ESTROGENIC RESPONSES IN ESTROGEN RECEPTOR-ALPHA DEFICIENT MICE REVEALA DISTINCT ESTROGEN SIGNALING PATHWAY

Estrogens are thought to regulate female reproductive functions by alt ering gene transcription in target organs primarily via the nuclear es trogen receptor-alpha (ER-alpha). By using ER-alpha ''knock-out'' (ERK O) mice, we demonstrate herein that a catecholestrogen, 4-hydroxyestra diol-17 beta (4-OH-E-2), and an environmental estrogen, chlordecone (k epone), up-regulate the uterine expression of an estrogen-responsive g ene, lactoferrin (LF), independent of ER-alpha, A primary estrogen, es tradiol-17 beta (E-2), did not induce this LF response, An estrogen re ceptor antagonist, ICI-182,780, or E-2 failed to inhibit uterine LF ge ne expression induced by 4-OH-E-2 or kepone in ERKO mice, which sugges ts that this estrogen signaling pathway is independent of both ER-alph a and the recently cloned ER-beta, 4-OH-E-2, but not E-2, also stimula ted increases in uterine water imbibition and macromolecule uptake in ovariectomized ERKO mice, The results strongly imply the presence of a distinct estrogen-signaling pathway in the mouse uterus that mediates the effects of both physiological and environmental estrogens, This e strogen response pathway will have profound implications for our under standing of the physiology and pathophysiology of female sex steroid h ormone actions in target organs.