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*Compound via MeSH
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*4,4'-BISPHENOL A
*BISPHENOL A DISODIUM SALT
*TAMOXIFEN
*THIOPHENE
Endocrinology Vol. 141, No. 9 3430-3439
Copyright © 2000 by The Endocrine Society

ARTICLES

Activation of a Uterine Insulin-Like Growth Factor I Signaling Pathway by Clinical and Environmental Estrogens: Requirement of Estrogen Receptor-{alpha}

Diane M. Klotz, Sylvia Curtis Hewitt, Kenneth S. Korach and Richard P. Diaugustine

Laboratories of Molecular Carcinogenesis (D.M.K., R.P.D.) and Reproductive and Developmental Toxicology (S.C.H., K.S.K.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Dr. Richard P. DiAugustine, National Institute of Environmental Health Sciences, P.O. Box 12233, Mail Drop D4–04, Research Triangle Park, North Carolina 27709. E-mail: diaugus2{at}niehs.nih.gov

Recent data indicate that insulin-like growth factor I (IGF-I) may have a function in mediating the mitogenic effects of 17ß-estradiol (E2) in the uterus and in regulating the growth of uterine neoplasms. This study was designed to determine whether synthetic and plant-derived chemicals that interact with estrogen receptor-{alpha} (ER{alpha}) and elicit estrogenic responses also mimic E2 by activating the uterine IGF-I signaling pathway. Ovariectomized adult female mice were treated with both environmental and clinically relevant chemicals previously reported to display estrogenic and/or antiestrogenic properties, and their uteri were evaluated for an activated IGF-I signaling pathway. Diethylstilbestrol, 4-hydroxytamoxifen, the raloxifene analog LY353381, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), bisphenol A, and genistein were shown to mimic E2 in the uterus by increasing the level of IGF-I messenger RNA, inducing IGF-I receptor (IGF-IR) tyrosine phosphorylation, stimulating the formation of IGF-IR signaling complexes, and increasing both proliferating cell nuclear antigen expression and the number of mitotic cells in the epithelium. The dose of chemical necessary to activate IGF-I signaling varied, with the order of potency: E2 = diethylstilbestrol > LY353381 > 4-hydroxytamoxifen > genistein > HPTE > bisphenol A. Administration of the chemicals to ER{alpha} knockout mice did not activate IGF-IR, indicating that ER{alpha} is required for activation of uterine IGF-IR by these diverse chemicals. This study demonstrates that several chemicals shown previously to display estrogenic activities also mimic E2 by activating uterine IGF-I signaling.




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