The xenoestrogen bisphenol A induces growth, differentiation, and c-fos gene expression in the female reproductive tract.
The xenoestrogen bisphenol A induces growth, differentiation, and c-fos gene expression in the female reproductive tract.
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DOI：
10.1210/endo.139.6.6027
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发表时间：
1998-06
期刊：
影响因子：
4.8
通讯作者：
R. Steinmetz;N. Mitchner;Andrea Grant;D. Allen;R. Bigsby;N. Ben-Jonathan
中科院分区：
文献类型：
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作者：
R. Steinmetz;N. Mitchner;Andrea Grant;D. Allen;R. Bigsby;N. Ben-Jonathan
异种雌激素双酚A（BPA）已被证明在体内和体外都能模拟雌激素。BPA刺激雌激素敏感的Fischer 344大鼠（F344）垂体后叶的PRL分泌和PRL调节因子的表达，但不刺激Sprague-Dawley（SD）大鼠。本研究的目的是检查BPA对生殖道的体内作用。具体目的是：1）描述BPA对子宫和阴道中细胞增殖和c-fos表达的短期影响，2）比较长期暴露于低剂量BPA对F344和SD大鼠生殖道的影响。通过溴脱氧尿苷免疫染色法测定，单次高剂量BPA治疗可诱导卵巢切除F344大鼠子宫和阴道中的细胞增殖。这种增殖是剂量依赖性的（从37.5-150毫克/公斤），并遵循一个类似的雌二醇（E2）的时间过程。定量RT-PCR显示，BPA和E2在2小时内使子宫中的c-fos信使RNA水平增加14至16倍，6小时后恢复到基础水平。在阴道中，BPA诱导的c-fos表达持续升高长达6小时，与E2引起的短暂增加相比。F344大鼠用连续释放胶囊治疗3天，连续释放胶囊提供低得多的BPA剂量（约0.3 mg/kg x天），导致子宫肥大、增生和粘液分泌以及阴道上皮增生和角化。SD大鼠的生殖道对BPA的这种治疗模式没有反应。结果表明：（1）BPA引起的子宫和阴道的分子和形态学改变与雌二醇几乎相同，（2）阴道对BPA的雌激素样作用特别敏感，（3）近交系F344大鼠生殖道对BPA的敏感性高于远交系SD大鼠;和4）持续暴露于微克水平的BPA足以发挥雌激素作用。
The xenoestrogen bisphenol A (BPA) has been shown to mimic estrogen both in vivo and in vitro. BPA stimulates PRL secretion and the expression of a PRL regulating factor from the posterior pituitary in the estrogen-sensitive Fischer 344 rat (F344), but not in Sprague-Dawley (SD) rats. The goal of the present studies was to examine the in vivo actions of BPA on the reproductive tract. The specific objectives were 1) to characterize the short term effects of BPA on cell proliferation and c-fos expression in the uterus and vagina, and 2) to compare the effects of prolonged exposure to low doses of BPA on the reproductive tract of F344 and SD rats. Treatment with single high doses of BPA induced cell proliferation in the uterus and vagina of ovariectomized F344 rats, as determined by bromodeoxyuridine immunostaining. This proliferation was dose dependent (from 37.5-150 mg/kg) and followed a time course similar to that of estradiol (E2). Quantitative RT-PCR revealed that both BPA and E2 increased c-fos messenger RNA levels in the uterus 14- to 16-fold within 2 h, which returned to basal levels after 6 h. In the vagina, BPA-induced c-fos expression remained elevated for up to 6 h, compared with the transient increase caused by E2. Treatment of F344 rats for 3 days with continuous release capsules that supplied a much lower dose of BPA (approximately 0.3 mg/kg x day) resulted in hypertrophy, hyperplasia, and mucus secretion in the uterus and hyperplasia and cornification of the vaginal epithelium. The reproductive tract of SD rats did not respond to this treatment paradigm with BPA. These studies demonstrate that 1) the molecular and morphological alterations induced by BPA in the uterus and vagina are nearly identical to those induced by estradiol; 2) the vagina appears to be especially sensitive to the estrogenic actions of BPA; 3) the reproductive tract of the inbred F344 rat appears more sensitive to BPA than that of the outbred SD rat; and 4) continuous exposure to microgram levels of BPA is sufficient for exerting estrogenic actions.