Liver Proteomic Alterations Induced by Chronic Fluoride Exposure in Type 2 Diabetic Mice: An Exploratory Study

Water fluoridation is recognized as one of the major public health achievements of the 20th century due to its effectiveness in reducing dental caries. Recommended fluoride concentrations in drinking water (0.7-1.5 mgF/L) aim to maximize dental benefits while minimizing adverse effects. The liver plays a central role in detoxification and lipid metabolism, and recent studies suggest that fluoride exposure may disrupt lipid metabolic pathways. This exploratory study evaluated alterations in hepatic morphology, lipid profile, and liver proteome in type 2 diabetic mice chronically exposed to fluoride. Diabetic C57BL/6J mice received a high-fat diet throughout the experimental period and drinking water containing fluoride (0, 10, or 50 mgF/L) for 21 days, whereas nondiabetic control mice were maintained on a normocaloric diet with fluoride-free water. Liver fluoride levels were significantly higher in the high-dose group than in the other groups. High-dose fluoride reduced serum TG and VLDL levels compared with diabetic and nondiabetic controls, whereas low-dose fluoride increased LDL levels compared to nondiabetic controls. Hepatic glycogen content was reduced in the low-dose group. Proteomic analysis revealed overall downregulation of lipid metabolism-associated proteins in the low-dose group and upregulation of these proteins in the high-dose group. Comparison between groups showed a predominant downregulation of proteins related to mitochondrial and peroxisomal lipid oxidation. Altogether, these findings highlight a dose-dependent metabolic response to chronic fluoride exposure and suggest that fluoride may modulate lipid handling and metabolic flexibility in mice with type 2 diabetes.