Effects of short-term exposure to hydroxyflutamide in utero on the development of the reproductive tract in male mice

Can J Physiol Pharmacol. 1995 Nov;73(11):1582-8. doi: 10.1139/y95-718.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / toxicity*
  • Androgens / biosynthesis
  • Animals
  • Epididymis / drug effects
  • Epididymis / growth & development
  • Female
  • Flutamide / analogs & derivatives*
  • Flutamide / toxicity
  • Genitalia, Male / drug effects*
  • Genitalia, Male / growth & development*
  • Gestational Age
  • Hypospadias / chemically induced
  • Hypospadias / pathology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Organ Size / drug effects
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Prostate / abnormalities
  • Prostate / drug effects
  • Rats
  • Seminal Vesicles / drug effects
  • Seminal Vesicles / growth & development
  • Spermatogenesis / drug effects
  • Testis / drug effects
  • Testis / metabolism
  • Testosterone / blood

Substances

  • Androgen Antagonists
  • Androgens
  • hydroxyflutamide
  • Testosterone
  • Flutamide