The Seminal Microenvironment as a Potentially Tractable Interface Between Metabolic Disease and Sperm Damage

Male reproductive disorders are increasingly linked to metabolic diseases, but mechanistic research remains predominantly focused on the testis. The seminal microenvironment, shaped by epididymal and accessory-gland secretions, contains metabolites, lipids, ions, cytokines, extracellular vesicles, and microbial products, and may act as a metabolically responsive post-testicular interface that continues to influence sperm after spermatogenesis. Obesity, insulin resistance, dyslipidemia, and chronic inflammation can remodel this environment by disrupting secretory activity, redox homeostasis, immune signaling, and microbial ecology. These changes may converge on oxidative and inflammatory pathways, promoting membrane lipid peroxidation, mitochondrial dysfunction, impaired motility and capacitation, oxidative DNA base lesions, DNA fragmentation, and potentially epigenetic alterations. Mouse studies separately report obesity-associated epididymal vesicle remodeling and RNA-dependent changes in embryonic gene expression. In this Review, we examine the regulation and metabolic remodeling of the seminal microenvironment, how these changes may translate systemic metabolic stress into sperm injury, and emerging interventions including metabolic correction, antioxidant strategies, and microbiome-targeted approaches. Overall, current evidence remains largely observational and cross-sectional, with additional technical limitations in low-biomass seminal microbiome studies. Longitudinal and mechanistic studies are therefore needed to determine whether the seminal microenvironment is a causal mediator of metabolic infertility and a clinically tractable target for mechanism-guided preconception care.