The specificity of mouse uterine heat shock protein expression and possible mechanisms for bisphenol A-induced uterine estrogen-like effects.

摘要

Bisphenol A (BPA) is a weak estrogenic chemical used in the manufacture of food containers. The ability of BPA to increase uterine weights of ovariectomized mice, similarly to β-estradiol (E₂), has been previously shown. However, its mechanism of action remains largely unknown. The estrogen receptor (ER) is involved in the E₂-induced increases in uterine weights. The studies that make up this dissertation have demonstrated the involvement of the ER in the BPA-induced increases in uterine weight and uterine luminal epithelial cell height following 4 consecutive days of treatment. A suite of uterine heat shock proteins, hsp90α, hsp72 and the glucose-regulated protein (grp) 94, are shown to be under estrogenic control. Increases in hsp90α, grp94, and hsp72 induced by E₂ or BPA after 4 consecutive days of treatment were antagonized by ICI 182,780 (ICI), an antiestrogen. This result suggests a role for the ER in estrogen-induced uterine hsp increases. The specificity of this response was demonstrated using several agonists of the ER and agonists for other receptors such as the progesterone receptor (PR) and the androgen receptor (AR). Whereas all ER agonists increased uterine hsp90α and grp94 levels, the PR agonist did not. The AR agonist, 17α-methyltestosterone, increased uterine hsp90α and grp94 levels, but these effects were antagonized only by ICI and not by the antiandrogen, flutamide. This further supports the conclusion that the ER is involved even in androgenic increases of uterine hsps.; The mechanism of action for the effects of E₂ and BPA on uterine hsp90α and hsp72 expression at 6 or 24 h after administration was examined. None of the effects of E₂ or BPA on uterine hsp90α or hsp72 mRNA and protein levels were antagonized by ICI. Regulation of uterine heat shock factor-1 (HSF-1) is restricted to E₂, as BPA failed to alter HSF-1 mRNA or protein levels. Both PKC and the ER are likely to be involved in the effects of E₂ on uterine HSF-1 expression. Collectively, the results of this dissertation suggest that BPA mimics E₂ in several responses in the uterus, but differs in its temporal effects and in the mechanism of hsp90α regulation.