【摘要】 目的 探讨全氟丁酸暴露对小鼠肾脏产生的毒效应与作用机制，重点分析肾脏代谢的改变及其潜在作用。方法 将无特定病原体级C57BL/6雄性小鼠随机分为对照组、低剂量组和高剂量组，每组10只；分别予剂量为0、35和350 mg/kg体质量的全氟丁酸溶液灌胃，1次/d，连续7 d。观察小鼠肾组织病理学改变情况，采用超高效液相色谱-四极杆-飞行时间质谱法检测小鼠肾脏代谢物，通过人类代谢组学数据库筛选差异代谢物（DAMs）；通过MetaboAnalyst 6.0平台和京都基因与基因组百科全书（KEGG）数据库分析探讨相关代谢通路。结果 肾组织病理学结果显示，低剂量组小鼠肾盂黏膜呈局灶性轻度炎症改变，肾组织结构未见明显损伤；高剂量组小鼠肾盂黏膜炎症反应加重，肾组织出现一定程度的结构破坏。与对照组比较，低剂量组和高剂量组小鼠肾脏脏器系数均下降（P值均<0.05），肾组织Paller评分均增加（P值均<0.05）；高剂量组小鼠肾组织Paller评分高于低剂量组（P<0.05）。代谢组学分析结果显示，低剂量组小鼠肾组织中筛选出46个DAMs(26个上调，20个下调)，高剂量组小鼠肾组织中筛选出104个DAMs(54个上调，50个下调)；2组共有26个共同DAMs。KEGG通路分析结果显示，DAMs主要集中在甘油磷脂、甘油脂、鞘脂和类固醇激素合成等代谢通路中。结论 全氟丁酸急性染毒可导致小鼠肾脏损伤；甘油磷脂和鞘脂代谢等脂质代谢通路可能参与了全氟丁酸急性肾脏毒效应的发生发展。更多还原

【Abstract】 Objective To explore the nephrotoxic effects of exposure to perfluorobutanoic acid(PFBA) and its mechanism in mice, with a particular focus on analyzing the changes in kidney metabolism and their potential implications. Methods The specific pathogen free C57 BL/6 mice were randomly divided into control group, low-dose group, and high-dose group, with 10 mice in each group. Mice in the three groups received intragastric administration of PFBA solution at doses of 0, 35 and 350 mg/kg body weight, once per day for seven consecutive days. The histopathological changes of kidneys of mice in these three groups were evaluated. Metabolomic profiling of mouse kidneys was performed using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Differentially accumulated metabolites(DAMs) were identified based on the Human Metabolome Database, and related metabolic pathways were analyzed through MetaboAnalyst 6.0 and Kyoto Encyclopedia of Genes and Genomes(KEGG). Results Histopathological analysis of kidneys showed that the renal pelvis mucosa of mice in the low-dose group presented focal mild inflammatory changes without marked structural damage, whereas mice in the high-dose group showed severe inflammation and partial destruction of renal structure. The kidney coefficient of mice in both low-dose group and the high-dose group decreased(both P<0.05), and the Paller scores of renal tissues increased(both P<0.05) compared with that in the control group. The Paller score of mouse renal tissue in the high-dose group was higher than that in the low-dose group(P<0.05). Metabolomic profiling identified 46 DAMs(26 upregulated, 20 downregulated) in the lowdose group and 104 DAMs(54 upregulated, 50 downregulated) in the high-dose group, with 26 shared DAMs between the two dose groups. KEGG pathway analysis revealed that DAMs were mainly involved in metabolic pathways such as glycerophospholipid metabolism, glycerolipid metabolism, sphingolipid and steroid hormone synthesis. Conclusion Acute exposure to PFBA can cause kidney injury in mice. Lipid metabolism pathways such as glycerophospholipid and sphingolipid metabolism is involved in the development of acute renal toxicity of PFBA.更多还原