Estrogen receptor subtypes selectively mediate female mouse reproductive abnormalities induced by neonatal exposure to estrogenic chemicals

Perinatal exposure to estrogens such as diethylstilbestrol (DES), and to estrogenic chemicals, induces persistent anovulation caused by alteration of hypothalamic–pituitary–gonadal (HPG) axis, polyovular follicles, uterine abnormalities and persistent vaginal changes in mice. Most activities of estrogenic chemicals are mediated through estrogen receptor α (ERα) and/or ERβ. However, little was known about the relative contribution of the individual ER subtypes in induction of abnormalities. We tested the effects of neonatal exposure to ER selective ligands and DES on female mice. Transactivation assays using mouse ERα and ERβ showed that 10−10 M DES activated both ER subtypes and that the ERα agonist (propyl pyrazole triol, PPT) and the ERβ agonist (diarylpropionitrile, DPN) selectively activated their respective ERs at 10−9 M. Neonatal female mice were injected subcutaneously with DES, PPT or DPN and the animals were examined at 13 and 15 weeks of age, respectively. Persistent estrous smears and anovulation were induced in all mice by 0.025–2.5 μg DES and 2.5–25 μg PPT, but not by DPN, suggesting that the observed anovulation was primarily mediated through ERα. Disorganization of uterine musculature and ovary-independent vaginal epithelial cell proliferation accompanied by persistent expression of EGF-related genes and interleukin-1-related genes were also mediated through ERα. In contrast, polyovular follicles were induced by neonatal treatment with both ERα and ERβ ligands, suggesting that ovarian abnormalities are mediated through both ER subtypes.