Direct fetal injections of diethylstilbestrol and 17 beta-estradiol: a method for investigating their teratogenicity.

The synthetic estrogen, diethylstilbestrol (DES), causes urogenital malformations in humans, primates, and rodents. This study was designed to determine whether these effects of DES are related to its estrogenicity. Therefore, DES (0.1, 1, and 10 micrograms) or the natural estrogen, estradiol (E2) (10 and 100 micrograms) was injected directly into day 19 rat fetuses. In the 6- to 7-week-old female offspring exposed to DES, a dose-related incidence of cleft phallus, hypospadias, and incomplete coiling of oviducts was observed. The single fetal injection of E2 elicited similar urogenital malformations, but was approximately 100-fold less potent than DES. A single subcutaneous dose of either DES (0.025, 0.25, or 2.5 mg/kg) or E2 (2.5 or 25 mg/kg) to dams on day 19 of pregnancy induced a spectrum of malformations similar to that following fetal injection. The offspring of treated dams, but not those injected directly as fetuses, had nonfunctioning ovaries (no corpora lutea) yet vaginal signs of estrous were present. It is concluded that DES can act directly in the fetus and its teratogenicity does not require maternal mediation. Since a high dose of E2 produced similar malformations when given to fetuses, it appears that excess estrogen during prenatal life is teratogenic. Thus, at least those endpoints of the teratogenicity of DES that were measured are accounted for by its estrogenic activity.