Multi-omics analysis investigates the mechanisms of plasticizer-induced male reproductive infertility in Northwest China

This study examines adverse factors impacting male reproductive health in northwest China, with a focus on phthalate exposure and its mechanisms. A questionnaire covering demographics, living environment, and medical history was used for data collection. From 1096 participants with complete questionnaires and semen data, 90 individuals-30 each from the normal, asthenozoospermia (AS), and oligozoospermia (OL) groups-were selected for further analysis. Urine, seminal plasma, and sperm samples were collected for high-throughput targeted metabolomics, lipidomics, and proteomics. This is the first multi-omics study to systematically correlate urinary metabolites with seminal plasma lipids and sperm proteome changes, clarifying underlying mechanisms. Results show a significant link between phthalate exposure and reduced sperm quality and identify distinct seminal plasma lipids and sperm proteins in AS and OL patients. Mouse experiments confirmed that the mitochondrial permeability transition pore (mPTP) inhibitor cyclosporin A (CSA) alleviates DEHP-induced mitochondrial dysfunction and improves sperm quality. Importantly, this research proposes distinct mechanisms for AS and OL: AS is mainly linked to abnormal mitochondrial energy metabolism, while OL is associated with autophagy dysregulation. These findings support precise classification and targeted therapy, clarify the phthalate-male reproductive health connection, and offer insights for managing idiopathic male infertility.