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 compromises the development of the male reproductive tract in mice, the androgen receptor antagonist hydroxyflutamide was administered orally to pregnant FVB/N mice and the reproductive tracts of the male offspring were examined when adult. Hydroxyflutamide (30 mg per day) for 5 days from day 11 to day 15 of gestation caused hypospadias in all male progeny. However, testis weights, seminal vesicle weights, and serum testosterone levels were not affected (p > 0.05) but caput-corpus epididymal weights were 15% lower than controls (p < 0.02). Shorter periods of treatment that included day 14 or 15 caused hypospadias, but treatments that did not include days 14 and 15 did not (p < 0.002). Hydroxyflutamide (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 later in pregnancy had prostates, but the weights were reduced (p < 0.001); testes were scrotal and seminal vesicles were abdominal; caput-corpus epididymal weights were 15-30% lower than controls (p < 0.05), but the tubule contained large numbers of spermatozoa. Furthermore, testis weights, serum testosterone, and the response of the testis to a human chorionic gonadotropin (hCG) challenge in vitro were not compromised by hydroxyflutamide, and seminiferous tubules exhibited normal spermatogenesis. When males that had been exposed to hydroxyflutamide on days 13 & 14, 15 & 16, 17 & 18 and 19 & 20 were housed with sexually mature females, pregnancies resulted only from the day 19 & 20 treatment group. Thus, there are long-term effects caused by short-term blockade of androgen action at critical times during pregnancy and such effects could result in the inability to impregnate, irrespective of any externally visible indications of developmental anomalies.
Silversides
D W
DW
Département de biomédecine vétérinaire, Université de Montréal, St-Hyacinthe, QC, Canada.
Price
C A
CA
Cooke
G M
GM
D000726:Androgen Antagonists / Q000633:toxicity*; D000728:Androgens / Q000096:biosynthesis; D000818:Animals; D004822:Epididymis / Q000187:drug effects / Q000254:growth & development; D005260:Female; D005485:Flutamide / Q000031:analogs & derivatives* / Q000633:toxicity; D005837:Genitalia, Male / Q000187:drug effects* / Q000254:growth & development*; D005865:Gestational Age; D007021:Hypospadias / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011467:Prostate / Q000002:abnormalities / Q000187:drug effects; D051381:Rats; D012669:Seminal Vesicles / Q000187:drug effects / Q000254:growth & development; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000378:metabolism; D013739:Testosterone / Q000097:blood
D000726:Androgen Antagonists; D000728:Androgens; C014290:hydroxyflutamide; D013739:Testosterone; D005485:Flutamide