Lipid metabolism links seminal PFAS exposure to IVF outcomes.

Per- and polyfluoroalkyl substances (PFASs) may affect reproductive health, but their impact on male in vitro fertilization (IVF) outcomes remains unclear, and the underlying mechanisms are not yet elucidated. This cohort study included 132 men, aiming to evaluate the associations of PFAS exposure with IVF outcomes and explore potential biological mechanisms through lipid metabolomics. The results showed that perfluorooctanoic acid (PFOA) [(RR (95%CI): 0.875 (0.779, 0.983), P = 0.0246)], perfluoroundecanoic acid (PFUdA) [(RR (95%CI): 0.803 (0.690, 0.935), P = 0.0047)], perfluorododecanoic acid (PFDoA) [(RR (95%CI): 0.831 (0.713, 0.968), P = 0.0173)], perfluorotridecanoic acid (PFTrDA) [(RR (95%CI): 0.833 (0.719, 0.965), P = 0.0152)], and 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (9Cl-PF3ONS) [(RR (95%CI): 0.925 (0.856, 1.000), P = 0.0497)] were inversely associated with the numbers of high-quality embryos. Increases in PFAS concentrations were associated with changes in specific lipid relative abundance, and specific lipid relative abundance was associated with IVF outcomes. In the group with poor IVF outcomes, the lipid pathways of phosphatidylcholine (PC) → diacylglycerol (DG) → PE → PS (Z-scores = -1.744 and -1.857, respectively) and triacylglycerol (TG) → DG → PE → PS (Z-scores = -1.985 and -2.080, respectively) were down-regulated, while the pathway of PS → PE → PC was up-regulated (Z-scores = 1.760 and 1.943, respectively). Network toxicology suggested that PFASs may be related to male infertility-associated lipid metabolism pathways through putative targets such as PTDSS and PEMT. This study provides epidemiological evidence that seminal PFAS exposure was associated with altered lipid metabolism and IVF outcomes. However, the associations were heterogeneous across lipid classes and IVF endpoints, suggesting that lipid metabolism may be involved in a complex biological response to PFAS exposure.