Division of Environmental Genetics and Molecular Toxicology, Department of Environmental and Public Health Sciences, University of Cincinnati, Cincinnati, Ohio, USA.
Center for Environmental Genetics, University of Cincinnati, Cincinnati, Ohio, USA.
Environ Health Perspect. 2020 Dec;128(12):127005. doi: 10.1289/EHP6875. Epub 2020 Dec 9.
Bisphenol A (BPA) is known to be biologically active in experimental models even at low levels of exposure. However, its impact on endometrial cancer remains unclear.
This study aimed to investigate whether lifelong exposure to different doses of BPA induced uterine abnormalities and molecular changes in a rat model.
Sprague-Dawley rats were exposed to 5 doses of BPA [0, 25, 250, 2,500, or body weight (BW)/d] or 2 doses of (EE2) (0.05 and BW/d) starting from gestational day 6 up to 1 y old according to the CLARITY-BPA consortium protocol. The BW, uterus weight, and histopathology end points of the uteri were analyzed at postnatal (PND) day 21, 90, and 365. Estrous cycling status was evaluated in PND90 and PND365 rats. Transcriptomic analyses of estrus stage uteri were conducted on PND365 rats.
Based on the analysis of the combined effects of all testing outcomes (including immunohistological, morphological, and estrous cycle data) in a semiblinded fashion, using statistical models, BW/d BPA [BPA(25)], or BW/d BPA [BPA(250)] exerted effects similar to that of EE2 at BW/d in 1-y-old rats. Transcriptome analyses of estrus stage uteri revealed a set of 710 genes shared only between the BPA(25) and BPA(250) groups, with 115 of them predicted to be regulated by estradiol and 57 associated with female cancers. An interesting finding is that the expression of 476 human orthologous genes in this rat BPA signature robustly predicted the overall survival (, ) of endometrial cancer patients.
Lifelong exposure of rats to low-dose BPA at 25 and BW/d altered the estrous cycle and uterine pathology with similarity to EE2. The exposure also disrupted a unique low-dose BPA-gene signature with predictive value for survival outcomes in patients with endometrial cancer. https://doi.org/10.1289/EHP6875.
双酚 A（BPA）在实验模型中即使在低暴露水平下也具有生物活性。然而，它对子宫内膜癌的影响尚不清楚。
本研究旨在探讨大鼠模型中终生暴露于不同剂量的 BPA 是否会引起子宫异常和分子变化。
根据 CLARITY-BPA 联盟协议，从妊娠第 6 天到 1 岁，Sprague-Dawley 大鼠分别接受 5 种剂量的 BPA[0、25、250、2500 或体重（BW）/d]或 2 种剂量的 （EE2）[0.05 和 BW/d]。在产后（PND）第 21、90 和 365 天分析 BW、子宫重量和子宫组织病理学终点。在 PND90 和 PND365 大鼠中评估动情周期状态。在 PND365 大鼠中进行动情期子宫的转录组分析。
基于所有测试结果（包括免疫组织化学、形态学和动情周期数据）的联合效应的半盲分析，使用统计模型，BW/d BPA [BPA（25）]或 BW/d BPA [BPA（250）]在 1 岁大鼠中发挥作用类似于 EE2 在 BW/d。动情期子宫的转录组分析显示，BPA（25）和 BPA（250）组之间仅共享的一组 710 个基因，其中 115 个基因被预测受雌二醇调节，57 个基因与女性癌症相关。一个有趣的发现是，该大鼠 BPA 特征中 476 个人类同源基因的表达强烈预测了子宫内膜癌患者的总生存（，）。
大鼠终生低剂量 BPA 暴露[25 和 BW/d]改变了动情周期和子宫病理学，与 EE2 相似。暴露还破坏了一个独特的低剂量 BPA-基因特征，该特征对子宫内膜癌患者的生存结果具有预测价值。https://doi.org/10.1289/EHP6875.
