Association between perfluorooctanoic acid-related poor embryo quality and metabolite alterations in human follicular fluid during IVF：A Cohort Study

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been shown to disrupt normal follicular development and ovulation. However, it is unknown which specific PFAS in follicular fluid negatively impact oocyte development and embryo quality or whether any of the metabolites present in the follicular fluid contribute to these adverse effects. We conducted a cross-sectional and cohort study to identify specific PFAS with significant adverse effects on embryo quality and their associated modes of action. We enrolled 378 women undergoing assisted reproductive technology (ART) and collected follicular fluid samples during oocyte retrieval. We performed PFAS detection and untargeted metabolomics on the follicular fluid. The association of individual PFAS with high-quality embryo rates and clinical pregnancy outcomes were assessed using beta regression and logistic regression, respectively, and potential joint effect of mixtures of PFAS using Bayesian kernel machine regression (BKMR) and Quantile g-computation models. A causal mediation effect model was performed to estimate the average indirect impact of PFAS, mediated by high-quality embryo rates, on the clinical pregnancy outcomes, as well as its direct impact representing all other causal effects. Spearman's rank correlation coefficient was used to identify the associations between the differentially expressed metabolites and the high-quality embryo rates. The detection frequencies of 15 PFAS exceeded 85%, and perfluorooctanoic acid (PFOA) had the highest median concentration (6.54 ng/mL). The PFAS mixture was negatively associated with the high-quality embryo rate, and PFOA was the major contributor (conditional posterior inclusion probability = 0.97295). PFAS was also negatively associated with the clinical pregnancy outcome, and the causal mediation analysis revealed that the embryo quality potentially mediated the relationship between the clinical pregnancy outcome with PFOA (proportion mediated: 0.181, 95% CI: 0.024, 0.755), Perfluoro-n-nonanoic acid (PFNA, proportion mediated: 0.148, 95% CI: 0.022, 0.656), or Perfluoro-n-tridecanoic acid (PFTrDA, proportion mediated: 0.130, 95% CI: 0.005, 0.693). The decreased organonitrogens (Pro-Trp and lauryldimethylamine oxide) and sphingolipids metabolites (phytosphingosine, N-myristoylsphinganine and N-lauroyl-d-erythro-sphinganine) in the follicular fluid were associated with PFOA related-poor embryo quality. High exposure to follicular fluid PFAS was negatively correlated with embryo quality during ART, with PFOA likely to be the major contributor. PFOA-related poor embryo quality was associated with the reduction of organonitrogens and sphingolipids metabolites that are crucial for the maintenance of normal cell growth and metabolism. https://doi.org/10.1289/EHP15422.