Effects of Fluoride and 8:2 FTOH on β-Cell Calcium Signaling and Insulin Homeostasis: An Exploratory Study

Background/Objectives: Fluoride (F) is widely used in public water fluoridation to prevent dental caries, and an optimal level of F has been linked to improved glucose metabolism in animal models. Per- and polyfluoroalkyl substances (PFAS), including fluorotelomer alcohols (FTOHs), are persistent environmental contaminants with potential effects on pancreatic function. Methods: This in vitro and in vivo study investigated the effects of 8:2 FTOH and F (NaF) on pancreatic β-cells, focusing on Ca²⁺ homeostasis, insulin secretion, and the GPR40 pathway. Results: Results showed that 8:2 FTOH alters Ca²⁺ influx in a dose-dependent, biphasic manner, enhancing it at low doses and inhibiting it at high doses, while F increased Ca²⁺ signaling at high doses. High-dose 8:2 FTOH also downregulated GPR40 protein in βTC-6 pancreatic cells and modulated pathways related to lipid metabolism, endoplasmic reticulum stress, and insulin regulation in the mouse pancreas by proteomic analyses (in vivo). Conclusions: These findings exploratory indicate that both PFAS and F can impact β-cell function through complex mechanisms, potentially affecting Ca²⁺ homeostasis. This work highlights the hormesis effect of F and provides novel insights into the pancreatic effects of environmentally relevant PFAS exposures, emphasizing the need for further mechanistic studies at low, human-relevant doses.