Somatic cell dysfunction precedes testicular degeneration in a surgical model of cryptorchidism

Cryptorchidism is the most common congenital anomaly requiring pediatric surgical correction. Although surgical repositioning of the undescended testis (orchidopexy) is effective anatomically, the molecular and cellular mechanisms underlying ongoing testicular damage after surgery remain poorly understood.

We established a surgically induced unilateral cryptorchidism model in adult mice, collected testicular tissues at day 0, 3, 7, 10, and 14 after induction, and performed bulk RNA sequencing on samples collected at day 0, 3, and 7. Differentially expressed genes (DEGs) were analyzed for pathway enrichment and protein-protein interactions. Cell-type-specific gene expression patterns were evaluated using publicly available single-cell RNA-seq data. Histological evaluation was performed to validate tissue-level changes.

Transcriptomic profiling revealed rapid upregulation of extracellular matrix remodeling and inflammatory signaling by day 3, primarily in somatic cells such as Sertoli and peritubular myoid cells. By day 7, we observed activation of pro-apoptotic and TGF-β signaling pathways. Key genes including Ddr1, Ltbp1, and Spp1 were enriched in somatic compartments. Histology confirmed progressive seminiferous tubule disorganization and germ cell depletion, consistent with somatic cell-driven structural deterioration.

This study provides hypothesis-generating evidence that somatic cell dysfunction may be an early feature of cryptorchidism-associated testicular injury in this adult mouse model. These findings identify candidate genes and pathways for further investigation. Validation in developmental cryptorchidism models and human tissue will be required to establish clinical relevance.