Exposure to per- and polyfluoroalkyl substances as a risk factor for gestational diabetes mellitus through interference with glucose homeostasis.

Per- and polyfluoroalkyl substances (PFASs) are hypothesized to trigger gestational diabetes mellitus (GDM) through modulation of glucose metabolism. However, studies investigating links between joint PFASs to GDM are limited and led to discrepant conclusions. This study included 171 women with GDM development in pregnancy and 169 healthy controls from Hangzhou, China between October 2020 and September 2021. By using the solid-phase extraction (SPE)-ultra performance liquid chromatography-tandem-mass-spectrometry (UPLC/MS-MS), 15 PFASs were detected to be widely distributed in maternal serum, with highest median concentrations of 7.43, 4.23, and 3.64 ng/mL for perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and 6:2 chlorinated polyfluorinated ether sulfonates (6:2 Cl-PFESA). Multivariable logistic regressions suggested that the adjusted odds ratios (ORs) with 95% confidence intervals (CI) of GDM for second and highest tertiles of PFOA were 2.57 (1.24, 4.86), p = 0.001 and 1.98 (1.06, 3.65), p = 0.023. Compared with the reference tertile, the ORs of GDM were also significantly increased at the highest tertile of perfluoroundecanoic acid (PFUnDA), perfluorododecanoic acid (PFDoA), PFOS and 6:2Cl-PFESA. Multiple linear regressions further indicated that exposure to these PFASs congeners were positively associated with continuous glycemic outcomes of fasting blood glucose (FBG), 1-h, and 2-h glucose after 75 g oral glucose tolerance (OGTT) test as well as glycohemoglobin (HbA1c). Nevertheless, perfluorohexane sulfonic acid (PFHxS), 4:2 fluorotelomer sulfonates (FTSs), and 3H-perfluoro-3-[(3-methoxy-propoxy) propanoic acid] (ADONA) exhibited protective effects on some of these glycemic outcomes. When assessing the PFASs as mixtures by conducting the Bayesian kernel machine regression (BKMR), the risks of GDM and values of glycemic outcomes increased significantly as the concentrations of the PFASs mixture increased, with PFOA being the largest contributor. We therefore propose that although the effects on glucose homeostasis varied between different PFAS congeners, the elevated combined exposures to PFASs may be associated with substantially increased GDM risks by altering glucose metabolism.