Low-Dose Bisphenol A in a Rat Model of Endometrial Cancer: A CLARITY-BPA Study,Environmental Health Perspectives

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Low-Dose Bisphenol A in a Rat Model of Endometrial Cancer: A CLARITY-BPA Study
Environmental Health Perspectives ( IF 10.1 ) Pub Date : 2020-12-9 , DOI: 10.1289/ehp6875
Yuet-Kin Leung _{1,

2} , Jacek Biesiada _{2,

3} , Vinothini Govindarajah ₁ , Jun Ying _{2,

3} , Ady Kendler ₄ , Mario Medvedovic _{2,

3} , Shuk-Mei Ho _{1,

2}

Affiliation

Abstract

Background:

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.

Objectives:

This study aimed to investigate whether lifelong exposure to different doses of BPA induced uterine abnormalities and molecular changes in a rat model.

Methods:

Sprague-Dawley rats were exposed to 5 doses of BPA [0, 25, 250, 2,500, or $25000 micrograms per kilogram$ body weight (BW)/d] or 2 doses of $17 lowercase alpha-ethynylestradiol$ (EE2) (0.05 and $0.5 microgram per kilogram$ 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.

Results:

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, $25 micrograms per kilogram$ BW/d BPA [BPA(25)], or $250 micrograms per kilogram$ BW/d BPA [BPA(250)] exerted effects similar to that of EE2 at $0.5 microgram per kilogram$ 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 ( $p = 1.68 \times 10^{- 5}$ , $hazard ratio equals 2.62$ ) of endometrial cancer patients.

Discussion:

Lifelong exposure of rats to low-dose BPA at 25 and $250 micrograms per kilogram$ 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

中文翻译：

子宫内膜癌大鼠模型中的低剂量双酚 A：一项 CLARITY-BPA 研究

抽象的

背景：

已知双酚 A (BPA) 在实验模型中即使在低水平暴露下也具有生物活性。然而，它对子宫内膜癌的影响仍不清楚。

目标：

本研究旨在调查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。

方法：

Sprague-Dawley 大鼠暴露于 5 剂量的 BPA [0、25、250、2,500 或 $25000 micrograms per kilogram$ 体重 (BW)/d] 或 2 剂 $17 lowercase alpha-ethynylestradiol$ (EE2) (0.05 和 $0.5 microgram per kilogram$ BW/d) 根据 CLARITY-BPA 联盟协议，从妊娠第 6 天开始直至 1 岁。在出生后 (PND) 第 21、90 和 365 天分析子宫的体重、子宫重量和组织病理学终点。评估 PND90 和 PND365 大鼠的动情周期状态。对 PND365 大鼠进行发情期子宫的转录组学分析。

结果：

基于以半盲方式使用统计模型对所有测试结果（包括免疫组织学、形态学和动情周期数据）的综合影响进行分析， $25 micrograms per kilogram$ BW/d BPA [BPA(25)]，或 $250 micrograms per kilogram$ BW/d BPA [BPA(250)] 在以下条件下发挥与 EE2 相似的效果： $0.5 microgram per kilogram$ 1 岁大鼠的体重/天。发情期子宫的转录组分析揭示了一组仅在 BPA(25) 和 BPA(250) 组之间共享的 710 个基因，其中 115 个预计受雌二醇调节，57 个与女性癌症相关。一个有趣的发现是，该大鼠 BPA 特征中 476 个人类直系同源基因的表达有力地预测了总体生存率（ $p = 1.68 \times 10^{- 5}$ , $hazard ratio equals 2.62$ ）子宫内膜癌患者。

讨论：

大鼠在 25 岁和 25 岁时终生接触低剂量 BPA $250 micrograms per kilogram$ BW/d 改变了动情周期和子宫病理，与 EE2 相似。这种暴露还破坏了一种独特的低剂量 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

更新日期：2020-12-09

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