Per- and polyfluoroalkyl substances are associated with reduced cumulus cell MFN1 expression and lower oocyte maturation rates

Purpose: To determine whether per- and polyfluoroalkyl substances (PFAS) are detectable in human follicular fluid (FF) and to evaluate their association with cumulus cell (CC) expression of Mitofusin-1 ( MFN1 ), a mitochondrial fusion gene linked to fertility, as well as selected assisted reproductive technology (ART) outcomes. Methods: This cross-sectional study included reproductive-aged women undergoing oocyte retrieval for IVF/ICSI. FF and CCs were collected at retrieval. Concentrations of 24 PFAS were measured in FF by liquid chromatography-mass spectrometry. MFN1 mRNA expression was measured in paired CCs by quantitative PCR. Associations between PFAS concentrations and MFN1 expression were assessed using Spearman correlation and tertile-based Kruskal-Wallis tests. Multivariable linear regression models were used to assess associations with ART outcomes. Results: Seventy FF samples from 57 women were analyzed, with perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) detected in all samples. Paired CCs were available for 38 FF samples. PFOS demonstrated a moderate inverse association with CC MFN1 expression (Spearman rank =-0.45, p=0.005), which persisted after adjustment for age (partial Spearman =-0.46, p=0.005). When PFOS was stratified into tertiles (low <1.83, middle 1.83-2.77, high >2.77ng/mL), median MFN1 expression declined progressively with 4.56 arbitrary unit (AU) in the lowest tertile, 2.79AU in the middle tertile, and 1.46AU in the highest tertile (Kruskal Wallis H=9.84, p=0.007). FF PFOS levels were independently associated with oocyte maturation rate, with each 1ng/mL increase in PFOS associated with a 2.06% decrease in maturation (95% CI -3.20 to -0.92, p=0.0007). No significant associations were observed between FF PFAS levels and other ART outcomes or patient characteristics. Conclusion: PFAS are ubiquitously detectable in human FF. Higher FF PFOS levels are independently associated with lower MFN1 expression in CCs and reduced oocyte maturation rates, supporting a potential mitochondrial mechanism linking PFAS exposure to impaired reproductive function. Capsule : Higher follicular fluid PFAS concentrations are associated with reduced cumulus cell MFN1 expression and impaired oocyte maturation, linking endogenous PFAS exposure to mitochondrial dysfunction in human IVF cycles.