Maternal PFOS Exposure Impairs β‑Cell Insulin Secretion and Glucose Tolerance in Rats.

Perfluorooctanesulfonic acid (PFOS) is epidemiologically linked to gestational diabetes mellitus (GDM), but the mechanisms remain undefined. We hypothesized that PFOS exposure impairs pancreatic β-cell function through mitochondrial dysfunction and deficits in ATP/cAMP signaling. Pregnant and non-pregnant rats received PFOS (50 μg/mL in drinking water) for 17 days (gestation day [GD] 4-20 in pregnant dams). PFOS-exposed pregnant dams exhibited fasting hypoinsulinemia (65% decrease) with normal fasting glucose. Glucose tolerance was impaired (31% increase in glucose AUC), with blunted insulin secretion (52% decrease in insulin AUC). In contrast, non-pregnant PFOS-exposed rats showed no changes in fasting glucose or insulin but developed glucose intolerance (25% increase in glucose AUC) with only modest early insulin suppression, revealing greater vulnerability in pregnancy. Pancreatic islet morphology and insulin content remained unchanged in PFOS-exposed dams. Isolated islets from PFOS-exposed dams and INS-1 β-cells treated with PFOS (10-100 μM) showed reduced glucose-stimulated insulin secretion despite normal Ins1 and Ins2 expression and insulin content. In INS-1 cells, PFOS selectively reduced Complex II subunits, depleted ATP (32-39%) and cAMP (57-74%), and impaired insulin secretion under low and high glucose. Co-treatment with the mitochondria-targeted antioxidant MitoQ (0.1μM) fully restored ATP, cAMP, and insulin secretion to control levels. These findings demonstrate that PFOS exposure causes gestational glucose intolerance and β-cell secretory failure, accompanied by reduced mitochondrial Complex II subunit abundance and ATP/cAMP depletion. The complete rescue by MitoQ highlights oxidative mitochondrial dysfunction as a mechanistic contributor linking PFOS exposure and GDM risk.