Comparison of the disposition of diethylstilbestrol and estradiol in the fetal rat. Correlation with teratogenic potency.

The dispositions of radiolabeled diethylstilbestrol (DES) and estradiol (E2) in the fetal rat were compared to determine whether kinetic differences accounted for their differences in teratogenic potency. 14C (from DES) was concentrated in fetal tissues relative to plasma, whereas 3H (from E2) was largely retained protein-bound in fetal plasma. Both compounds were rapidly metabolized in the fetus (and mother) to less or non-estrogenic products. Fetal levels of E2 declined faster than those of DES (E1 was the primary circulating estrogen within 1-3 hr of E2 injection) so that exposure to unchanged DES was of longer duration than to E2. The unchanged compounds were retained longer and at higher concentrations in the target genital tissue compared to other tissues. Although these differences were consistent with the potencies, the concentration of the unchanged estrogen in fetal genital tract was lower after a teratogenic dose of DES than after a threshold teratogenic dose of E2. However, the 3H in fetal plasma and genital tract cytosol at 1 hr after injection of [3H]E2 at 2 ng or 10 micrograms/fetus was found to be highly protein-bound. DES competed poorly for these binding sites. It is suggested that the concentration of E2 which is "free" in the cell (as DES is), rather than the total content, correlates with its teratogenicity. Thus, in the rat, rapid metabolism and extensive protein-binding, both extra- and intracellularly, reduce the teratogenicity of the natural estrogen compared to the synthetic estrogen.