Activation of a uterine insulin-like growth factor I signaling pathway by clinical and environmental estrogens: requirement of estrogen receptor-alpha.
Recent data indicate that insulin-like growth factor I (IGF-I) may have a function in mediating the mitogenic effects of 17beta-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 (ERalpha) 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 ERalpha knockout mice did not activate IGF-IR, indicating that ERalpha 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.
Klotz
D M
DM
Laboratories of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Hewitt
S C
SC
Korach
K S
KS
Diaugustine
R P
RP
D000818:Animals; D001559:Benzhydryl Compounds; D015152:Blotting, Northern; D045166:Estradiol Congeners / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000494:pharmacology*; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000187:drug effects; D010052:Ovariectomy; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011233:Precipitin Tests; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014599:Uterus / Q000378:metabolism*; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D045166:Estradiol Congeners; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D007334:Insulin-Like Growth Factor I; D010636:Phenols; D010880:Piperidines; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D012260:Ribonucleases; D013629:Tamoxifen; D013876:Thiophenes; C016601:afimoxifene; C115121:LY 353381; C404910:2,2-bis(4-hydroxyphenyl)-1,1,1-trichloroethane; C006780:bisphenol A; D000098826:Bisphenol A Compounds