Syncytin-a deficiency compromises murine sperm function by suppressing PRL/PGE2 and PI3K/AKT/mTOR pathway

The human endogenous retrovirus W envelope protein syncytin-1 (syncytin-a in mus) can be involved in fetal development and tumorigenesis. The role of syncytin-1 in male infertility has not been identified. To explore the mechanisms of syncytin-1 in male infertility, the prostatic epithelial-specific syncytin-a knockout (syna CKO) mouse model was constructed. Firstly, male infertility, abnormal testicular seminiferous tubule, and prostate gland were discovered in syna CKO mice. Then, irregular sperm motility, morphology, and MMAF-associated gene expression (AKAP3, SPAG6) were detected in syna CKO mice. Increased PGE2 and PRL modulate the lipid metabolism of the testis in syna CKO mice. Syna CKO with inhibitor or activator treatment identified that syna knockout could inhibit the PI3K/AKT/mTOR pathway, Ca²⁺ levels, and elevate caspase 3 expression. Therefore, we propose a hypothesis that syna deficiency exacerbates testicular lipid accumulation and apoptosis by suppressing the PI3K/AKT/mTOR and Ca2+ pathway, ultimately leading to spermatogenic dysfunction and male infertility. The study initially included 3 WT and 3 KO samples. After quality control and exploratory analysis, one control sample (WT1) was identified as a biological outlier and excluded from the final differential expression analysis.