Germ cell apoptosis in the testes of Sprague Dawley rats following testosterone withdrawal by ethane 1,2-dimethanesulfonate administration: Relationship to Fas?

Germ cell apoptosis, which occurs normally during spermatogenesis, increase s after testosterone withdrawal from the testis. The molecular mechanism by which this occurs remains uncertain. The Fas system has been implicated as a possible key regulator of apoptosis in various cells: binding of Fas lig and (FasL), a type II transmembrane protein, to Fas, a type I transmembrane receptor protein, triggers apoptosis in cells expressing Fas. Recently, Fa s has been localized to germ cells, and Fast to Sertoli cells, within the r at testis. We hypothesized that Fas protein content would rise in response to reduced levels of testosterone as part of a suicide pathway that would r esult in germ cell apoptosis. To test this hypothesis, ethane 12-dimethanes ulfonate (EDS), a Leydig cell toxicant, was used to kill Leydig cells and t hus reduce intratesticular testosterone levels in Sprague Dawley rats, Apop tosis was examined in situ and biochemically, and Fas protein content in th e testis was monitored by Western blot analysis. We show that EDS injection results in the following sequence of events: apoptotic death of Leydig cel ls by a mechanism that does not involve Fas; reduced testosterone; increase d testicular Fas content; and germ cell apoptosis. These results suggest th at Fas may play a role in the apoptotic death of germ cells that results fr om reduced intratesticular testosterone levels, and that testosterone may p lay a role its germ cell survival via its suppression of Fas.