Long-term arsenic exposure decreases mice body weight and liver lipid droplets

Arsenic (As) is a widespread global pollutant, and there is significant controversy surrounding its complex relationship with obesity, primarily focused on short-term exposure. Recognizing the prolonged nature of dietary arsenic exposure, this study involved feeding mice with arsenic-contained food for 14 months. The results showed that mice exposed to arsenic developed a non-alcoholic fatty liver condition, characterized by a light-yellow hue on the liver surface and various pathological alterations in the liver cells, including enlarged nuclei, cellular necrosis, inflammatory infiltration, dysfunctional mitochondria, and endoplasmic reticulum disorganization. There were also disruptions in biochemistry indices, with a significant increase in total cholesterol (TC) level and a decrease in high-density lipoprotein (HDL) level. However, some contradictory observations occurred, such as a significant decrease in body weight, triglyceride (TG) level, and the numbers of lipid droplets. Several genes related to lipid metabolism were tested, and a model was used to explain these discrepancies. Besides, examinations of the colon revealed compromised intestinal barrier function and signs of inflammation. Fecal 16S rRNA sequencing and pseudo-targeted metabolomics revealed disruptions in internal homeostasis, such as modules, nodes, connections, and lipid-related KEGG pathways. Fecal targeted metabolomics analyses of short-chain fatty acids (SCFAs) and bile acids (BAs) demonstrated a significant upregulation in three primary bile acids (CA, CDCA, TCDCA), four secondary bile acids (TUDCA, DCA, LCA, GUDCA), and total SCFAs level. Oxidative stress and inflammation were also evident. Additionally, based on correlation analysis and mediation analysis, it was assumed that changes in the microbiota (e.g., Dubosiella) can impact the liver metabolites (e.g., TGs) through alterations in fecal metabolites (e.g., LPCs). These findings provide a theoretical reference for the long-term effect of arsenic exposure on liver lipid metabolism.