Endocrine Disruptors and Heart Health

内分泌干​​扰物与心脏健康

• 批准号: 10330458
• 负责人: Jack Rubinstein
• 金额: $ 35.2万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330458
• 关键词: Action Potentials; Address; Adult; Animal Experiments; Animal Model; Animals; Arrhythmia; Canis familiaris; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac health; Cardiotoxicity; Cardiovascular Diseases; Chemical Agents; Chemicals; Cohort Studies; Communities; Data; Data Set; Dose; Echocardiography; Electrocardiogram; Electrophysiology (science); Endocrine Disruptors; Epidemiology; Estrogens; Exposure to; Gender; Goals; Health; Heart; Heart Abnormalities; Heart Diseases; Human; Ion Channel; Knowledge; Lead; Linear Regressions; Link; Long QT Syndrome; Long-Term Effects; Malignant - descriptor; Measures; Modeling; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Potassium Channel; Regression Analysis; Reporting; Research; Risk; Risk Factors; Rodent; Safety; Shapes; Specificity; Study models; Techniques; Tissues; Toxic effect; Toxicology; Ventricular; Ventricular Arrhythmia; Xenobiotics; analog; bisphenol A; clinically relevant; cohort; electrical property; epidemiology study; estrogenic; experimental study; exposed human population; female sex hormone; heart function; human female; insight; postnatal; prenatal; sudden cardiac death; urinary

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.

双酚A（BPA）是一种常见的环境内分泌干扰化学品（EDC）， 潜在的不良健康影响。越来越多的流行病学和实验研究表明， 高BPA暴露与心血管疾病之间的潜在联系。在以前的研究中，我们报道 一些关于双酚A在啮齿动物心脏中致炎作用的第一批证据。我们进一步表明， 双酚S（BPS）也具有BPA的促孕作用，BPS是一种BPA类似物， “无BPA”产品。我们的研究结果证明了BPA的潜在促炎毒性，并强调了 需要进一步确定BPA和相关EDCs对人类心脏健康的影响。 我们提案的目的是确定BPA和BPS在大型动物中的促生殖毒性， 包括人类，特别是通过延长心电图（ECG）的QT间期。Qt 间隔反映心脏的心室兴奋的持续时间。在人类和其他较大的物种中， 致心律失常的机制是QT间期延长。重要的是，QT间期延长是心脏病的常见形式。 化学和药物制剂的毒性，并且被公认为心脏安全性的中心问题。 研究表明，包括雌激素在内的女性性激素可延长人和哺乳动物的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的支持下， 我建议解决一个中心假设，即在包括人类在内的较大物种的心脏中，低剂量BPA BPS通过延迟心室复极和延长QT而具有促心律失常毒性 这种促心律失常作用在存在QT间期延长的心脏中尤其显著，例如 特发性长QT综合征（LQT）患者。 这项研究结合了兔子的动物实验和流行病学分析， 来自Fernald社区队列的生物标本和数据。妇女署行动的性别特异性 双酚化学品将在每个目标中得到解决。提出了三个目标。长期（目标1）和快速 (Aim 2）BPA和BPS暴露对心脏电生理和心肌发生的影响将被 使用兔子模型进行检查。在目标3中，成人BPA暴露与ECG标志物的相关性 将在Fernald社区队列中检查心脏电异常。拟议研究 是重要的，因为它预计将提供重要的洞察力的行动和根本机制， BPA和BPS对较大动物心脏的影响。此外，我们的研究将提供更好的了解的风险因素， 心律失常，特别是在患有心脏病的脆弱亚群中。Fernald队列研究 代表了第一个关于BPA暴露与心脏电活动之间关系的流行病学研究。 这一发现填补了我们对BPA毒性认识的一个主要空白。