Medlock K L, Branham W S, Sheehan D M
Division of Reproductive and Developmental Toxicology, Food and Drug Administration, Jefferson, Arkansas 72079-9502.
Proc Soc Exp Biol Med. 1995 Mar;208(3):307-13. doi: 10.3181/00379727-208-43861.
Phytoestrogens found in clover, alfalfa, and soybeans have caused reproductive toxicity in several mammalian species. Other estrogens, such as diethylstilbestrol (DES), are developmental toxicants, reducing uterine estrogen receptor (ER) concentration, altering uterine growth, and eliciting reproductive tract abnormalities in the rat. The present study examines the effects of the phytoestrogens coumestrol and equol on the developing rat uterus. Various doses of these compounds were injected sc on postnatal days (PND) 1-5 or 1-10 to ascertain their effects 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 dry) while equol increased dry weight only, with a potency of 10(-5) that of DES. Although the 10 and 100 micrograms doses of coumestrol (PND 1-5 or 1-10) initially increased uterine wet weight, by PND 20 uterine weights either equaled or fell significantly below controls. The 100-micrograms dose of coumestrol (PND 1-5 or 1-10) reduced ER levels at all ages, while the 10-micrograms 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-micrograms coumestrol dose. When given on PND 10-14 (the critical period of gland genesis), 10 micrograms and 100 micrograms of coumestrol and 10 micrograms DES greatly increased uterine weight, while no effect was elicited by equol. Although coumestrol and equol inhibited uterine gland genesis in a dose-dependent manner, neither abolished gland genesis as did 10 micrograms of DES or tamoxifen. These data demonstrate that coumestrol elicits uterine biochemical and morphological toxicity much like DES. Equol decreased uterine gland number without increasing uterine wet weight or luminal epithelial hypertrophy, which is inconsistent with either an estrogenic or antiestrogenic action in the uterus.
在三叶草、苜蓿和大豆中发现的植物雌激素已在几种哺乳动物物种中引起生殖毒性。其他雌激素，如己烯雌酚（DES），是发育毒物，会降低大鼠子宫雌激素受体（ER）浓度，改变子宫生长，并引发生殖道异常。本研究考察了植物雌激素香豆雌酚和雌马酚对发育中的大鼠子宫的影响。在出生后第1至5天或第1至10天皮下注射不同剂量的这些化合物，以确定它们对子宫重量和ER水平的影响，并在出生后第10至14天注射以确定它们对子宫重量和腺体发生的影响。香豆雌酚（出生后第1至5天）增加子宫重量（湿重或干重）的效力约为DES的10^(-3)，而雌马酚仅增加干重，效力为DES的10^(-5)。尽管10微克和100微克剂量的香豆雌酚（出生后第1至5天或第1至10天）最初增加了子宫湿重，但到出生后第20天，子宫重量要么与对照组相等，要么显著低于对照组。100微克剂量的香豆雌酚（出生后第1至5天或第1至10天）在所有年龄段都降低了ER水平，而10微克剂量的效果则不那么明显。雌马酚（出生后第1至5天或第1至10天）对ER水平没有影响。对于出生后第1至5天给予100微克香豆雌酚的剂量，在出生后第9天就出现了子宫腺体过早发生的情况。当在出生后第10至14天（腺体发生的关键时期）给予时，10微克和100微克的香豆雌酚以及10微克DES极大地增加了子宫重量，而雌马酚则没有产生影响。尽管香豆雌酚和雌马酚以剂量依赖的方式抑制子宫腺体发生，但它们都没有像10微克DES或他莫昔芬那样完全消除腺体发生。这些数据表明，香豆雌酚引起的子宫生化和形态毒性与DES非常相似。雌马酚减少了子宫腺体数量，但没有增加子宫湿重或腔上皮肥大，这与子宫中的雌激素或抗雌激素作用均不一致。
