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.