ABNORMALITIES IN FUNCTIONAL-DEVELOPMENT OF THE SERTOLI CELLS IN RATS TREATED NEONATALLY WITH DIETHYLSTILBESTROL - A POSSIBLE ROLE FOR ESTROGENS IN SERTOLI-CELL DEVELOPMENT

Diethylstilbestrol (DES) was administered neonatally (Days 2-12; 10 mu g on alternate days) to rats, and developmental changes in Sertoli ce ll function were evaluated at 18, 25, and 35 days of age and compared to those observed in rats administered a GnRH antagonist (GnRHa; Days 2 and 5; 10 mg/kg) or a vehicle (controls). DES and GnRHa treatments r esulted in similar reductions in both Sertoli cell numbers (40% for DE S, 48% for GnRHa) and suppression of testicular growth at 18 and 25 da ys, though by 35 days the suppression was more pronounced (p < 0.001) in DES-treated animals. Plasma FSH levels were suppressed markedly at 18 and 25 days, but not at 35 days, in GnRHa-treated rats,whereas in D ES-treated rats the FSH levels were suppressed significantly only at 3 5 days. Both treatments suppressed plasma levels of inhibin B, though this was more pronounced (p < 0.05) in DES- than in GnRHa-treated rats . In controls, Sertoli cell immunoexpression of inhibin a, sulfated gl ycoprotein-1 (SGP-1), and androgen receptor (AR) increased in intensit y and changed to an adult, stage-dependent pattern by 25 days. In GnRH a-treated rats these changes were reduced in Intensity but were simila r to those in controls at 35 days. In DES-treated rats, the increase i n intensity and stage-dependent pattern of immunoexpression of inhibin alpha, SGP-1, and AR were virtually absent at 25 days but were presen t by 35 days. Germ cell volume per Sertoli cell was reduced in GnRHa- and DES-treated rats compared with controls at 18 and 25 days but was significantly greater (p < 0.001) in DES- than in GnRHa-treated rats a t 35 days. The proportion of apoptotic to viable germ cells was increa sed (p < 0.01) in GnRHa- and DES-treated rats compared with controls a t 18 and 25 days; but at 35 days, values in GnRHa-treated rats had dec lined to control values whereas those for DES-treated rats remained 10 -fold elevated (p < 0.001). In adulthood, testis weight and daily sper m production were reduced by 43% and 44%, respectively, in GnRHa-treat ed rats, but spermatogenesis was grossly normal. Comparable changes we re observed in similar to 25% of DES-treated rats, but the majority ex hibited > 60% reduction in testis weight with many Sertoli cell-only t ubules and very low daily sperm production. Taken together, these data are interpreted as providing evidence for direct modulation of Sertol i cell (maturational) development by DES.