Surgically induced cryptorchidism-related degenerative changes in spermatogonia are associated with loss of cyclic adenosine monophosphate-dependent phosphodiesterases type 4 in abdominal testes of rats

The present study was undertaken to investigate the role of phosphodiestera se type 4 (PDE4) enzymes in cryptorchidism-induced apoptosis of the germ ce lls. Regulation of expression of PDE4 enzymes was studied in the abdominal and scrotal testes of surgically induced cryptorchid rats for 10, 20, and 3 0 days. In some cases orchidopexy was performed after 30 days of cryptorchi dism, and rats were allowed to recover for an additional 50 days. Upon hist ological examination, marked degenerative changes in the epithelial lining of the seminiferous tubules within abdominal testes were observed compared with contralateral control or age-matched sham-operated rats. These changes included degeneration of some spermatogonia, apoptosis of the secondary sp ermatocytes, incomplete spermatogenesis, and lack of spermatozoa in the lum en. In contrast, contralateral scrotal testes exhibited normal histology. S ignificant improvement in the regeneration of spermatogonia was observed in rats after 50 days of recovery following orchidopexy. Immunocytochemical e xamination suggested the presence of PDE4A in germ cells while PDE4B was pr edominantly expressed on somatic cells. Western blotting using PDE4 subtype -selective antibodies showed the presence of two PDE4A variants (a 109-kDa PDE4A8 and a previously uncharacterized 88-kDa PDE4A variant) and two PDE4B (78-kDa PDE4B2 and 66-kDa PDE4B variant) bands. In unilaterally cryptorchi d animals, the abdominal testis showed a time-dependent decrease in both PD E4A8 and 88-kDa PDE4A variants. In contrast, the expression of 66-kDa PDE48 was markedly increased in a time-dependent fashion in abdominal testes of cryptorchid rats. Animals surgically corrected for cryptorchidism and allow ed to recover for 50 days exhibited normal expression of both PDE4A and PDE 4B variants compared with aged-matched, sham-operated controls. In conclusi on, this study suggests that down-regulation of PDE4A variants in cryptorch id testes may play an important role in the degeneration of spermatogonia a nd increased apoptotic activity in the germ cells.