The role of selenium in modulating sperm count and ferroptosis pathways in male reproductive health

This study elucidates the role of selenium in male fertility via the SLC7A11-GPX4 Ferroptosis pathway. In a six-week dietary intervention, KM mice fed a selenium-deficient diet (<0.01 mg/kg) exhibited significantly decreased prostate indices (P < 0.05) and disrupted seminiferous tubule structure compared to controls, while epididymal sperm counts showed a decreasing trend that did not reach statistical significance. Selenium supplementation (sodium selenite, 3.2 mg/kg) significantly increased testis indices (P < 0.05) and improved tubule organization, with a non-significant increase in sperm counts. Crucially, testicular gpx4 (P < 0.001) and slc7a11 (P < 0.05) gene expression were significantly downregulated in the deficient group. In GC2-spd spermatocytes, the Ferroptosis inducer Erastin significantly suppressed proliferation (P < 0.05) and induced ferroptotic ultrastructural damage. Selenomethionine (SeM,5.0 μM) significantly attenuated Erastin-induced proliferation suppression and upregulated GPX4 protein (P < 0.05), while sodium selenite showed non-significant protection. Lentiviral GPX4 knockdown confirmed SeM's effects are GPX4-dependent. In human studies, seminal selenium levels were comparable between groups and showed no correlation with GPX4 or SLC7A11. Oligozoospermia cases exhibited significantly decreased seminal GPX4 (P < 0.001) but unchanged SLC7A11 levels (P = 0.900). However, multivariable analysis identified lower GPX4 and higher SLC7A11 (per SD increase) as independent risk factors (GPX4: OR<0.001, P < 0.001; SLC7A11: OR = 1.48, P = 0.032), revealing a characteristic biomarker dissociation However, multivariable analysis identified lower GPX4 and higher SLC7A11 (per SD increase) as independent risk factors (GPX4: OR<0.001, P < 0.001; SLC7A11: OR = 1.48, P = 0.032), revealing a characteristic biomarker dissociation. In conclusion, selenium significantly influences testicular morphology and Ferroptosis pathway gene expression in vivo, although its effects on sperm count under these experimental conditions were not statistically significant. In vitro, Selenomethionine effectively mitigates Erastin-induced Ferroptosis and proliferation suppression in spermatocytes primarily through GPX4-mediated mechanisms. In patients with oligozoospermia, seminal plasma GPX4 concentration was significantly decreased and was identified as an independent protective factor, while SLC7A11 level was associated with increased risk in multivariable analysis; neither biomarker correlated with seminal plasma selenium concentration.

Ferroptosis; GPX4; SLC7A11; Selenomethionine; Sodium selenite.