Exploring the link between PFASs exposure and gestational diabetes risk within the TRAEC framework

Per- and polyfluoroalkyl substances (PFASs) are environmentally persistent industrial substances with potential health impacts during pregnancy. However, evidence linking PFASs exposure to gestational diabetes mellitus (GDM) remains inconclusive. This study systematically evaluated the PFASs-GDM association using the Toxicological Risk Assessment for Environmental Chemicals (TRAEC) strategy. A systematic literature search was conducted using PubMed and Web of Science to identify epidemiological studies, animal models, and cell-based experiments. To validate the evidence, we performed targeted mouse experiments on gestational exposure to typical PFASs. The TRAEC strategy assessed the reliability, correlation, and risk intensity of the evidence sources. The evaluation integrated findings from 36 studies on nine PFASs subtypes and GDM risk. Our mouse experiments showed that prenatal perfluorononanoic acid (PFNA) exposure increased baseline blood glucose levels, impaired glucose tolerance, and reduced insulin sensitivity, confirming epidemiological observations. The TRAEC evaluation revealed a significant correlation between PFASs exposure and GDM risk, with moderate-strength evidence across study designs. Perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and PFNA exhibited the strongest associations. By integrating epidemiological, animal, and mechanistic evidence via a standardized framework, this study robustly confirms PFASs exposure elevates GDM risk, highlighting the need for public health interventions to protect maternal-fetal metabolic health.