The effect of phthalates on the heart: molecular pathways and clinical relevance

邻苯二甲酸盐对心脏的影响：分子途径和临床相关性

• 批准号: 8003464
• 负责人: Nikki Gillum Posnack
• 金额: $ 4.76万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003464
• 关键词: Adhesions; Adverse effects; Affect; Animals; Awareness; Biological Assay; Calcium; Candidate Disease Gene; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cells; Connexin 43; Diethylhexyl Phthalate; Echocardiography; Exposure to; Functional disorder; Gene Expression; Genomics; Goals; Health; Heart; Human; Intravenous; Liquid substance; Maps; Measures; Medical; Medical Device; Modification; Molecular; Motion; Myocardium; Neonatal; Optics; Pathway interactions; Plastics; Polyvinyl Chloride; Procedures; Pump; Rattus; Reporting; Reproductive Health; Risk; Serum; Source; Tissues; Toxic effect; Validation; Ventricular; boys; carcinogenicity; clinically relevant; flexibility; in vivo; monolayer; phthalates; premature; public health relevance

DESCRIPTION (provided by applicant): Di(2-ethylhexyl) phthalate (DEHP) is used in a variety of medical products, as it allows stiff plastics, such as polyvinyl chloride, to become more flexible. DEHP is commonly found in medical devices, including intravenous bags and tubing that are used for various procedures. DEHP is highly hydrophobic, and as a result, it leaches from plastics when in contact with blood, serum, and other lipophilic fluids. Since a number of animal studies have reported toxic effects of DEHP, phthalate leaching is a source of concern for human health. The majority of previous studies focused on DEHP carcinogenicity and its adverse effects on reproductive health. Indeed, the risk of testicular toxicity was found to be substantial enough to warrant the use of DEHP-free plastics for premature boys. In contrast, little is known about the adverse effects of DEHP on the heart, and awareness of its potential cardiotoxicity is essentially non-existent. When clinically relevant concentrations of DEHP were applied to monolayers of rat neonatal cardiomyocytes, treatment markedly impaired conduction velocity and diminished the amount of connexin-43. DEHP treatment also affected the adhesion and motion of the cell layers. The main goals of the proposed studies are to confirm and understand the mechanism behind DEHP's effect on cardiac muscle and to establish its clinical relevance. Aim 1 of the proposal is to dissect the molecular pathways affected by DEHP that leads to cardiac electrical uncoupling using genomics and computational strategies. Clinically relevant concentrations of DEHP will be delivered parenterally via implantable osmotic pumps. Ventricular cardiac tissue will be collected and modifications in gene expression will be assessed. Key candidate genes will be further investigated using functional validation assays. Aim 2 of the proposal is to determine if in vivo exposure to DEHP leads to cardiac dysfunction. DEHP will be delivered parenterally via implantable osmotic pumps. Echocardiography will be conducted to assess contractility in vivo, both before and after DEHP treatment. Optical mapping of excised hearts will measure changes in local conduction velocities, calcium transients and calcium handling. PUBLIC HEALTH RELEVANCE: Project Narrative A number of animal studies have reported toxic effects of Di(2-ethylhexyl) phthalate (DEHP), phthalate leaching is a source of concern for human health. However, the majority of previous studies focused on DEHP carcinogenicity and its adverse effects on reproductive health. In contrast, little is known about the adverse effects of DEHP on the heart, and awareness of its potential cardiotoxicity is essentially non-existent.

描述(申请人提供)：邻苯二甲酸二(2-乙基己基)酯(DEHP)用于各种医疗产品，因为它使硬质塑料，如聚氯乙烯，变得更灵活。DEHP通常存在于医疗设备中，包括用于各种程序的静脉输液袋和管子。DEHP是高度疏水的，因此，当它与血液、血清和其他亲脂液体接触时，会从塑料中渗出。由于一些动物研究已经报道了DEHP的毒性作用，邻苯二甲酸盐浸出是人类健康的一个担忧来源。以前的研究大多集中在DEHP的致癌性及其对生殖健康的不利影响上。事实上，睾丸毒性的风险被发现足够大，因此有理由对早产男孩使用不含DEHP的塑料。相比之下，人们对DEHP对心脏的不利影响知之甚少，而且对其潜在的心脏毒性的认识基本上是不存在的。当临床相关浓度的DEHP作用于新生大鼠心肌细胞单层时，处理显著降低传导速度，并减少连接蛋白-43的含量。DEHP处理也影响了细胞层的黏附和运动。拟议研究的主要目标是确认和了解DEHP对心肌的影响背后的机制，并确定其临床相关性。该提案的目标1是利用基因组学和计算策略剖析DEHP影响的导致心脏电解偶联的分子通路。临床上相关浓度的DEHP将通过植入式渗透泵进行非肠道给药。将收集心室心肌组织，并评估基因表达的修改。关键候选基因将使用功能验证分析进行进一步研究。该提案的目标2是确定体内暴露于DEHP是否会导致心脏功能障碍。DEHP将通过植入式渗透泵进行非肠道给药。在DEHP治疗前和治疗后，将进行超声心动图评估体内的收缩能力。切除心脏的光学标测将测量局部传导速度、钙瞬变和钙处理的变化。 公共卫生相关性：项目简介一些动物研究报告了邻苯二甲酸二(2-乙基己基)酯(DEHP)的毒性效应，邻苯二甲酸盐浸出是人类健康的一个令人担忧的来源。然而，以前的研究大多集中在DEHP的致癌性及其对生殖健康的不利影响上。相比之下，人们对DEHP对心脏的不利影响知之甚少，而且对其潜在的心脏毒性的认识基本上是不存在的。