Mechanism of arsenic-induced liver injury in rats revealed by metabolomics and ionomics based approach

Arsenic (As) is an environmental toxicant and human carcinogen, and long-term exposure to As can lead to varying degrees of liver injury. In order to futher explore the mechanism of As-induced liver injury in rats, a rat model of As poisoned was established in this study, and metabolomics and ionomics methods were applied to study the differences of liver metabolites and ion concentrations between As poisoned rats. By metabolomic analysis, a total of 164 differentially expressed metabolites (DEMs) were identified between the As poisoned group and the Contrl(Ctrl) group, in which metabolic pathways such as nicotinate and nicotinamide metabolism, steroid hormone biosynthesis, and taurine and hypotaurine metabolism were significantly enriched. Ionomics results showed that ten ions were elevated in the As poisoned group, including As, cadmium (Cd), mercury (Hg), and manganese (Mn), while lead (Pb) and thallium (Tl) were reduced (p < 0.05). Spearman Correlation analysis of DEMs and differentially ions showed that As, Cd, Hg and Pb were negatively correlated with androstenedione, protoporphyrinogen and estriol, while As was positively correlated with progesterone, Cd and nicotinamide adenine dinucleotide (NAD+), Mn and 5-L-glutamyltaurine. This study revealed the changes in liver metabolites and ions level in As poisoned rats, as well as the relationship between them and the potential mechanisms of As induced liver injury, among them, the steroid hormone biosynthesis pathway plays an important role in arsenic hepatotoxicity.

砷（Arsenic, As）是一种环境毒物与人类致癌物，长期接触砷可引发不同程度的肝损伤。为进一步探究大鼠砷诱导肝损伤的潜在机制，本研究构建了大鼠砷中毒模型，采用代谢组学（metabolomics）与离子组学（ionomics）方法，分析砷中毒组与对照组（Control, Ctrl）大鼠肝脏代谢物及离子浓度的差异。通过代谢组学分析，在砷中毒组与对照组之间共鉴定出164个差异表达代谢物（differentially expressed metabolites, DEMs），其中烟酸与烟酰胺代谢、类固醇激素生物合成、牛磺酸与次牛磺酸代谢等通路显著富集。离子组学结果显示，砷中毒组中有10种离子水平升高，包括砷、镉（Cd）、汞（Hg）与锰（Mn）；而铅（Pb）与铊（Tl）水平显著降低（p < 0.05）。对差异表达代谢物与差异离子进行斯皮尔曼相关性分析发现，砷、镉、汞与铅与雄烯二酮、原卟啉原及雌三醇呈负相关；而砷与孕酮、镉与烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD+）、锰与5-L-谷氨酰牛磺酸呈正相关。本研究揭示了砷中毒大鼠肝脏代谢物与离子水平的变化特征，及其与砷诱导肝损伤潜在机制的关联，其中类固醇激素生物合成通路在砷性肝毒性中发挥重要作用。