Gouze Marie-Estelle, Laffitte Joëlle, Pinton Philippe, Dedieux Geneviève, Galinier Anne, Thouvenot Jean-Paul, Loiseau Nicolas, Oswald Isabelle P, Galtier Pierre
Laboratoire de Pharmacologie-Toxicologie, UR66, INRA, 180 Chemin de Tournefeuille, 31931 Toulouse, France.
Vet Res. 2007 Jul-Aug;38(4):635-46. doi: 10.1051/vetres:2007022. Epub 2007 Jun 13.
Nivalenol (NIV) is a toxic Fusarium secondary trichothecene metabolite occurring naturally in cereal grains. In order to evaluate the no observed adverse effect level (NOAEL), we tested the effects of a large array of oral doses of this toxin for responses on plasma biochemistry, the immune system and hepatic drug metabolism in mice. C57Bl6 mice received oral doses of toxin (0.014, 0.071, 0.355, 1.774 or 8.87 mg/kg bw) 3 days a week for 4 weeks. Only the highest dose of NIV induced an increase in plasma phosphate, decreases in plasma urea and immunoglobulin M and additional changes like increases in plasma alkaline phosphatase and immunoglobulin G. Interleukin 4 production was increased in cultured murine splenocytes. Regarding liver drug metabolising enzymes, the only glutathione transferase activity accepting 1-chloro-2,4-dinitro-benzene as substrate was transiently increased in mice receiving low doses (0.071 and 0.355 mg/kg bw) of NIV. Regarding the cytochrome P450 monooxygenases, no significant change was observed in ethoxyresorufin O-deethylase activity whereas both methoxyresorufin and pentoxyresorufin O-dealkylase activities were decreased by 38-45% for the highest dose (8.87 mg/kg bw) of NIV. However, when analysed by Western blot analysis, the protein expression of mouse P450 1a, 2b, 2c, 3a and 4a subfamilies was unchanged in animals receiving NIV. In conclusion, the NOAEL of this toxin in our study was 1.774 mg/kg bw, corresponding to an exposure to 5 ppm contaminated food. Indeed hepatotoxicity appears in the only mice treated with a five fold higher oral dose of 8.87 mg/kg bw of NIV. Such exposure levels appear to be by far higher than the maximal natural occurrence measured in European cereals, known to range from 0.34 to 1.86 ppm.
雪腐镰刀菌烯醇（NIV）是一种有毒的镰刀菌次生单端孢霉烯族毒素代谢产物，天然存在于谷物中。为了评估无观察到有害作用水平（NOAEL），我们测试了一系列口服剂量的这种毒素对小鼠血浆生物化学、免疫系统和肝脏药物代谢的影响。C57Bl6小鼠每周3天接受口服毒素剂量（0.014、0.071、0.355、1.774或8.87毫克/千克体重），持续4周。只有最高剂量的NIV导致血浆磷酸盐增加、血浆尿素和免疫球蛋白M降低，以及血浆碱性磷酸酶和免疫球蛋白G增加等其他变化。培养的小鼠脾细胞中白细胞介素4的产生增加。关于肝脏药物代谢酶，在接受低剂量（0.071和0.355毫克/千克体重）NIV的小鼠中，唯一以1-氯-2,4-二硝基苯为底物的谷胱甘肽转移酶活性短暂增加。关于细胞色素P450单加氧酶，乙氧异吩唑酮O-脱乙基酶活性未观察到显著变化，而最高剂量（8.87毫克/千克体重）的NIV使甲氧基异吩唑酮和戊氧基异吩唑酮O-脱烷基酶活性降低了38 - 45%。然而，通过蛋白质免疫印迹分析，在接受NIV的动物中，小鼠P450 1a、2b、2c、3a和4a亚家族的蛋白质表达没有变化。总之，在我们的研究中，这种毒素的NOAEL为1.774毫克/千克体重，相当于接触5 ppm受污染的食物。实际上，只有用五倍高的口服剂量8.87毫克/千克体重的NIV处理的小鼠出现了肝毒性。这种暴露水平似乎远高于在欧洲谷物中测量到的最大自然发生率，已知其范围为0.34至1.86 ppm。
