Perfluorooctane sulfonate-induced oxidative stress contributes to pancreatic ll-cell apoptosis by inhibiting cyclic adenosine monophosphate pathway: Prevention by pentoxifylline

Endocrine-disrupting chemical perfluorooctane sulfonate (PFOS) acute exposure stimulates insulin secretion from pancreatic ll-cells. However, chronic exposure to PFOS on pancreatic ll-cells, its role in insulin secretion, and the underlying mechanisms have not been studied. We used rat insulinoma INS-1 and human 1.1b4 islet cells to investigate the chronic effects of PFOS on glucose-stimulated insulin secretion and toxicity implicated in the downregulation of ll-cell functionality. Chronic exposure of INS-1 cells or human pancreatic 1.1b4 ll-cells to PFOS stimulated the small G-protein RAC1-guanosine triphosphate-dependent nicotinamide adenine dinucleotide phosphate oxidase (NOX2/gp91phox) subunit expression and activation. Upregulated NOX2/gp91phox activa-tion led to elevated reactive oxygen species (ROS) production with a decrease in the cyclic adenosine mono-phosphate/protein kinase A (cAMP/PKA) pathway in both cell types. Inhibition of cAMP/PKA signaling induces ll-cell mitochondrial dysfunction and endoplasmic stress via the loss of PDX1-SERCA2B and glucose-stimulated insulin release. Inhibiting RAC1-NOX2/gp91phox activation or elevating cAMP by pentoxifylline, a Food and Drug Administration-approved phosphodiesterase inhibitor, significantly reduced PFOS-induced ROS production and restored insulin secretory function of pancreatic ll-cells. Enhanced secretory function in pentoxifylline-treated cells was associated with increased stability of PDX1-SERCA2B protein levels. Intriguingly, inhibition of cAMP/PKA signaling impaired pentoxifylline-induced insulin secretion caused by the activation of ROS production and mitochondrial dysfunction. Overall, our findings show that PFOS has a new and first-ever direct chronic effect on pancreatic ll-cell failure through increased RAC1-NOX2/gp91phox activation and pentoxifylline-induced cAMP/PKA signaling, which inhibits PFOS-mediated mitochondrial dysfunction.

Automated summary

Chronic exposure to perfluorooctane sulfonate (PFOS) stimulates insulin secretion from pancreatic β-cells through the activation of RAC1-NOX2/gp91phox and inhibition of cAMP/PKA signaling, resulting in mitochondrial dysfunction and endoplasmic stress. Inhibition of RAC1-NOX2/gp91phox activation or elevation of cAMP levels restores insulin secretory function. However, inhibition of cAMP/PKA signaling impairs pentoxifylline-induced insulin secretion. Overall, our study reveals the direct chronic effect of PFOS on β-cell failure and suggests potential therapeutic targets for PFOS-induced β-cell dysfunction.