Leydig cell hyperplasia in fetal mice treated transplacentally with ethinyl estradiol

Pregnant female mice were given ethinyl estradiol on days 11 through 17 of gestation. On day 18 the dams were killed and the male fetuses were examined for testicular differentiation. Three of 12 males from dams treated with the highest dose of ethinyl estradiol showed cryptorchid testes with uterine tubes. Light and electron microscopic evaluation of the testes, both cryptorchid and normal, demonstrated foci of hyperplasia of Leydig cells showing cytoplasmic and nuclear pleomorphism, increase in lipid droplets, and decrease in smooth endoplasmic reticulum and ribosomes when compared to testes from control fetal mice. Morphometric determinations of the testes indicated that the number of Leydig cells in a unit area (mm2) in the interstitial tissue showed a dose-response relationship to ethinyl estradiol in the normal testes. The number of Leydig cells in the testes exposed to the highest dose of estrogen showed a significant difference between cryptorchid and normal testes: the former had fewer Leydig cells than the latter. These morphological observations indicate that hyperplasia of Leydig cells of fetal mouse testis at term can be induced by transplacental treatment with ethinyl estradiol and suggest that a malignant transformation into a Leydig cell tumor is possible.