EFFECTS OF SHORT-TERM EXPOSURE TO HYDROXYFLUTAMIDE IN-UTERO ON THE DEVELOPMENT OF THE REPRODUCTIVE-TRACT IN MALE-MICE

To determine if and when short-term ablation of androgen action compro mises the development of the male reproductive tract in mice, the andr ogen receptor antagonist hydroxyflutamide was administered orally to p regnant FVB/N mice and the reproductive tracts of the male offspring w ere examined when adult. Hydroxyflutamide (30 mg per day) for 5 days f rom day 11 to day 15 of gestation caused hypospadias in all male proge ny. However, testis weights, seminal vesicle weights, and serum testos terone levels were not affected (p > 0.05) but caput-corpus epididymal weights were 15% lower than controls (p < 0.02). Shorter periods of t reatment that included day 14 or 15 caused hypospadias, but treatments that did not include days 14 and 15 did not (p < 0.002). Hydroxyfluta mide (30 mg, once or twice daily for 2 consecutive days) between days 15 and 20 of gestation demonstrated that androgen ablation on days 15 & 16 caused hypospadias, absence of prostate, and scrotal location of the seminal vesicles with abdominal testes (p < 0.05). Males exposed l ater in pregnancy had prostates, but the weights were reduced (p < 0.0 01); testes were scrotal and seminal vesicles were abdominal; caput-co rpus epididymal weights were 15-30% lower than controls (p < 0.05), bu t the tubule contained large numbers of spermatozoa. Furthermore, test is weights, serum testosterone, and the response of the testis to a hu man chorionic gonadotropin (hCG) challenge in vitro were not compromis ed by hydroxyflutamide, and seminiferous tubules exhibited normal sper matogenesis. When males that had been exposed to hydroxyflutamide on d ays 13 & 14, 15 & 16, 17 & 18, and 19 & 20 were housed with sexually m ature females, pregnancies resulted only from the day 19 & 20 treatmen t group. Thus, there are long-term effects caused by short-term blocka de of androgen action at critical times during pregnancy and such effe cts could result in the inability to impregnate, irrespective of any e xternally visible indications of developmental anomalies.