Effects of beta-estradiol and bisphenol A on heat shock protein levels and localization in the mouse uterus are antagonized by the antiestrogen ICI 182,780.
Bisphenol A (BPA) exhibits many estrogen-like effects in the rodent uterus, but not all of these can be attenuated by antiestrogens. This suggests the involvement of alternate pathways of BPA action that do not involve the estrogen receptor (ER). An examination of the in vivo effects of BPA on uterine gene expression and protein levels should contribute to an understanding of its mechanism of action. In this study we examined the dose-related effects of BPA on levels of a suite of heat shock proteins (hsps) and on the localization of hsp90alpha, a chaperone of the ER, in uteri of ovariectomized B6C3F1 mice and compared these effects with those of beta-estradiol (E2). The antiestrogen ICI 182,780 (ICI) was co-administered with BPA or E2 in order to examine the potential role of the ER. BPA, although less potent than E2, increased hsp90alpha and grp94 to similar levels, but was much less effective than E2 in increasing levels of hsp72. Treatment with 100 mg BPA/kg/day or 2 microg E2/kg/day increased hsp90alpha to 300% of control levels and altered its tissue expression pattern. In uteri of corn oil (control)-treated mice, hsp90alpha predominantly localized in the cytoplasm and nuclei of epithelial cells. Upon treatment with BPA or E2 there was increased intensity of staining in the stroma and myometrium, and in the epithelium hsp90alpha was localized almost exclusively in the cytoplasm. The effects of BPA or E2 on hsp levels and hsp90alpha localization were attenuated by ICI. These results suggest an involvement of the ER in BPA- and E2-induced increases in uterine levels of hsp90alpha, grp94, and hsp72, and localization of hsp90alpha.
Papaconstantinou
A D
AD
Department of Biological Sciences, George Washington University, Washington, DC 20052, USA.
Fisher
B R
BR
Umbreit
T H
TH
Goering
P L
PL
Lappas
N T
NT
Brown
K M
KM
D000818:Animals; D001559:Benzhydryl Compounds; D015153:Blotting, Western; D003593:Cytoplasm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D004968:Estrogens, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D051379:Mice; D008815:Mice, Inbred Strains; D018832:Molecular Chaperones / Q000378:metabolism*; D009215:Myometrium / Q000187:drug effects; D010052:Ovariectomy; D010636:Phenols / Q000008:administration & dosage / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000502:physiology; D013997:Time Factors; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004958:Estradiol; D004965:Estrogen Antagonists; D004968:Estrogens, Non-Steroidal; D000077267:Fulvestrant; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D010636:Phenols; D011960:Receptors, Estrogen; C006780:bisphenol A; D000098826:Bisphenol A Compounds