Metabolomic Characterizations of Liver Injury Caused by Acute Arsenic Toxicity in Zebrafish

Arsenic is one of the most common metalloid contaminants in groundwater and it has both acute and chronic toxicity affecting multiple organs. Details of the mechanism of arsenic toxicity are still lacking and profile studies at metabolic level are very limited. Using gas chromatography coupled with mass spectroscopy (GC/MS), we first generated metabolomic profiles from the livers of arsenic-treated zebrafish and identified 34 significantly altered metabolite peaks as potential markers, including four prominent ones: cholic acid, glycylglycine, glycine and hypotaurine. Combined results from GC/MS, histological examination and pathway analyses suggested a series of alterations, including apoptosis, glycogenolysis, changes in amino acid metabolism and fatty acid composition, accumulation of bile acids and fats, and disturbance in glycolysis related energy metabolism. The alterations in glycolysis partially resemble Warburg effect commonly observed in many cancer cells. However, cellular damages were not reflected in two conventional liver function tests performed, Bilirubin assay and alanine aminotransferase (ALT) assay, probably because the short arsenate exposure was insufficient to induce detectable damage. This study demonstrated that metabolic changes could reflect mild liver impairments induced by arsenic exposure, which underscored their potential in reporting early liver injury.砷是地下水中最常见的类金属（metalloid）污染物之一，兼具急性与慢性毒性，可累及多个脏器。目前砷中毒的具体致病机制仍未完全阐明，代谢层面的组学研究也极为匮乏。本研究采用气相色谱-质谱联用（gas chromatography coupled with mass spectroscopy, GC/MS）技术，对砷暴露斑马鱼的肝脏样本进行代谢组谱分析，共鉴定出34个显著差异的代谢物峰作为潜在生物标志物，其中包括4种标志性差异代谢物：胆酸（cholic acid）、甘氨酰甘氨酸（glycylglycine）、甘氨酸（glycine）及亚牛磺酸（hypotaurine）。结合GC/MS检测结果、组织病理学检查与通路富集分析，本研究发现了一系列代谢紊乱事件：包括细胞凋亡（apoptosis）、糖原分解（glycogenolysis）异常、氨基酸代谢与脂肪酸组成改变、胆汁酸与脂肪堆积，以及糖酵解相关能量代谢紊乱。其中糖酵解的异常改变与多种癌细胞中常见的瓦伯格效应（Warburg effect）具有一定相似性。然而，本次检测的两项常规肝功能指标——胆红素测定（bilirubin assay）与丙氨酸氨基转移酶（alanine aminotransferase, ALT）活性检测——均未体现出细胞损伤情况，这可能是由于砷酸盐（arsenate）暴露时长过短，尚未引发可被检测到的肝损伤。本研究证实，代谢组学变化可反映砷暴露诱导的轻度肝损伤，这凸显了其在早期肝损伤预警中的应用潜力。