Seminal plasma metallomics: a new horizon for diagnosing and managing male infertility

Seminal plasma contains a wide range of biomolecules-including inorganic elements- that may significantly influence male reproductive function. Historically, semen analysis has focused on sperm count and motility, while overlooking the diagnostic potential of this acellular fraction. This narrative review synthesizes historical perspectives on seminal plasma metallomics, elucidates the biological functions of its diverse elemental constituents, and critically evaluates methodological advancements in their detection. Furthermore, it examines future clinical and research directions by addressing key topics, including the evolution of multi-element analyses in seminal plasma, the interplay between metal exposure and male reproductive health, and the application of omicsbased and machine-learning approaches in characterizing male infertility. Progress in analytical chemistry, particularly inductively coupled plasma mass spectrometry, now enables high-precision multi-element measurements in seminal plasma. The "metallomic" profiles reveal both essential elements-such as calcium, magnesium, potassium, sodium, zinc and selenium-and potentially toxic metals, including cadmium and lead, that reflect environmental exposures and may impair fertility. Seminal plasma metallomics also underscores fraction-specific differences between prostatic and seminal vesicular secretions, suggesting that certain chemicals may rise in seminal plasma before shifts appear in blood, thereby making it a promising biomarker for infertility risk assessment. Machine-learning approaches, such as clustering based on seminal plasma-to-serum ratios, offer new diagnostic insights by identifying subtypes of male infertility. By complementing traditional semen parameters and advanced biomarkers (e.g., DNA fragmentation index), these integrative tools can refine diagnoses and guide interventions, including nutritional supplementation and avoidance of specific toxicants, potentially improving pregnancy outcomes. However, significant challenges remain: standardized protocols, validated reference ranges, and larger prospective studies are needed for clinical translation. Addressing these gaps is crucial for integrating metallomic analyses into routine evaluations of male infertility. As this field continues to evolve, it has the potential to reshape infertility assessments and foster more personalized and effective management strategies.