Estrogenic responses in estrogen receptor-alpha deficient mice reveal a distinct estrogen signaling pathway.

Estrogens are thought to regulate female reproductive functions by altering gene transcription in target organs primarily via the nuclear estrogen receptor-alpha (ER-alpha). By using ER-alpha "knock-out" (ERKO) mice, we demonstrate herein that a catecholestrogen, 4-hydroxyestradiol-17beta (4-OH-E2), and an environmental estrogen, chlordecone (kepone), up-regulate the uterine expression of an estrogen-responsive gene, lactoferrin (LF), independent of ER-alpha. A primary estrogen, estradiol-17beta (E2), did not induce this LF response. An estrogen receptor antagonist, ICI-182,780, or E2 failed to inhibit uterine LF gene expression induced by 4-OH-E2 or kepone in ERKO mice, which suggests that this estrogen signaling pathway is independent of both ER-alpha and the recently cloned ER-beta. 4-OH-E2, but not E2, also stimulated 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 estrogen response pathway will have profound implications for our understanding of the physiology and pathophysiology of female sex steroid hormone actions in target organs.

[1]  J. Gustafsson,et al.  Mouse estrogen receptor beta forms estrogen response element-binding heterodimers with estrogen receptor alpha. , 1997, Molecular endocrinology.

[2]  S. Cowley,et al.  Estrogen Receptors α and β Form Heterodimers on DNA* , 1997, The Journal of Biological Chemistry.

[3]  R. Karas,et al.  Estrogen inhibits the vascular injury response in estrogen receptor α-deficient mice , 1997, Nature Medicine.

[4]  K. Korach,et al.  Endothelial dysfunction in a man with disruptive mutation in oestrogen-receptor gene , 1997, The Lancet.

[5]  N. Copeland,et al.  Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. , 1997, Molecular endocrinology.

[6]  K. Grandien,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors � and � , 2022 .

[7]  S. Dey,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Differential Expression of the erbB2 Gene in the Periimplantation Mouse Uterus: Potential Mediator of Signaling by Epidermal Growth Factor-Like Growth , 2022 .

[8]  J. Gustafsson,et al.  Estrogen receptor-beta mRNA expression in rat ovary: down-regulation by gonadotropins. , 1997, Molecular endocrinology.

[9]  Y. Lee,et al.  Estrogen-induced transcription of the progesterone receptor gene does not parallel estrogen receptor occupancy. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Gustafsson,et al.  Orphan nuclear receptors--the first eight years. , 1996, Molecular endocrinology.

[11]  K. Korach,et al.  Disruption of estrogen receptor gene prevents 17 beta estradiol-induced angiogenesis in transgenic mice. , 1996, Endocrinology.

[12]  K. Horwitz,et al.  Nuclear receptor coactivators and corepressors. , 1996, Molecular endocrinology.

[13]  A. Glasebrook,et al.  Identification of an Estrogen Response Element Activated by Metabolites of 17β-Estradiol and Raloxifene , 1996, Science.

[14]  J. Polman,et al.  ERβ: Identification and characterization of a novel human estrogen receptor , 1996 .

[15]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Liehr,et al.  4-Hydroxylation of estrogens as marker of human mammary tumors. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  B. Katzenellenbogen,et al.  Tripartite steroid hormone receptor pharmacology: interaction with multiple effector sites as a basis for the cell- and promoter-specific action of these hormones. , 1996, Molecular endocrinology.

[18]  R. Karas,et al.  Human vascular smooth muscle cells express an estrogen receptor isoform , 1995, FEBS letters.

[19]  B. O’Malley,et al.  Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily , 1995, Science.

[20]  K. Korach,et al.  Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. , 1995, Molecular endocrinology.

[21]  S. Dey,et al.  Amphiregulin is an implantation-specific and progesterone-regulated gene in the mouse uterus. , 1995, Molecular endocrinology.

[22]  M. Shupnik,et al.  Estrogen regulates the expression of several different estrogen receptor mRNA isoforms in rat pituitary. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Andrew A. Rooney,et al.  Gonadal steroidogenesis in vitro from juvenile alligators obtained from contaminated or control lakes. , 1995, Environmental health perspectives.

[24]  S. Safe,et al.  Environmental and dietary estrogens and human health: is there a problem? , 1995, Environmental health perspectives.

[25]  J. Auger,et al.  Debate about sperm count decline. , 1998, Environmental health perspectives.

[26]  M. Wehling.  Nongenomic actions of steroid hormones , 1994, Trends in Endocrinology & Metabolism.

[27]  Y. Yamasaki,et al.  Estrogen regulation of the insulin-like growth factor I gene transcription involves an AP-1 enhancer. , 1994, The Journal of biological chemistry.

[28]  K. Korach,et al.  Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  M. Tetzlaff,et al.  Identification of an isoform of the estrogen receptor messenger RNA lacking exon four and present in the brain. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[30]  H. Oshima,et al.  Higher levels of control: modulation of steroid hormone-regulated gene transcription. , 1992, Molecular endocrinology.

[31]  K. Korach,et al.  Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[32]  C. Teng,et al.  Estrogen response module of the mouse lactoferrin gene contains overlapping chicken ovalbumin upstream promoter transcription factor and estrogen receptor-binding elements. , 1992, Molecular endocrinology.

[33]  S. Dey,et al.  Initiation of Embryo Implantation and Maintenance of Early Pregnancy in the Rat by Chlordecone (Kepone) , 1990, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[34]  O. Meyuhas,et al.  The mouse ribosomal protein L7 gene. Its primary structure and functional analysis of the promoter region. , 1990, The Journal of biological chemistry.

[35]  S. Dey,et al.  Catechol estrogen formation in the mouse uterus and its role in implantation , 1990, Molecular and Cellular Endocrinology.

[36]  S. Dey,et al.  Role of early and late oestrogenic effects on implantation in the mouse. , 1987, Journal of reproduction and fertility.

[37]  K. Korach,et al.  Diethylstilbestrol metabolites and analogs. Biochemical probes for differential stimulation of uterine estrogen responses. , 1985, The Journal of biological chemistry.

[38]  F. Naftolin,et al.  Kinetics of catechol estrogen-estrogen receptor dissociation: A possible factor underlying differences in catechol estrogen biological activity , 1983, Steroids.

[39]  A. Hsueh,et al.  Binding of 2-hydroxyestradiol to rat anterior pituitary cell membranes. , 1980, The Journal of biological chemistry.

[40]  S. Dey,et al.  Expression of the epidermal growth factor receptor gene is regulated in mouse blastocysts during delayed implantation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[41]  S. Safe,et al.  Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). , 1990, Critical reviews in toxicology.