基于UPLC-MS研究纳米二氧化钛对成年小鼠血浆代谢谱的影响

Investigation on the effect of nano-TiO_(2) on the plasma metabolic spectrum in mice based on UPLC-MS

目的:观察不同染毒剂量的纳米二氧化钛(TiO_(2))对C57BL/6成年小鼠血浆代谢谱的变化,探讨其产生毒性效应可能的作用机制,并尝试寻求其毒性相关生物靶点。方法:运用纳米TiO_(2)制备不同染毒剂量的小鼠模型,将小鼠随机分为对照组及10,30,100和300 mg·kg^(-1)组。利用UPLC-MS技术结合主成分分析、偏最小二乘分析等方法对血浆数据进行分析,鉴定出潜在生物标志物,通过变量对模型的重要性(variable important in projection, VIP)及非参数检验筛选差异代谢物;运用Pathway Analysis数据库对差异标志物进行拓扑分析。结果:从血浆中筛选出35种差异代谢物,发现纳米TiO_(2)发挥干预作用可能与亚油酸代谢、鞘脂代谢、缬氨酸、亮氨酸和异亮氨酸的生物合成、组氨酸代谢、花生四烯酸代谢、烟酸酯和烟酰胺代谢、甘油磷脂代谢等通路有关。结论:纳米TiO_(2)经过28 d染毒后,所产生的毒性作用机制可能与体内氨基酸代谢、脂质类代谢异常相关。

Objective: To investigate the changes of the plasma metabolic spectrum of C57 BL/6 young mice treated with different doses of nano-TiO_(2), explore the possible mechanism of its toxic side effects, and identify its toxicity-related biological targets. Methods: Mice were randomly assigned to receive nano-TiO_(2) at doses of 0(control group), 10, 30, 100, or 300 mg·kg^(-1). The plasma data were analyzed using UPLC-MS technology combined with principal component and partial least squares analyses. The results revealed differences between the control group and each nano-TiO_(2) group, with the effect becoming more pronounced with increasing doses. Topological analysis of the different metabolites was conducted using the Pathway Analysis database. Results: In total, 35 different metabolites were screened from plasma, and Nano-TiO_(2) treatment was revealed to affect linoleic acid metabolism, biosynthesis of valine, leucine and isoleucine, sphingolipid metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism, histidine metabolism, and other pathways. Conclusion: The results indicated that the toxicity mechanism of Nano-TiO_(2) after 28 days of exposure may be related to abnormal amino acid and lipid metabolism.