Trihalomethane Exposure, Seminal Plasma Metabolomics, and Semen Quality in Healthy Men: A Meet-in-the-Middle Approach

Exposure to trihalomethanes (THMs) has been linked to reduced human semen quality, but the critical windows of vulnerability and underlying biological mechanisms remain unclear. We therefore measured untargeted seminal plasma metabolomics to identify metabolic biomarkers and biological pathways linking blood THM concentrations to repeated measurements of semen quality (4146 measurements over a 3 month follow-up period) among 762 healthy Chinese men. We found inverse associations between blood THM concentrations (i.e., chloroform, bromodichloromethane, and chlorinated THMs) and semen volume and total sperm count (all P values <0.05), which were most pronounced for exposure measured 70–90 days prior to semen collection (corresponding to the early stage of spermatogenesis). Metabolome-wide association analyses identified 90 metabolites that were simultaneously associated with blood THM concentrations and sperm-quality parameters. Mediation analyses further revealed that 44 metabolites, enriched in the pathways of unsaturated fatty acid biosynthesis, steroid hormone biosynthesis, arachidonic acid metabolism, linoleic acid metabolism, pantothenate and CoA biosynthesis, and β-alanine metabolism, mediated a considerable proportion (8.1–41.3%) of the inverse relationships between THM exposure and semen quality. Our results suggest that THM exposure during the early stage of spermatogenesis is associated with reduced human semen quality, potentially driven by perturbations in lipid metabolism, steroid hormone synthesis, and antioxidant-related metabolisms.