DataSheet4_Integration of Transcriptomic and Metabolomic Data to Compare the Hepatotoxicity of Neonatal and Adult Mice Exposed to Aristolochic Acid I.CSV

Aristolochic acid (AA) is a group of structurally related compounds what have been used to treat various diseases in recent decades. Aristolochic acid I (AAI), an important ingredient, has been associated with tumorigenesis. Recently, some studies indicated that AAI could induce liver injury in mice of different age, but comprehensive mechanisms of AAI-induced differences in liver injury in various age groups have not yet been elucidated. This study aims to evaluate the causal relationship between AAI-induced liver injury and age based on neonatal mice and adult mice. A survival experiment indicated that all neonatal mice survived. Moreover, the adult mice in the high-dose AAI group all died, whereas half of the adult mice in the low-dose AAI group died. In observation experiments, AAI induced more severe liver injury in neonatal mice than adult mice under long-term than short-term exposure. Furthermore, integrated metabolomics and transcriptomics indicated that AAI disturbing steroid hormone biosynthesis, arachidonic acid metabolism, the drug metabolism-cytochrome P450 pathway and glycerophospholipid metabolism induced neonatal mice liver injury. The important role of age in AAI-induced liver injury was illustrated in our study. This study also lays a solid foundation for scientific supervision of AA safety.

马兜铃酸（Aristolochic acid, AA）是一类结构相似的化合物，近数十年来被用于多种疾病的治疗。其中马兜铃酸I（Aristolochic acid I, AAI）作为关键组分，被证实与肿瘤发生密切相关。近期有研究表明，AAI可在不同年龄段的小鼠中诱发肝损伤，但目前尚未阐明不同年龄段小鼠AAI诱导肝损伤存在差异的完整机制。本研究以新生小鼠与成年小鼠为研究对象，旨在明确AAI诱导肝损伤与年龄之间的因果关联。生存实验结果显示，所有新生小鼠均存活；而高剂量AAI组的成年小鼠全部死亡，低剂量AAI组的成年小鼠则有半数死亡。在观察实验中，相较于短期暴露，长期暴露条件下AAI对新生小鼠造成的肝损伤程度显著高于成年小鼠。此外，整合代谢组学（metabolomics）与转录组学（transcriptomics）分析结果显示，AAI通过干扰类固醇激素生物合成、花生四烯酸代谢、药物代谢-细胞色素P450（cytochrome P450）通路以及甘油磷脂代谢，诱发新生小鼠肝损伤。本研究阐明了年龄在AAI诱导肝损伤过程中的重要作用，同时为马兜铃酸安全性的科学监管奠定了坚实基础。