P53 and Fas are sequential mechanisms of testicular germ cell apoptosis.

Testicular germ cell apoptosis in the cryptorchid testis is induced by abdominal heat stress. p53-dependent apoptosis appears responsible for the initial phase of germ cell loss in experimental cryptorchidism based on a 3-day delay of apoptosis in p53-/- mice. However, the mechanisms underlying the subsequent p53-independent apoptosis have not been identified. Although studies have suggested that Fas plays a role in testicular germ cell apoptosis, no direct evidence has been shown. To test the hypothesis that Fas is involved in testicular germ cell apoptosis and is responsible for the p53-independent phase of apoptosis in the cryptorchid testis, p53-/-, lpr/lpr (a spontaneous mutation in the Fas gene, which causes autoimmune disease) double-mutant mice were generated and unilateral cryptorchidism was induced in these mice. It was found that testicular weight reduction and germ cell apoptosis were delayed by an additional 3 days, and the Fas production increased in the time frame of p53-independent apoptosis in the experimental cryptorchid testis of wild-type mice. These results suggest that Fas is involved in testicular germ cell apoptosis, and that Fas-dependent apoptosis is responsible for the p53-independent phase of germ cell apoptosis in the cryptorchid testis. The cascade of testicular germ cell apoptosis in response to heat stress implies the existence of sequential quality control mechanisms in spermatogenesis.