[Impact of arsenic exposure on the hepatic metabolic molecular network in obese pregnant mice using metabolomics and proteomics]

Abstract

Arsenic is a ubiquitous environmental toxin that can affect normal physiological processes. Although the health impacts of arsenic have been investigated, its influence on hepatic metabolism in obese pregnant women and the underlying mechanisms remain unclear. Multi-omics analysis, including metabolomics and proteomics, can improve the understanding of arsenic-induced hepatotoxicity in obese pregnant women. This study aimed to investigate the adverse effects of gestational arsenic exposure on hepatic metabolism in high-fat-diet-induced obese pregnant mice. Following arsenic exposure during pregnancy, the liver tissue was evaluated comprehensively using metabolomics and proteomics techniques combined with pathological and biochemical analyses. Arsenic exposure not only significantly increased lipid accumulation in the livers of obese pregnant mice but also elevated inflammatory factors and oxidative stress markers. Specifically, histopathological examination revealed more steatosis, inflammatory cell infiltration, and hepatocyte ballooning in the livers of arsenic-exposed mice than in those of controls. These changes indicate that arsenic exposure exacerbates hepatic lipid accumulation and induces liver damage in the context of obesity. Metabolomic analysis provided further insight into the metabolic-level disruption caused by arsenic exposure. Significant changes were observed in lipid metabolism pathways, particularly the arachidonic acid metabolism pathway. As arachidonic acid and its metabolites play important roles in inflammation and oxidative stress, this pathway may be critical in arsenic-induced hepatotoxicity. Additionally, proteomic analysis showed differences in the expression levels of several key proteins involved in lipid synthesis, oxidative stress, and inflammatory response. Notably, oxidative-stress-related proteins, including glutathione peroxidase 4 (GPX4), were upregulated, suggesting an increased oxidative burden. In summary, there are complex interaction mechanisms among arsenic exposure, inflammatory response, and related lipid metabolism. The integration of metabolomics and proteomics aided in clarifying the molecular alterations induced by arsenic. The results show that arsenic exposure significantly affects hepatic lipid metabolism in obese pregnant mice through multiple metabolic pathways and protein regulatory mechanisms. In addition to providing new insights into the relationship between arsenic exposure and obesity as well as related metabolic diseases, this study can act as a reference for environmental health risk assessment and the formulation of public health policies. This enhanced understanding of the adverse effects of arsenic on hepatic metabolism will contribute to the development of strategies for mitigating the health risks associated with environmental toxins, particularly for vulnerable groups such as obese pregnant women.

Keywords: arsenic; liver; metabolomics; obesity; pregnant mice; proteomics.

图1. 砷暴露对(a)肥胖孕鼠体重变化系数、肝脏系数(n=11)与(b)血清生化指标(n=11)的影响以及(c)砷暴露小鼠肝脏组织病理染色和免疫组化染色结果

图2. (a)肝脏蛋白组的OPLS-DA及999次置换检验结果,(b)对照和砷暴露组差异蛋白的火山图,(c)差异蛋白质的富集分析结果,(d)蛋白相互作用网络分析结果

图3. (a)肝脏代谢组的OPLS-DA及999次置换检验结果,对照组和砷暴露组差异代谢物的(b)火山图及(c)分类饼图,(d)差异代谢物的KEGG富集结果

图4. 砷暴露影响肥胖孕鼠肝脏的脂质代谢通路