THE EFFECTS OF PHYTOESTROGENS ON NEONATAL RAT UTERINE GROWTH AND DEVELOPMENT

Phytoestrogens found in clover, alfalfa, and soybeans have caused repr oductive toxicity in several mammalian species. Other estrogens, such as diethylstilbestrol (DES), are developmental toxicants, reducing ute rine estrogen receptor (ER) concentration, altering uterine growth, an d eliciting reproductive tract abnormalities in the rat. The present s tudy examines the effects of the phytoestrogens coumestrol and equol o n the developing rat uterus. Various doses of these compounds were inj ected sc on postnatal days (PND) 1-5 or 1-10 to ascertain their effect s on uterine weight and ER levels, and on PND 10-14 to determine their effects on uterine weight and gland genesis. Coumestrol (PND 1-5) was about 10(-3) as potent as DES in increasing uterine weight (wet or dr y) while equol increased dry weight only, with a potency of 10(-5) tha t of DES. Although the 10 and 100 mu g doses of coumestrol (PND 1-5 or 1-10) initially increased uterine wet weight, by PND 20 uterine weigh ts either equaled or fell significantly below controls. The 100-mu g d ose of coumestrol (PND 1-5 or 1-10) reduced ER levels at all ages, whi le the 10-mu g dose was not as effective. Equol (PND 1-5 or 1-10) did not affect ER levels. Premature uterine gland genesis occurred by PND 9 for the PND 1-5 100-mu g coumestrol dose. When given on PND 10-14 (t he critical period of gland genesis), 10 mu g and 100 mu g of coumestr ol and 10 mu g DES greatly increased uterine weight, while no effect w as elicited by equol. Although coumestrol and equol inhibited uterine gland genesis in a dose-dependent manner, neither abolished gland gene sis as did 10 mu g of DES or tamoxifen. These data demonstrate that co umestrol elicits uterine biochemical and morphological toxicity much l ike DES. Equol decreased uterine gland number without increasing uteri ne wet weight or luminal epithelial hypertrophy, which is inconsistent with either an estrogenic or antiestrogenic action in the uterus.