Papaconstantinou A D, Fisher B R, Umbreit T H, Goering P L, Lappas N T, Brown K M
Department of Biological Sciences, George Washington University, Washington, DC 20052, USA.
Toxicol Sci. 2001 Oct;63(2):173-80. doi: 10.1093/toxsci/63.2.173.
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.
双酚A（BPA）在啮齿动物子宫中表现出许多类似雌激素的作用，但并非所有这些作用都能被抗雌激素减弱。这表明BPA作用的替代途径的参与，这些途径不涉及雌激素受体（ER）。研究BPA对子宫基因表达和蛋白质水平的体内影响应有助于理解其作用机制。在本研究中，我们检查了BPA对一组热休克蛋白（hsps）水平的剂量相关影响，以及对ER的伴侣蛋白hsp90α在去卵巢B6C3F1小鼠子宫中的定位的影响，并将这些影响与β-雌二醇（E2）的影响进行比较。抗雌激素ICI 182,780（ICI）与BPA或E2共同给药，以检查ER的潜在作用。BPA虽然比E2效力低，但能将hsp90α和grp94增加到相似水平，但在增加hsp72水平方面比E2效果差得多。以100 mg BPA/kg/天或2 μg E2/kg/天治疗可使hsp90α增加至对照水平的300%，并改变其组织表达模式。在玉米油（对照）处理小鼠的子宫中，hsp90α主要定位于上皮细胞的细胞质和细胞核中。用BPA或E2处理后，基质和肌层中的染色强度增加，并且在上皮中hsp90α几乎完全定位于细胞质中。ICI减弱了BPA或E2对hsp水平和hsp90α定位的影响。这些结果表明ER参与了BPA和E2诱导的子宫中hsp90α、grp94和hsp72水平的增加以及hsp90α的定位。
