Urogenital teratogenicity of synthetic and natural estrogens in the rat: diethylstilbestrol and estradiol

Thesis/Dissertation · Sun Jan 01 00:00:00 EST 1984

OSTI ID:6695766

Henry, E C

Diethylstilbestrol (DES), a synthetic estrogen and a carcinogen, is a potent urogenital teratogen in humans and rodents. The natural estrogen, estradiol (E/sub 2/), induces malformations in rats only at a maternal toxic dose. This difference in potency could result from differences in fetal sensitivity, or in the distribution and/or metabolism of the two compounds. The current studies tested the hypothesis that the teratogenicity of DES is mediated by its estrogenic activity (rather than its metabolic activation). The two estrogens were directly compared by injecting them into day 19 fetuses, bypassing any maternal modifying factors. Both DES (0.1, 1 or 10 ..mu..g/fetus) and E/sub 2/ (10 or 100 ..mu..g/fetus) caused dose-related incidences of urogenital malformations (diagnosed at 6-7 weeks), but DES was 10- to 100-fold more potent. Between 24 h and 9 days after DES or E/sub 2/ exposure, histologic evidence of estrogenic stimulation was observed, including premature myometrial growth and differentiation, and vaginal epithelial thickening. Thus, DES and E/sub 2/ act directly in the fetus, to produce similar teratogenic effects, without maternal mediation. Following both maternal and fetal administration of /sup 14/C-DES or /sup 3/H-E/sub 2/, the /sup 14/C (from DES) was concentrated in fetal tissues, whereas /sup 3/H (from E/sub 2/) was retained in fetal plasma (protein-bound). Fetal genital tract contained the largest proportion of unchanged E/sub 2/ (74%) or DES (86%). It was concluded that (1) the teratogenicity of DES reflects its estrogenic activity in the fetus; (2) the fetus is sensitive to a brief exposure to estrogens, including LY and (3) the synthetic estrogen is more potent that estradiol because of its greater availability to fetal genital tissues: protein binding and rapid metabolism reduce the teratogenicity of the natural estrogen.

• Research Organization: Rochester Univ., NY (USA)
• OSTI ID: 6695766
• Resource Relation: Other Information: Thesis (Ph. D.)
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ESTRADIOL
BIOLOGICAL EFFECTS
TISSUE DISTRIBUTION
FETUSES
BLOOD PLASMA
RATS
TERATOGENESIS
STILBESTROL
CARBON 14 COMPOUNDS
CARCINOGENS
CONGENITAL MALFORMATIONS
ESTROGENS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ANIMALS
AROMATICS
BIOLOGICAL MATERIALS
BLOOD
BODY FLUIDS
DISTRIBUTION
ESTRANES
HORMONES
HYDROXY COMPOUNDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MALFORMATIONS
MAMMALS
MATERIALS
ORGANIC COMPOUNDS
PATHOLOGICAL CHANGES
PHENOLS
POLYPHENOLS
RODENTS
STEROID HORMONES
STEROIDS
VERTEBRATES
551001* - Physiological Systems- Tracer Techniques