<br>双酚 A 及其代谢物 MBP 对斑马鱼的心血管作用和分子机制。,Environmental Science & Technology

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双酚 A 及其代谢物 MBP 对斑马鱼的心血管作用和分子机制。
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2018-12-20 , DOI: 10.1021/acs.est.8b04281
A Ross Brown ₁ , Jon M Green ₁ , John Moreman ₁ , Lina M Gunnarsson ₁ , Sulayman Mourabit ₁ , Jonathan Ball ₁ , Matthew J Winter ₁ , Maciej Trznadel ₁ , Ana Correia ₁ , Christian Hacker ₁ , Alexis Perry ₁ , Mark E Wood ₁ , Malcolm J Hetheridge ₁ , Richard A Currie ₂ , Charles R Tyler ₁

Affiliation

塑料单体双酚 A (BPA) 是世界上产量最高的化学品之一，经常在野生动物和人类（尤其是儿童）中检测到。 BPA 与许多与其雌激素和其他激素特性相关的不良健康结果有关，但在人类和动物模型中，直接因果关系尚不清楚。在这里，我们使用荧光报告基因胚胎幼虫斑马鱼模拟了测量的 (1×) 和预测的最坏情况 (10×) BPA 最大胎儿暴露量或其代谢物 MBP 的等效浓度，能够量化整个过程中雌激素反应元件 (ERE) 的激活身体。心脏瓣膜是 BPA 和 MBP 激活 ERE 的主要位点，显微解剖心脏组织的转录组分析表明，这两种化学物质都靶向构成钙化性主动脉瓣疾病 (CAVD) 生物标志物的多种分子途径，包括细胞外基质 (ECM) 改变。高水平 MBP 暴露的组织病理学证实了 ECM 胶原蛋白缺乏和对心脏瓣膜结构完整性的影响，房室瓣的结构缺陷（异常曲率）与心血管功能受损（心室搏动率和血流量降低）相对应。我们的结果首次证明了 BPA 的反应性代谢产物 MBP 激活心脏瓣膜中的 ERE 与瓣膜心血管疾病状态的发展之间存在合理的机制联系。

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Cardiovascular Effects and Molecular Mechanisms of Bisphenol A and Its Metabolite MBP in Zebrafish.

The plastic monomer bisphenol A (BPA) is one of the highest production volume chemicals in the world and is frequently detected in wildlife and humans, particularly children. BPA has been associated with numerous adverse health outcomes relating to its estrogenic and other hormonal properties, but direct causal links are unclear in humans and animal models. Here we simulated measured (1×) and predicted worst-case (10× ) maximum fetal exposures for BPA, or equivalent concentrations of its metabolite MBP, using fluorescent reporter embryo-larval zebrafish, capable of quantifying Estrogen Response Element (ERE) activation throughout the body. Heart valves were primary sites for ERE activation by BPA and MBP, and transcriptomic analysis of microdissected heart tissues showed that both chemicals targeted several molecular pathways constituting biomarkers for calcific aortic valve disease (CAVD), including extra-cellular matrix (ECM) alteration. ECM collagen deficiency and impact on heart valve structural integrity were confirmed by histopathology for high-level MBP exposure, and structural defects (abnormal curvature) of the atrio-ventricular valves corresponded with impaired cardiovascular function (reduced ventricular beat rate and blood flow). Our results are the first to demonstrate plausible mechanistic links between ERE activation in the heart valves by BPA's reactive metabolite MBP and the development of valvular-cardiovascular disease states.

更新日期：2018-12-21

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