Work

Fluoride caused injury to endothelial cells by disrupting cholesterol synthesis

Year: 2025

Type: article

Abstract: Fluoride has been identified as an important risk factor for cardiovascular disease, with endothelial cell dysfunction serving as a critical initiating event in its onset and progression. As cholesterol serves as an essential structural component of the endothelial cell membrane, alterations in cholesterol levels can significantly compromise endothelial function. However, the precise mechanisms underlying fluoride-induced cholesterol dysregulation in endothelial cells remain poorly understood. Through a well-established fluorosis mouse model, we observed that fluoride lead to significant detachment and pathological alterations of endothelial cells in mouse aorta. Transcriptomic profiling and enrichment analysis revealed that fluoride disrupted cholesterol biosynthesis pathway in HUVECs, particularly through downregulation of two key enzymes, HMGCR and CYP51A1. Subsequent validation experiments confirmed reductions in TC, HDL-C and LDL-C levels in mouse serum, accompanied by decreased expression of HMGCR and CYP51A1 in both mouse aortic endothelial cells and HUVECs. The reduction of cholesterol synthesis in fluoride induced endothelial injury was regulated by miR-200c-3p, a key regulator involved in fluorosis. To further substantiate the effect of fluoride on cholesterol levels, we conducted an epidemiological investigation and found a significant decrease in serum HDL-C levels and an elevated TG/HDL-C ratio in the population. In conclusion, this study demonstrated that fluoride exposure impaired endothelial cells by disrupting cholesterol synthesis, and fluoride induced dyslipidemia in populations may represent a potential mechanism underlying fluoride associated cardiovascular diseases, which may provide a new perspective on the mechanism of cardiovascular system injury caused by fluoride.

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2025.119160