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

Abstract

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.

Detection and Removal of Aristolochic Acid in Natural Plants, Pharmaceuticals, and Environmental and Biological Samples: A Review

“…Additionally, Shi et al investigated the effects of sex and age on the carcinogenic capacity of AAs and found that female patients had a lower rate of renal failure due to the inhibitory effect of 17-estradiol on AAN. When exposure was prolonged, AAI caused more severe liver damage in newborn mice than in adult mice [ 16 ]. AAs not only have a high mortality rate but also accumulate in the environment and indirectly enter the human body through the food chain, leading to a range of diseases.…”