The HIF-Mediated PI3K-AKT Signaling Pathway Is a Key Signaling Pathway Triggering Testicular Spermatogenic Disorders...

Cryptorchidism is one of the major reproductive diseases affecting testicular function in yaks. However, the mechanisms underlying its impact on testicular spermatogenesis remain unclear. In this study, high-throughput transcriptomics (RNA-seq) and proteomics technologies were employed to analyze the key signaling pathways involved in cryptorchidism-induced spermatogenic dysfunction in yak, and a mouse model was established for validation. The results indicate that differentially expressed genes (DEGs) in the testes of yak with cryptorchidism are primarily enriched in the hypoxia-inducible factor (HIF) signaling pathway and the PI3K-AKT signaling pathway. Experimental results from the hypoxic mouse model indicate that the hypoxic environment remarkably raised HIF-1α content in the blood of mice while activating the PI3K-AKT signaling pathway, accompanied by decreased testicular expression of the cell adhesion molecules (CAMs) claudin 2, claudin 3, E-cadherin, and N-cadherin. Cell culture experiments showed that cell adhesion molecule expression was significantly downregulated when HIF-1α and PI3K expression were inhibited among mouse Sertoli cells, indicating that the HIF-1α/PI3K-AKT signaling pathway regulated cell adhesion molecule expression among mouse testes. Decreased CAMs directly affect tight junctions and the adhesion of spermatogenic and Sertoli cells, thus affecting sperm production and potentially also testis development. This study provides data to support research on the regulatory mechanisms involved in reproductive function and hypoxia adaptation in male animals in a low-oxygen environment.