The effect of endocrine disrupting chemicals on cardiac physiology

内分泌干​​扰化学物质对心脏生理的影响

• 批准号: 8618646
• 负责人: Nikki Gillum Posnack
• 金额: $ 10.5万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8618646
• 关键词: Accounting; Action Potentials; Acute; Address; Adverse effects; Affect; Animal Experimentation; Animals; Atherosclerosis; Attenuated; Award; Beverages; Biological Assay; Biological Monitoring; Blood; Calcium; Cannulations; Cardiac; Cardiac Myocytes; Cardiac ablation; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Maintenance; Cell model; Cell physiology; Cells; Child; Chronic; Clinical; Communities; Connexin 43; Coronary Arteriosclerosis; Coupled; DNA Microarray Chip; Data; Decision Making; Dependence; Diethylhexyl Phthalate; Discipline; Disease susceptibility; Dose; Electrocardiogram; Endocrine Disruptors; Environmental Health; Epidemiologic Studies; Epidemiology; Etiology; Excision; Exposure to; Fatty Acids; Figs - dietary; Food; Food Container; Foundations; Functional disorder; Future; Gene Proteins; General Population; Genomics; Goals; Health; Heart; Heart Block; Heart Diseases; Heart Injuries; Heart Rate; Heart failure; Homeostasis; Hormones; Human; Hypertension; Implant; In Situ; In Vitro; Injury; Life; Link; Maps; Measures; Mechanics; Medical; Medical Device; Mentors; Metabolic; MicroRNAs; Modeling; Modification; Molecular; Molecular Biology; Molecular Profiling; Monitor; Myocardial Infarction; National Health and Nutrition Examination Survey; Nature; Neonatal; Operative Surgical Procedures; Optics; Organ; Organism; Outcome; Phase; Phenotype; Physiology; Plastics; Population; Principal Investigator; Process; Production; Publishing; Rattus; Research; Research Design; Research Personnel; Risk; Risk Factors; Signal Transduction Pathway; Source; Stem cells; Surveys; System; Techniques; Telemetry; Temperature; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxicology; Toxin; Toy; Training; Ventricular Dysfunction; Vulnerable Populations; adverse outcome; base; bisphenol A; body system; clinically relevant; consumer product; design; experience; exposed human population; high risk; human embryonic stem cell; human stem cells; implantation; in vivo; in vivo Model; insight; multidisciplinary; non-genomic; patient population; phthalates; prenatal exposure; pressure; programs; radiofrequency; research study; signal processing; stomach cardia; tool

DESCRIPTION (provided by applicant): The overall objective of this proposal is to define the effect of two common endocrine-disrupting compounds (EDCs) on cardiac function in healthy and high-risk subjects, and to establish the potential applicability of these findings to humans. The ubiquitous nature of plastics has raised concerns pertaining to continuous exposure to plastic additives and human health risks. Of particular concern is the use of EDCs in plastic production, including bisphenol A (BPA) and di-2-ethylhexylphthalate (DEHP). Despite the popularity of BPA-free and phthalate-free plastics, these compounds are found in many consumer products, including food and beverage containers, children's toys and medical devices. As a result, exposure to these EDCs has become virtually continuous and essentially unavoidable, a fact that is highlighted by human biomonitoring studies. Recently, human epidemiological and animal experimental studies have associated EDC exposure with cardiovascular disorders. However, their toxicity remains hotly debated, mainly because 1) epidemiological studies are useful in identifying associations and not causal links, and 2) animal research studies frequently employ high exposure doses that impede extrapolation to humans. Consequently, there is a need on behalf of the public, scientific, medical and regulatory communities to resolve the direct effect of EDCs on cardiac physiology and to understand the risks to both general and vulnerable patient populations. The proposed project will address this need by utilizing a comprehensive set of models (acute in situ, chronic in vivo, prenatal exposure, heart failure model) to thoroughly investigate the cardia processes altered by EDCs while mimicking human exposure. This is significant, as examining the effect of clinically relevant concentrations using an in situ model will allow one to quantify direct effects on the heart, while an in vivo model takes into account the indirect effects between organ systems and the impact of the metabolic system. Specifically, the effect of EDCs will be quantified on cardiac electrical and mechanical function and a determination of whether the presence of blood negates these effects will be employed. These in situ studies will be accomplished by acutely exposing hearts to clinically-relevant doses of BPA and DEHP. Next, an examination of the in vivo effect of EDCs on the cardiovascular system, and a determination of whether such effects are exacerbated in those with pre-existing heart conditions and other high-risk populations will be performed. To accomplish these studies, the principal investigator will compare and contrast the chronic effect(s) of BPA and DEHP exposure between healthy, prenatally exposed, and heart failure animals. Modifications in cardiovascular function will be assessed using a telemetry implant system that monitors heart rate, temperature, and ECG parameters in freely moving animals. Finally, the principal investigator will investigate the applicability of the findings to human cells and identify potential mechanisms of EDC cardiac toxicity. To complete these studies, human cardiomyocyte networks will be exposed to BPA and DEHP to measure modifications in cardiac function, and identify genomic and non-genomic mechanisms of toxicity. The later will be accomplished using DNA microarrays, miRNA expression analysis, and pharmacological assays. During the K99 phase, the principal investigator will receive extensive training in surgical techniques (nonsurvival: heart excision, annulation, LV pressure; survival: telemetry transmitter implantation, radiofrequency cardiac ablation), epicardial optical mapping and signal processing, human embryonic stem cell maintenance and cardiac differentiation, and miRNA expression profiling. At the end of the K99 mentored phase, the principal investigator will possess the tools necessary to become an independent investigator with expertise in cardiovascular toxicity that encompasses multiple disciplines and models (cell layers, whole heart organ, live animal physiology, prenatal exposure, and heart injury and stem cell models). The principal investigator will apply this new training to her overall study design during the R00 phase of this award, which aims to address significant gaps in the current understanding of EDC cardiac toxicity. The expertise gained during the K99 phase, together with the principal investigator's molecular biology and genomics background, will allow the principal investigator to develop an integrated research program designed to assess how environmental toxins affect cardiovascular function at the molecular, cellular, tissue and organism level. This multidisciplinary experience will allow the principal investigator to investigate the effect of environmental toxins on cardiovascular disease etiology and progression, and also the mechanistic explanation for these effects (e.g., signal transduction pathways, gene, protein, miRNA expression). Completion of this proposal will advance the cardiovascular and environmental health sciences by providing mechanistic insight into a highly controversial topic, i.e., the negative impact of endocrine disruptors on cardiovascular function. Results of this proposal will provide a foundation for objective decision making by the public, scientific, medical and regulatory communities. This proposal will also bridge the gap between clinical observations published from the NHANES surveys with the underlying pathophysiology of EDCs. If adverse outcomes are observed in the proposed studies, it will pinpoint additional variables to investigate in future human epidemiological studies. Finally, at the conclusion of this award, the Principal Investigator will be well positiond to develop an independent multifaceted research program, which will investigate how environmental toxins contribute to cardiovascular disease, and identify risk factors that influence cardiac disease susceptibility.

描述（由申请人提供）： 该提案的总体目标是确定两种常见的内分泌干扰化合物 (EDC) 对健康和高危受试者心脏功能的影响，并确定这些发现对人类的潜在适用性。塑料的普遍存在引起了人们对持续接触塑料添加剂和人类健康风险的担忧。特别值得关注的是塑料生产中 EDC 的使用，包括双酚 A (BPA) 和邻苯二甲酸二-2-乙基己酯 (DEHP)。尽管不含 BPA 和邻苯二甲酸盐的塑料很受欢迎，但这些化合物仍存在于许多消费品中，包括食品和饮料容器、儿童玩具和医疗设备。因此，接触这些 EDC 几乎是连续的，而且基本上是不可避免的，人类生物监测研究强调了这一事实。最近，人类流行病学和动物实验研究已将 EDC 暴露与心血管疾病联系起来。然而，它们的毒性仍然存在激烈争论，主要是因为 1) 流行病学研究有助于确定关联性而非因果关系，2) 动物研究经常采用高暴露剂量，这妨碍了对人类的推断。因此，需要代表公众、科学、医疗和监管界解决 EDC 对心脏生理学的直接影响，并了解对普通患者群体和弱势患者群体的风险。拟议的项目将通过利用一套全面的模型（急性原位模型、慢性体内模型、产前暴露模型、心力衰竭模型）来彻底研究 EDC 在模拟人类暴露时改变的心脏过程，从而满足这一需求。这很重要，因为使用原位模型检查临床相关浓度的影响将允许量化对心脏的直接影响，而体内模型则考虑器官系统之间的间接影响和代谢系统的影响。具体而言，将量化 EDC 对心脏电功能和机械功能的影响，并确定血液的存在是否会抵消这些影响。这些原位研究将通过将心脏急剧暴露于临床相关剂量的 BPA 和 DEHP 来完成。接下来，将检查 EDC 对心血管系统的体内影响，并确定这种影响在患有心脏病和其他高危人群中是否会加剧。为了完成这些研究，主要研究者将比较和对比健康动物、产前暴露动物和心力衰竭动物之间接触 BPA 和 DEHP 的慢性影响。将使用遥测植入系统来评估心血管功能的改变，该系统可监测自由活动动物的心率、体温和心电图参数。最后，主要研究者将研究这些发现对人类细胞的适用性，并确定 EDC 心脏毒性的潜在机制。为了完成这些研究，人类心肌细胞网络将暴露于 BPA 和 DEHP，以测量心脏功能的变化，并确定基因组和非基因组毒性机制。后者将使用 DNA 微阵列、miRNA 表达分析和药理学测定来完成。在K99阶段，主要研究者将接受广泛的手术技术培训（非生存：心脏切除、环化、左心室压力；生存：遥测发射器植入、射频心脏消融）、心外膜光学测绘和信号处理、人类胚胎干细胞维护和心脏分化和 miRNA 表达谱。在 K99 指导阶段结束时，主要研究者将拥有成为独立研究者所需的工具，具有心血管毒性方面的专业知识，涵盖多个学科和模型（细胞层、整个心脏器官、活体动物生理学、产前暴露和心脏毒性）。损伤和干细胞模型）。主要研究者将在该奖项的 R00 阶段将这种新的培训应用到她的整体研究设计中，该阶段旨在解决目前对 EDC 心脏毒性的理解中的重大差距。在 K99 阶段获得的专业知识，加上首席研究员的分子生物学和基因组学背景，将使首席研究员能够开发一个综合研究计划，旨在评估环境毒素如何在分子、细胞、组织和有机体水平上影响心血管功能。这种多学科经验将使主要研究者能够研究环境毒素对心血管疾病病因和进展的影响，以及这些影响的机制解释（例如信号转导途径、基因、蛋白质、miRNA 表达）。该提案的完成将为一个高度争议的话题（即内分泌干扰物对心血管功能的负面影响）提供机制见解，从而推动心血管和环境健康科学的发展。该提案的结果将为公众、科学、医学和监管界做出客观决策提供基础。该提案还将弥合​​ NHANES 调查发表的临床观察结果与 EDC 的潜在病理生理学之间的差距。如果在拟议的研究中观察到不良结果，它将确定其他变量以在未来的人类流行病学研究中进行调查。最后，在该奖项结束时，首席研究员将有能力开发一个独立的多方面研究计划，该计划将调查环境毒素如何导致心血管疾病，并确定影响心脏病易感性的危险因素。