Seminal Plasma Metabolomics Reveals Potential Metabolic Pathways Linking Organophosphate Flame Retardant Exposure to Impaired Semen Quality

Abstract Organophosphate flame retardants (OPFRs) may affect semen quality, but the mechanisms remain unclear. This study included 157 men from the SEARCH cohort and evaluated the associations between urinary OPFR levels and semen quality, and the role of the seminal plasma metabolome. Overall, bis(2-butoxyethyl) phosphate (BBOEP) was negatively associated with progressive motility (β [95% confidence interval (CI)]: −0.090 [−0.175, −0.005]), and some associations between OPFRs and semen quality were more pronounced among men with male-factor infertility. Furthermore, widespread associations were observed between OPFRs and metabolites, as well as between metabolites and semen quality. For example, BBOEP was negatively associated with alkyl-phosphatidylethanolamine (O-PE) (β [95% CI] = −0.030 [−0.058, −0.002]), while O-PE exhibited an inverted U-shaped dose–response relationship with progressive motility (P overall = 0.041, P nonlinear = 0.020). The lipid pathway of O-PE → phosphatidylethanolamine plasmalogen (P-PE) → plasmalogen phosphatidylcholine (P-PC) was downregulated in men with lower sperm counts (Z-score = −2.345, P = 0.019). Adverse outcome pathway (AOP) analysis predicted that OPFR-related reproductive toxicity may be associated with mitochondrial dysfunction, oxidative stress, and apoptosis involving the phospholipase A2 (PLA2) gene family. In conclusion, our findings may provide new clues to the mechanisms underlying the reproductive toxicity of OPFRs.