阿朴酯颗粒剂对小鼠肝肾组织毒性、血清炎性因子及体液免疫水平的影响

Effects of Apo-ester granules on liver and kidney tissue toxicity, serum inflammatory factors and humoral immunity in mice

  • 摘要: 【目的】观察长期添加阿朴酯颗粒剂对昆明小鼠肝脏、肾脏组织结构与功能及其体液免疫水平的影响,系统评价其安全性,为阿朴酯在畜禽生产中的科学应用提供参考依据。【方法】通过急性毒性试验测定阿朴酯颗粒剂对昆明小鼠的半数致死量(LD50),然后设50% LD50(1.4 g/kg)和80% LD50(2.2 g/kg)作剂量组,以等量生理盐水为空白对照。单次灌胃1.4 g/kg阿朴酯悬浊液后,于灌胃后第4、12、36和60 h及第7和14 d进行眼球采血,用于测定血常规指标;按1.4和2.2 g/kg的剂量分别连续灌胃阿朴酯悬浊液21 d后,分析小鼠体重增重、血清生化指标、尿常规指标及免疫指标的变化情况,并采集小鼠肝脏和肾脏制作石蜡切片进行组织学观察。【结果】阿朴酯颗粒剂对昆明小鼠的LD50为2.74 g/kg,95%置信限为2.69~3.41 g/kg。依据WHO毒性分级标准,阿朴酯颗粒剂属低毒级物质。按1.4 g/kg的剂量单次灌胃阿朴酯悬浊液后,昆明小鼠血液中性粒细胞数量在灌胃后第4 h显著升高(P<0.05,下同),白细胞总数在灌胃后第12和36 h显著升高,淋巴细胞数量在灌胃后第4和12 h极显著升高(P<0.01,下同),红细胞总数和平均红细胞血红蛋白含量在灌胃后第36 h显著升高。以2.2 g/kg的剂量连续灌胃阿朴酯悬浊液21 d后,昆明小鼠的体重增重和平均日增重极显著降低,血清中的碱性磷酸酶活性和尿素含量极显著升高、而谷草转移酶活性和肌酐含量极显著降低;尿液中白细胞数量及蛋白、微白蛋白和酮体含量显著上升;肝脏黄染、淤血,肝索与肝窦紊乱不清,肝细胞碎裂溶解,发生肿胀或坏死;肾脏明显肿大、黄染,肾小体破损消亡,髓质部呈弥漫性出血;血清免疫细胞因子IL-1β、TNF-α和IL-10水平显著或极显著升高,而免疫球蛋白IgM和SIgA浓度显著下降。【结论】阿朴酯颗粒剂属低毒级物质,但高剂量使用可快速升高血细胞数量,破坏小鼠肝肾组织结构并引起功能障碍,且对体液免疫有抑制作用。因此,建议在家禽生产中不可超量或长期添加,尤其拌料时需保证均匀,避免误食高剂量阿朴酯而造成肝肾功能损伤。

     

    Abstract: 【Objective】The effects of long-term addition of Apo-ester(APO)granules on the structure and function of liver,kidney and humoral immunity levels in Kunming mice were investigated,and its safety was systematically evalua-ted,which would provide a reference for the scientific application of APO in livestock and poultry production.【Method】 The median lethal dose(LD50)of APO granules was measured by acute toxicity test on Kunming mice. Then,50% LD50 (1.4 g/kg)and 80% LD50(2.2 g/kg)were set as dose groups and equal amount of saline was used as blank control. After a single gavage of 1.4 g/kg APO suspension,eye blood was collected on the 4th,12th,36th and 60th h and on the 7th d and 14th d after the gavage for the determination of blood routine indexes. After 21 d of continuous gavage of APO suspension at 1.4 and 2.2 g/kg,the weight gain,blood biochemical indexes,urinary indexes immune indexes of mice were analyzed. Besides,the liver and kidney were collected for histological observation in paraffin sections.【Result】The LD50 of APO granules on Kunming mice was 2.74 g/kg with the 95% confidence limit of 2.69-3.41 g/kg. According to the toxicity grading standard of WHO,APO granule was a low-toxicity substance. The blood neutrophils of Kunming mice increased significantly(P<0.05,the same below)at the 4th h after single gavage of APO suspension at a dose of 1.4 g/kg. The total number of white blood cells was significantly increased at 12th and 36th h after gavage,and the number of lymphocytes was extremely significantly increased at 4th and 12th h after gavage(P<0.01,the same below). The total number of erythrocytes and the mean erythrocyte hemoglobin content increased significantly at 36th h after gavage. The body weight gain and mean daily weight gain of Kunming mice were extremely significantly reduced after 21 d of continuous gavage of APO suspension at a dose of 2.2 g/kg. Serum alkaline phosphatase activity and urea content were extremely significantly increased,while tangrass transferase activity and creatinine content were extremely significantly reduced. The number of white blood cells,the levels of urinary microalbumin and ketone body in the urine were increased significantly. Liver yellowing,congestion,disorder of hepatic cord and sinusoids,the fragmentation and dissolution of liver cells even swelling or necrosis were observed. The kidneys were obviously enlarged and yellowish. The renal corpuscle was broken and extinct,and medulla showed diffuse hemorrhage. Serum levels of immune cytokines IL-1β,TNF-α and IL-10 were significantly or extremely significantly increased,while the concentrations of immunoglobulins IgM and SIgA were significantly decreased.【Conclusion】APO granules are low-toxic substances,while high-dose addition can lead to the rapid increase of blood cells,and the tissue structure of liver and kidney in mice can also be damaged. Furthermore,the humoral immunity can be inhibited. Therefore,it is recommended not to add excessive amounts or long-term addition in poultry production. The mixing ingredients should be ensured uniformity to avoid the damage of liver and kidney function through ingesting high doses of APO.

     

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