Perfluoroalkyl Substances (PFAS) Exposure and Preeclampsia Risk: Impaired Angiogenesis Through Suppression of VEGF Signaling

Per- and polyfluoroalkyl substances (PFAS) are linked to preeclampsia (PE), a condition involving abnormal angiogenesis. Prior research on this association has been inconclusive. We investigated the relationship between maternal PFAS exposure and PE risk in Wisconsin. We also examined if PFAS disrupts angiogenesis and, if so, what mechanisms are involved. We conducted a case-control study with 40 PE cases and 40 controls. Maternal serum was analyzed for 38 different PFAS compounds using LC MS/MS. Functional in vitro experiments assessed PFOS effects on angiogenesis and mechanisms. Maternal serum samples from women with PE exhibited significantly higher PFOS and PFHPS concentrations than controls. After adjusting for confounders, each log-scale IQR increase in PFOS and PFHPS concentrations was associated with a 7.18-fold (95% CI: 2.24, 23.0) and 5.40-fold (95% CI: 1.81, 16.1) higher odds of PE, respectively. Furthermore, PFOS and PFHPS were positively associated with sFLT1 levels and the sFLT1/PLGF ratio. In vitro experiments revealed that PFOS exposure impaired HUVEC proliferation, migration, and tube formation, essential processes for angiogenesis. The membrane-based antibody array showed that PFOS decreased expression of multiple angiogenic proteins, including I-TAC, uPAR, VEGFR2, MMP-1, IL-1α, Angiopoietin-2, IL-1β, PECAM-1, TIE-2, and TIMP-2. The qPCR analysis demonstrated that PFOS decreased VEGFR2, the upstream target of VEGF, at the transcriptional level. In conclusion, elevated PFAS, especially PFOS and PFHPS, are linked to increased PE risk. PFOS may suppress angiogenesis via attenuated VEGFR2-mediated signaling, providing a molecular mechanism linking PFAS and PE pathogenesis.