Endocrine Disruptors and Heart Health

双酚A(BPA)是一种常见的环境内分泌干扰物(EDC)，具有多种 潜在的健康不良影响。越来越多的流行病学和实验研究表明， 更高的双酚A暴露与心血管疾病之间的潜在联系。在之前的研究中，我们报告说 关于双酚A在啮齿动物心脏中致心律失常作用的一些初步证据。我们进一步表明， 双酚A的促心律失常作用与双酚S(BPS)相同，双酚A的类似物被用于许多 “不含双酚A”产品。我们的发现证明了双酚A潜在的促心律失常毒性，并强调了 需要进一步定义双酚A和相关的内分泌细胞对人类心脏健康的影响。 我们建议的目标是确定BPA和BPS在较大动物中的促心律失常毒性， 包括人类，特别是通过延长心电图的QT间期。QT 间期反映了心脏的心室兴奋持续时间。在人类和其他较大的物种中，一种独特的 致心律失常机制为QT延长。重要的是，QT延长是一种常见的心脏疾病 对化学和药物的毒性，并被公认为心脏安全的中心问题。 已有研究表明，包括雌激素在内的女性荷尔蒙可以延长两人的QT间期 女性和动物模型。然而，BPA，一种几乎无处不在的雌激素EDC，对QT风险的影响 延长和相关的心律失常是完全未知的。在令人信服的初步研究支持下，我们 建议解决以下中心假设：在包括人类在内的较大物种的心脏中，低剂量双酚A BPS通过延缓心室复极和延长QT间期而具有致心律失常的作用 这种促心律失常作用在存在QT延长的心脏中尤其显著，例如 特发性长QT间期综合征(LQT)患者。 该研究采用了动物实验和流行病学分析相结合的方法。 生物标本和来自费尔纳德社区队列的数据。政府行为的性别特殊性 在每个目标中都将涉及双酚类化学品。提出了三个目标。长期(目标1)和快速 (目的2)BPA和BPS暴露对心脏电生理和心律失常的影响将是 使用兔模型进行检查。在目标3中，成人接触双酚A与心电标记物的相关性 心脏电异常的情况将在费尔纳德社区队列中进行检查。拟议的研究 具有重要意义，因为它有望为了解 BPA和BPS在较大的动物心脏上。此外，我们的研究将提供更好的了解风险因素 心律失常，特别是在心脏病易感人群中。费尔纳德队列研究 代表了首个关于双酚A暴露与心脏电之间关系的流行病学研究 在我们了解双酚A的毒性方面，弥合了一个重大的知识鸿沟。

Bisphenol A (BPA) is a common environmental endocrine disrupting chemical (EDC) with a range of potential adverse health effects. Growing epidemiologic and experimental studies have demonstrated a potential link between higher BPA exposure and cardiovascular diseases. In previous studies, we reported some of the first evidence on the arrhythmogenic actions of BPA in rodent hearts. We further showed that the pro-arrhythmic effects of BPA was shared by bisphenol S (BPS), a BPA analog that is used in many of the “BPA-free” products. Our findings demonstrate the potential pro-arrhythmic toxicity of BPA, and highlight the need to further define the impact of BPA and related EDCs on human heart health. The goal of our proposal is to determine the pro-arrhythmic toxicity of BPA and BPS in larger animals, including humans, particularly through prolongation of the QT interval of the electrocardiogram (ECG). QT interval reflects the duration of ventricular excitation of the heart. In human and other larger species, a distinct arrhythmogenic mechanism is QT prolongation. Importantly, QT prolongation is a common forms of cardiac toxicity for chemical and pharmaceutical agents, and is well recognized as a central issue in cardiac safety. It has been shown that female sex hormones, including estrogen, prolong QT interval in both human females and animal models. However, the impact of BPA, a near ubiquitous estrogenic EDC, on the risk of QT prolongation and related arrhythmias is entirely unknown. Supported by compelling preliminary studies, we propose to address the central hypothesis that in the hearts of larger species including human, low-dose BPA and BPS have pro-arrhythmic toxicity through delay of ventricular repolarization and prolongation of the QT interval; this pro-arrhythmic action is particularly significant in hearts with existing QT prolongation, such as those of idiopathic long QT syndrome (LQT) patients. The study uses a combination of animal experiments using rabbits, and epidemiology analysis using biospecimens and data from the Fernald Community Cohort. The gender-specificity of the actions of the bisphenol chemicals will be addressed in each Aim. Three aims are proposed. The long-term (Aim 1) and rapid (Aim 2) effects of BPA and BPS exposure on cardiac electrophysiology and arrhythmogenesis will be examined using the rabbit model. In Aim 3, the correlation of BPA exposure in human adults and ECG markers of cardiac electrical abnormalities will be examined in the Fernald Community Cohort. The proposed research is significant because it is expected to provide important insights into the action and underlying mechanism of BPA and BPS on larger animal hearts. Further, our study will provide better understanding of the risk factors of cardiac arrhythmia, particularly in vulnerable subpopulations with cardiac disease. The Fernald Cohort study represents the first epidemiologic study on the association between BPA exposure and cardiac electrical abnormalities, bridging a major knowledge gap in our understanding of the toxicity of BPA.