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

描述（由申请人提供）：邻苯二甲酸二（2-乙基己基）酯（DEHP）用于各种医疗产品，因为它可以使硬质塑料（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注射袋和管。DEHP是高度疏水性的，因此，当与血液、血清和其他亲脂液体接触时，它会从塑料中滤出。由于许多动物研究报告了DEHP的毒性作用，邻苯二甲酸盐浸出是人类健康关注的一个来源。以往的研究大多集中在DEHP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是相当大的，足以保证对早产儿使用不含dehp的塑料。相比之下，DEHP对心脏的不良影响知之甚少，对其潜在心脏毒性的认识基本上是不存在的。当将临床相关浓度的DEHP应用于大鼠新生心肌细胞单层时，治疗明显损害传导速度并减少连接蛋白43的量。DEHP处理也影响了细胞层的粘附和运动。提出的研究的主要目的是确认和了解DEHP对心肌影响的机制，并确定其临床相关性。该提案的目的1是剖析受DEHP影响的分子途径，使用基因组学和计算策略导致心脏电解偶联。临床相关浓度的DEHP将通过植入式渗透泵经肠外输送。将收集心室心脏组织并评估基因表达的改变。关键候选基因将使用功能验证分析进一步研究。该提案的目的2是确定体内暴露于DEHP是否会导致心功能障碍。DEHP将通过植入式渗透泵经肠外输送。在DEHP治疗前后，将进行超声心动图评估体内收缩力。切除心脏的光学成像将测量局部传导速度、钙瞬态和钙处理的变化。

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.