricted to the outer stripe of the outer medulla and consisted of disorganization of the tubule arrangement, frequent apoptotic cells, and abnormally enlarged nuclei scattered through the S3 tubules. Consistent with the histopathology, 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 treated animals. The most prominent change in the composition of urine induced by OTA analyzed by 1H NMR and principal component analysis consisted of a major increase in the excretion of trimethylamine N-oxide. However, typical changes observed with other proximal tubular toxins such 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 indicative of nephrotoxicity, although urinary volume was increased at the higher-dose groups. Taken together, the uncommon changes induced by OTA suggest that a unique mechanism may be involved in OTA nephrotoxicity and carcinogenicity.
赭曲霉毒素A（OTA）是由曲霉属和青霉属的几种真菌产生的一种霉菌毒素，可能会污染农产品，导致人类长期接触。在大鼠中，OTA是一种强效肾毒素，以高达0.21mg/kg体重的剂量给大鼠重复给药2年，导致近端肾小管上皮细胞产生肾肿瘤的发生率很高。OTA在肾脏中形成肿瘤的机制尚不清楚，关于作用方式已发表了有争议的结果。本研究的目的是通过应用临床化学、生化标志物和毒代动力学来表征OTA诱导的剂量依赖性变化，以便更好地推断作用方式。通过口服灌胃给雄性F344大鼠（每组n = 3）给予OTA（0、0.25、0.5、1和2mg/kg体重）2周，导致OTA血浆浓度以及肝脏和肾脏中OTA浓度呈剂量依赖性增加。尽管氧化应激与OTA致癌性有关，但用OTA处理并未诱导明显的脂质过氧化或肾脏中8-氧代-7,8-二氢-2'-脱氧鸟苷（8-OH-dG）增加。在肾脏中，在所有给药剂量水平均出现OTA诱导的病理学变化，且严重程度与剂量呈明显正相关。病理学变化局限于外髓质的外带，表现为肾小管排列紊乱、频繁出现凋亡细胞以及S3肾小管中散在的核异常增大。与组织病理学一致，在处理动物的肾脏中观察到增殖细胞核抗原（PCNA）表达呈剂量依赖性增加，表明细胞增殖，但在肝脏中未观察到。通过1H NMR和主成分分析分析，OTA诱导的尿液成分最显著变化是三甲胺N-氧化物排泄大幅增加。然而，在任何给药剂量下均未观察到其他近端肾小管毒素常见的变化，如葡萄糖排泄增加。同样，尽管高剂量组尿量增加，但OTA处理对指示肾毒性的临床化学参数没有明显影响。综上所述，OTA诱导的不常见变化表明，OTA肾毒性和致癌性可能涉及独特的机制。
