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

Metalómica del plasma seminal: un nuevo horizonte para el diagnóstico y manejo de la infertilidad masculina

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 omics-based 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.

Resumen

El plasma seminal contiene una amplia gama de biomoléculas—incluidos elementos inorgánicos—que pueden influir de manera significativa en la función reproductiva masculina. Históricamente, el análisis de semen se ha centrado en la concentración y motilidad espermáticas, pasando por alto el potencial diagnóstico de esta fracción acelular. Esta revisión narrativa integra perspectivas históricas de la metalómica del plasma seminal, aclara las funciones biológicas de sus diversos componentes elementales y evalúa críticamente los avances metodológicos en su detección. Además, examina futuras orientaciones clínicas e investigativas al abordar temas clave como la evolución de los análisis multielementales en el plasma seminal, la interrelación entre la exposición a metales y la salud reproductiva masculina, y la aplicación de enfoques ómicos y de aprendizaje automático en la caracterización de la infertilidad masculina. Los avances en química analítica, particularmente la espectrometría de masas con plasma acoplado inductivamente, permiten ahora mediciones multielementales de alta precisión en el plasma seminal. Estos perfiles “metalómicos” revelan tanto elementos esenciales—como calcio, magnesio, potasio, sodio, zinc y selenio—como metales potencialmente tóxicos, incluidos el cadmio y el plomo, que reflejan exposiciones ambientales y pueden perjudicar la fertilidad. Asimismo, la metalómica del plasma seminal destaca diferencias específicas de fracción entre las secreciones prostáticas y vesiculares seminales, sugiriendo que ciertos compuestos podrían elevarse en el plasma seminal antes de manifestarse en la sangre, lo que lo convierte en un biomarcador prometedor para evaluar el riesgo de infertilidad. Los enfoques de aprendizaje automático, como la agrupación basada en las proporciones entre plasma seminal y suero, brindan nuevas perspectivas diagnósticas al identificar subtipos de infertilidad masculina. Al complementar los parámetros tradicionales del semen y biomarcadores avanzados (p. ej., índice de fragmentación del ADN), estas herramientas integradoras pueden refinar el diagnóstico y orientar intervenciones que incluyan suplementos nutricionales y la reducción de exposiciones a tóxicos específicos, con la posible mejora en los resultados de embarazo. Sin embargo, persisten desafíos notables: se requieren protocolos estandarizados, rangos de referencia validados y estudios prospectivos de mayor envergadura para su traducción clínica. Afrontar estas brechas resulta esencial para incorporar los análisis metalómicos en la evaluación rutinaria de la infertilidad masculina. A medida que este ámbito evoluciona, ofrece el potencial de reformular las evaluaciones de la infertilidad y fomentar estrategias de manejo más personalizadas y eficaces.

Male infertility; Seminal plasma; Metallomics; Trace elements; Environmental exposure; Machine learning; Personalized medicine; Semen analysis; Zinc; Phosphorus

Palabras Clave

Infertilidad masculina; Plasma seminal; Metalómica; Elementos traza; Exposición ambiental; Aprendizaje automático; Medicina personalizada; Análisis de Semen; Zinc; Fósforo

[1] Wang F, Yang W, Ouyang S, Yuan S. The vehicle determines the destination: the significance of seminal plasma factors for male fertility. International Journal of Molecular Sciences. 2020; 21: 8499.

[2] Rodriguez-Martinez H, Martinez EA, Calvete JJ, Pena Vega FJ, Roca J. Seminal plasma: relevant for fertility? International Journal of Molecular Sciences. 2021; 22: 4368.

[3] Vashisht A, Gahlay GK. Understanding seminal plasma in male infertility: emerging markers and their implications. Andrology. 2024; 12: 1058–1077.

[4] Moustakli E, Zikopoulos A, Skentou C, Stavros S, Sofikitis N, Georgiou I, et al. Integrative assessment of seminal plasma biomarkers: a narrative review bridging the gap between infertility research and clinical practice. Journal of Clinical Medicine. 2024; 13: 3147.

[5] Drabovich AP, Saraon P, Jarvi K, Diamandis EP. Seminal plasma as a diagnostic fluid for male reproductive system disorders. Nature Reviews Urology. 2014; 11: 278–288.

[6] Abdel-Naser MB, Altenburg A, Zouboulis CC, Wollina U. Schistosomiasis (bilharziasis) and male infertility. Andrologia. 2019; 51: e13165.

[7] Vogiatzis CG, Zachariadis GA. Tandem mass spectrometry in metallomics and the involving role of icp-ms detection: a review. Analytica Chimica Acta. 2014; 819: 1–14.

[8] Tanaka T, Kojo K, Nagumo Y, Ikeda A, Shimizu T, Fujimoto S, et al. A new clustering model based on the seminal plasma/serum ratios of multiple trace element concentrations in male patients with subfertility. Reproductive Medicine and Biology. 2024; 23: e12584.

[9] Mann T. The biochemistry of semen. 2008. Available at: https://archive.org/details/biochemistryofse00mann/page/88/mode/2up (Accessed: 05 January 2025)

[10] Wong WY, Flik G, Groenen PM, Swinkels DW, Thomas CM, Copius-Peereboom JH, et al. The impact of calcium, magnesium, zinc, and copper in blood and seminal plasma on semen parameters in men. Reproductive Toxicology. 2001; 15: 131–136.

[11] Abou-Shakra FR, Ward NI, Everard DM. The role of trace elements in male infertility. Fertility and Sterility. 1989; 52: 307–310.

[12] Karabulut S, Korkmaz S, Gunes E, Kabil E, Keskin I, Usta M, et al. Seminal trace elements and their relationship with sperm parameters. Andrologia. 2022; 54: e14610.

[13] Lopez-Botella A, Sanchez R, Paul R, Aizpurua J, Gomez-Torres MJ, Todoli-Torro JL. Analytical determination of heavy metals in human seminal plasma—a systematic review. Life. 2023; 13: 925.

[14] Heitland P, Koster HD. Human biomonitoring of 73 elements in blood, serum, erythrocytes and urine. Journal of Trace Elements in Medicine and Biology. 2021; 64: 126706.

[15] Iyengar GV, Kollmer WE, Bowen HJM. The elemental composition of human tissues and body fluids: a compilation of values for adults. 2022. Available at: https://archive.org/details/elementalcomposi0000iyen_b1s1/ (Accessed: 05 January 2025)

[16] Kojo K, Oguri T, Tanaka T, Ikeda A, Shimizu T, Fujimoto S, et al. Inductively coupled plasma mass spectrometry performance for the measurement of key serum minerals: a comparative study with standard quantification methods. Journal of Clinical Laboratory Analysis. 2025; 2: e25140.

[17] Feng RX, Lu JC, Zhang HY, Lu NQ. A pilot comparative study of 26 biochemical markers in seminal plasma and serum in infertile men. BioMed Research International. 2015; 2015: 805328.

[18] Stojsavljevic A, Zecevic N, Mihailovic M, Jagodic J, Durdic S, Perovic M, et al. Elemental profiling of human semen with confirmed normozoospermia: baseline levels for 44 elements. Journal of Trace Elements in Medicine and Biology. 2022; 74: 127081.

[19] Tvrdá E, Sikeli P, Lukáčová J, Massányi P, Lukáč N. Mineral nutrients and male fertility. Journal of Microbiology, Biotechnology and Food Science. 2013; 3: 1–14.

[20] Mirnamniha M, Faroughi F, Tahmasbpour E, Ebrahimi P, Beigi Harchegani A. An overview on role of some trace elements in human reproductive health, sperm function and fertilization process. Reviews on Environmental Health. 2019; 34: 339–348.

[21] Riaz M, Mahmood Z, Shahid M, Saeed MU, Tahir IM, Shah SA, et al. Impact of reactive oxygen species on antioxidant capacity of male reproductive system. International Journal of Immunopathology and Pharmacology. 2016; 29: 421–425.

[22] Pant N, Banerjee AK, Pandey S, Mathur N, Saxena DK, Srivastava SP. Correlation of lead and cadmium in human seminal plasma with seminal vesicle and prostatic markers. Human & Experimental Toxicology. 2003; 22: 125–128.

[23] Antonouli S, Di Nisio V, Messini C, Samara M, Salumets A, Daponte A, et al. Sperm plasma membrane ion transporters and male fertility potential: a perspective under the prism of cryopreservation. Cryobiology. 2024; 114: 104845.

[24] Galeska E, Wrzecinska M, Kowalczyk A, Araujo JP. Reproductive consequences of electrolyte disturbances in domestic animals. Biology. 2022; 11: 1006.

[25] Chao HH, Zhang Y, Dong PY, Gurunathan S, Zhang XF. Comprehensive review on the positive and negative effects of various important regulators on male spermatogenesis and fertility. Frontiers in Nutrition. 2022; 9: 1063510.

[26] Jimenez T, McDermott JP, Sanchez G, Blanco G. Na,K-atpase a4 isoform is essential for sperm fertility. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108: 644–649.

[27] Beigi Harchegani A, Dahan H, Tahmasbpour E, Bakhtiari Kaboutaraki H, Shahriary A. Effects of zinc deficiency on impaired spermatogenesis and male infertility: the role of oxidative stress, inflammation and apoptosis. Human Fertility. 2020; 23: 5–16.

[28] Marin de Jesus S, Vigueras-Villasenor RM, Cortes-Barberena E, Hernandez-Rodriguez J, Montes S, Arrieta-Cruz I, et al. Zinc and its impact on the function of the testicle and epididymis. International Journal of Molecular Sciences. 2024; 25: 8991.

[29] Yuan S, Zhang Y, Dong PY, Chen Yan YM, Liu J, Zhang BQ, et al. A comprehensive review on potential role of selenium, selenoproteins and selenium nanoparticles in male fertility. Heliyon. 2024; 10: e34975.

[30] Kim JJ, Kim YS, Kumar V. Heavy metal toxicity: an update of chelating therapeutic strategies. Journal of Trace Elements in Medicine and Biology. 2019; 54: 226–231.

[31] Fashola MO, Ngole-Jeme VM, Babalola OO. Heavy metal pollution from gold mines: environmental effects and bacterial strategies for resistance. International Journal of Environmental Research and Public Health. 2016; 13: 1047.

[32] Abd Elnabi MK, Elkaliny NE, Elyazied MM, Azab SH, Elkhalifa SA, Elmasry S, et al. Toxicity of heavy metals and recent advances in their removal: a review. Toxics. 2023; 11: 580.

[33] Fan Y, Jiang X, Xiao Y, Li H, Chen J, Bai W. Natural antioxidants mitigate heavy metal induced reproductive toxicity: prospective mechanisms and biomarkers. Critical Reviews in Food Science and Nutrition. 2024; 64: 11530–11542.

[34] Wdowiak N, Wojtowicz K, Wdowiak-Filip A, Pucek W, Wrobel A, Wrobel J, et al. Environmental factors as the main hormonal disruptors of male fertility. Journal of Clinical Medicine. 2024; 13: 1986.

[35] Dai P, Zou M, Cai Z, Zeng X, Zhang X, Liang M. Ph homeodynamics and male fertility: a coordinated regulation of acid-based balance during sperm journey to fertilization. Biomolecules. 2024; 14: 685.

[36] Quinn PJ, White IG, Wirrick BR. Studies of the distribution of the major cations in semen and male accessory secretions. Journal of Reproduction and Fertility. 1965; 10: 379–388.

[37] Alavi SM, Cosson J. Sperm motility in fishes. (II) effects of ions and osmolality: a review. Cell Biology International. 2006; 30: 1–14.

[38] Rastogi R, Su J, Mahalingam A, Clark J, Sung S, Hope T, et al. Engineering and characterization of simplified vaginal and seminal fluid simulants. Contraception. 2016; 93: 337–346.

[39] Rosecrans RR, Jeyendran RS, Perez-Pelaez M, Kennedy WP. Comparison of biochemical parameters of human blood serum and seminal plasma. Andrologia. 1987; 19: 625–628.

[40] Fernandez-Fuertes B. Review: the role of male reproductive tract secretions in ruminant fertility. Animal. 2023; 17: 100773.

[41] Clases D, Gonzalez de Vega R. Facets of icp-ms and their potential in the medical sciences-part 1: fundamentals, stand-alone and hyphenated techniques. Analytical and Bioanalytical Chemistry. 2022; 414: 7337–7361.

[42] Binder GA, Metcalf R, Atlas Z, Daniel KG. Evaluation of digestion methods for analysis of trace metals in mammalian tissues and nist 1577c. Analytical Biochemistry. 2018; 543: 37–42.

[43] Jecht EW, Poon CH. Preparation of sperm-free seminal plasma from human semen. Fertility and Sterility. 1975; 26: 1–5.

[44] Padilla L, Barranco I, Parrilla I, Lucas X, Rodriguez-Martinez H, Roca J. Measurable cytokine concentrations in pig seminal plasma are modified by semen handling and storage. Biology. 2020; 9: 276.

[45] Mendiola J, Moreno JM, Roca M, Vergara-Juarez N, Martinez-Garcia MJ, Garcia-Sanchez A, et al. Relationships between heavy metal concentrations in three different body fluids and male reproductive parameters: a pilot study. Environmental Health. 2011; 10: 6.

[46] Živković T, Tariba B, Pizent A. Multielement analysis of human seminal plasma by octopole reaction cell ICP-MS. Journal of Analytical Atomic Spectrometry. 2014; 29: 2114–2126.

[47] Hamdi SM, Sanchez E, Garimbay D, Albarede S. External quality assessment program for biochemical assays of human seminal plasma: a french 6-years experience. Basic and Clinical Andrology. 2020; 30: 18.

[48] Verze P, Cai T, Lorenzetti S. The role of the prostate in male fertility, health and disease. Nature Reviews Urology. 2016; 13: 379–386.

[49] Noda T, Ikawa M. Physiological function of seminal vesicle secretions on male fecundity. Reproductive Medicine and Biology. 2019; 18: 241–246.

[50] Drake RR, White KY, Fuller TW, Igwe E, Clements MA, Nyalwidhe JO, et al. Clinical collection and protein properties of expressed prostatic secretions as a source for biomarkers of prostatic disease. Journal of Proteomics. 2009; 72: 907–917.

[51] Healy MW, Yauger BJ, James AN, Jezior JR, Parker P, Dean RC. Seminal vesicle sperm aspiration from wounded warriors. Fertility and Sterility. 2016; 106: 579–583.

[52] Ndovi TT, Parsons T, Choi L, Caffo B, Rohde C, Hendrix CW. A new method to estimate quantitatively seminal vesicle and prostate gland contributions to ejaculate. British Journal of Clinical Pharmacology. 2007; 63: 404–420.

[53] Valsa J, Skandhan KP, Khan PS, Sumangala B, Gondalia M. Split ejaculation study: semen parameters and calcium and magnesium in seminal plasma. Central European Journal of Urology. 2012; 65: 216–218.

[54] Bjorndahl L. What is required for better progress in clinical and scientific andrology involving sperm assessments? Asian Journal of Andrology. 2024; 26: 229–232.

[55] Nagai A, Watanabe M, Nasu Y, Iguchi H, Kusumi N, Kumon H. Analysis of human ejaculation using color doppler ultrasonography: a comparison between antegrade and retrograde ejaculation. Urology. 2005; 65: 365–368.

[56] Bjorndahl L, Kvist U. Sequence of ejaculation affects the spermatozoon as a carrier and its message. Reproductive BioMedicine Online. 2003; 7: 440–448.

[57] Anamthathmakula P, Winuthayanon W. Mechanism of semen liquefaction and its potential for a novel non-hormonal contraceptiondagger. Biology of Reproduction. 2020; 103: 411–426.

[58] Lindholmer C. Survival of human spermatozoa in different fractions of split ejaculate. Fertility and Sterility. 1973; 24: 521–526.

[59] Hebles M, Dorado M, Gallardo M, Gonzalez-Martinez M, Sanchez-Martin P. Seminal quality in the first fraction of ejaculate. Systems Biology in Reproductive Medicine. 2015; 61: 113–116.

[60] Pourian MR, Kvist U, Bjorndahl L, Oliw EH. Rapid and slow hydroxylators of seminal e prostaglandins among men in barren unions. Andrologia. 1995; 27: 71–79.

[61] Robert M, Gagnon C. Purification and characterization of the active precursor of a human sperm motility inhibitor secreted by the seminal vesicles: identity with semenogelin. Biology of Reproduction. 1996; 55: 813–821.

[62] Smyth SP, Nixon B, Anderson AL, Murray HC, Martin JH, MacDougall LA, et al. Elucidation of the protein composition of mouse seminal vesicle fluid. Proteomics. 2022; 22: e2100227.

[63] Yamasaki K, Yoshida K, Yoshiike M, Shimada K, Nishiyama H, Takamizawa S, et al. Relationship between semenogelins bound to human sperm and other semen parameters and pregnancy outcomes. Basic and Clinical Andrology. 2017; 27: 15.

[64] Elzanaty S, Richthoff J, Malm J, Giwercman A. The impact of epididymal and accessory sex gland function on sperm motility. Human Reproduction. 2002; 17: 2904–2911.

[65] Preiano M, Correnti S, Butt TA, Viglietto G, Savino R, Terracciano R. Mass spectrometry-based untargeted approaches to reveal diagnostic signatures of male infertility in seminal plasma: a new laboratory perspective for the clinical management of infertility? International Journal of Molecular Sciences. 2023; 24: 4429.

[66] Amelar RD, Hotchkiss RS. The split ejaculate: its use in the management of male infertility. Fertility and Sterility. 1965; 16: 46–60.

[67] Amelar RD, Dubin L. A new method of promoting fertility. Obstetrics & Gynecology. 1975; 45: 56–59.

[68] Johnsen O, Eliasson R. Evaluation of a commercially available kit for the colorimetric determination of zinc in human seminal plasma. International Journal of Andrology. 1987; 10: 435–440.

[69] Van Dreden P, Richard P, Gonzales J. Fructose and proteins in human semen. Andrologia. 1989; 21: 576–579.

[70] Laffin RJ, Chan DW, Tanasijevic MJ, Fischer GA, Markus W, Miller J, et al. Hybritech total and free prostate-specific antigen assays developed for the beckman coulter access automated chemiluminescent immunoassay system: a multicenter evaluation of analytical performance. Clinical Chemistry. 2001; 47: 129–132.

[71] Comhaire FH, Vermeulen L, Pieters O. Study of the accuracy of physical and biochemical markers in semen to detect infectious dysfunction of the accessory sex glands. Journal of Andrology. 1989; 10: 50–53.

[72] Lu JC. Automatic detection and clinical application of semen biochemical markers. National Journal of Andrology. 2018; 24: 291–296. (In Chinese)

[73] Andrade-Rocha FT. Physical analysis of ejaculate to evaluate the secretory activity of the seminal vesicles and prostate. Clinical Chemistry and Laboratory Medicine. 2005; 43: 1203–1210.

[74] Zhang H, Zhou XP. The effect of neutral alpha-glucosidase on semen parameters. Urologia Internationalis. 2024; 108: 479–486.

[75] Yuan Q, Hong R, Ni Y, Jiang M, Liu J, Chen Z, et al. Correlation between seminal plasma biochemical markers and semen parameters in idiopathic oligoasthenoteratospermia: identification of biomarkers for l-carnitine therapy. Frontiers in Endocrinology. 2024; 15: 1330629.

[76] Smits RM, Mackenzie-Proctor R, Yazdani A, Stankiewicz MT, Jordan V, Showell MG. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews. 2019; 3: CD007411.

[77] Bergamo P, Volpe MG, Lorenzetti S, Mantovani A, Notari T, Cocca E, et al. Human semen as an early, sensitive biomarker of highly polluted living environment in healthy men: a pilot biomonitoring study on trace elements in blood and semen and their relationship with sperm quality and redox status. Reproductive Toxicology. 2016; 66: 1–9.

[78] Lettieri G, Marra F, Moriello C, Prisco M, Notari T, Trifuoggi M, et al. Molecular alterations in spermatozoa of a family case living in the land of fires. A first look at possible transgenerational effects of pollutants. International Journal of Molecular Sciences. 2020; 21: 6710.

[79] Guzikowski W, Szynkowska MI, Motak-Pochrzest H, Pawlaczyk A, Sypniewski S. Trace elements in seminal plasma of men from infertile couples. Archives of Medical Science. 2015; 11: 591–598.

[80] Chen G, Feng Y, Yang R, Li H, Huang Z, Li Z, et al. Association between zinc ion concentrations in seminal plasma and sperm quality: a Chinese cross-sectional study. To be published in Biological Trace Element Research. 2024. [Preprint].

[81] Chiba M, Shinohara A. Trace elements and reproduction. Journal of the Vitamin Society of Japan. 2008; 82: 25–33. (In Japanese).

[82] Slivkova J, Popelkova M, Massanyi P, Toporcerova S, Stawarz R, Formicki G, et al. Concentration of trace elements in human semen and relation to spermatozoa quality. Journal of Environmental Science and Health. 2009; 44: 370–375.

[83] Minguez-Alarcon L, Mendiola J, Roca M, Lopez-Espin JJ, Guillen JJ, Moreno JM, et al. Correlations between different heavy metals in diverse body fluids: studies of human semen quality. Advances in Urology. 2012; 2012: 420893.

[84] Abed A, Jarad A. Significance of some trace elements in semen of infertile men. Ibnosina Journal of Medicine and Biomedical Sciences. 2022; 06: 145–151.

[85] Waheed MM, Meligy A, Alhaider AK, Ghoneim IM. Relation of seminal plasma trace mineral in the arabian stallion’s semen with the semen characteristics and subsequent fertility. Heliyon. 2022; 8: e11128.

[86] Yin T, Ji D, Su X, Zhou X, Wang X, He S, et al. Using bayesian and weighted regression to evaluate the association of idiopathic oligoastenoteratozoospermia with seminal plasma metal mixtures. Chemosphere. 2024; 351: 141202.

[87] Liu K, Mao X, Pan F, Chen Y, An R. Correlation analysis of sperm DNA fragmentation index with semen parameters and the effect of sperm dfi on outcomes of art. Scientific Reports. 2023; 13: 2717.