Exposure to Perfluorooctanoic Acid Perturbs Serotonin Signaling in Maternal Pancreatic Islets and Induces Gestational Diabetes in Mice

Abstract Perfluorooctanoic acid (PFOA) is linked to adverse pregnancy outcomes including gestational diabetes in humans. The mechanisms by which PFOA contributes to gestational diabetes are understudied. The present study investigated whether PFOA exposure resulted in lower pancreatic islet serotonin abundance and β-cell proliferation, cellular events that are causally associated with gestational diabetes in mice. The study also tested whether exposure adversely influenced glucose tolerance, insulin secretion, and insulin sensitivity. The purpose of this study was to assess whether PFOA exposure impairs pancreatic islet serotonin-driven β-cell proliferation and causes gestational diabetes in C57BL/6J mice. Adult female C57BL/6J mice were fed 5 μg PFOA/kg body weight/day for 2 weeks prior to mating through gestation. Pancreatic islet serotonin abundance and β-cell proliferation were measured by immunofluorescence. Metabolic assays, including glucose tolerance test, glucose-stimulated insulin secretion, and insulin tolerance test were used to characterize gestational diabetes-like phenotypes. Bulk RNA sequencing was used to analyze differentially expressed genes and gene set enrichment in pancreatic islets isolated from control and PFOA-exposed pregnant mice. PFOA exposure lowered islet serotonin abundance and β-cell proliferation in gestational day (GD) 12.5 pregnant dams. No differences in glucose tolerance were observed at GD12.5. Investigation at later gestation (GD16.5) revealed that PFOA exposure was associated with glucose intolerance, impaired insulin secretion, and greater insulin resistance in dams. β-Cell proliferation at GD12.5 and glucose tolerance at GD16.5 was improved in PFOA-exposed dams treated with a serotonin receptor 2B agonist (BW-723C86). RNA-seq identified four differentially expressed genes and broad reductions in coordinated transcriptional pathway activity in maternal pancreatic islets of PFOA-exposed GD12.5 dams. Lower pancreatic islet serotonin abundance in PFOA-exposed pregnant mice was causally linked to gestational diabetes.