Exposure to phthalates affects calcium handling and intercellular connectivity of human stem cell-derived cardiomyocytes.
Exposure to phthalates affects calcium handling and intercellular connectivity of human stem cell-derived cardiomyocytes.
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DOI：
10.1371/journal.pone.0121927
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sarvazyan N
中科院分区：
文献类型：
--
作者：
Posnack NG;Idrees R;Ding H;Jaimes R 3rd;Stybayeva G;Karabekian Z;Laflamme MA;Sarvazyan N
塑料的普遍性引起了人们对持续接触塑料添加剂对人类健康影响的担忧。特别值得关注的是在生产柔性聚氯乙烯 (PVC) 产品时使用邻苯二甲酸盐。邻苯二甲酸二-2-乙基己酯 (DEHP) 是一种常用的邻苯二甲酸酯增塑剂，可赋予 PVC 产品柔韧性和弹性。最近的流行病学研究报告了尿邻苯二甲酸盐浓度与心血管疾病之间的相关性，包括高血压和冠状动脉风险增加。然而，几乎没有直接证据表明邻苯二甲酸盐暴露与人体细胞（包括心肌细胞）的不良影响有关。使用单层 gCAMP3 人胚胎干细胞衍生的心肌细胞（含有内源性钙传感器）检查 DEHP 对钙处理的影响。将心肌细胞暴露于 DEHP (5 – 50 μg/mL)，并使用蔡司共焦成像系统记录钙瞬变。 DEHP 暴露（24 – 72 小时）对心肌细胞具有负变时性和正性肌力作用，增加了外部起搏所需的最小阈值电压，并改变了 connexin-43 的表达。应用过氧化物酶体增殖物激活受体 α 激动剂 Wy-14,643 (100 μM) 并没有复制 DEHP 对钙瞬时形态或自发搏动率的影响。邻苯二甲酸盐会影响人类心肌细胞的正常生理机能，其中 DEHP 会扰乱心脏钙处理和细胞间连接。我们的研究结果需要进一步的研究来阐明邻苯二甲酸盐暴露对心脏功能的影响程度，特别是对于面临高邻苯二甲酸盐暴露风险的弱势患者群体。
The pervasive nature of plastics has raised concerns about the impact of continuous exposure to plastic additives on human health. Of particular concern is the use of phthalates in the production of flexible polyvinyl chloride (PVC) products. Di-2-ethylhexyl-phthalate (DEHP) is a commonly used phthalate ester plasticizer that imparts flexibility and elasticity to PVC products. Recent epidemiological studies have reported correlations between urinary phthalate concentrations and cardiovascular disease, including an increased risk of high blood pressure and coronary risk. Yet, there is little direct evidence linking phthalate exposure to adverse effects in human cells, including cardiomyocytes. The effect of DEHP on calcium handling was examined using monolayers of gCAMP3 human embryonic stem cell-derived cardiomyocytes, which contain an endogenous calcium sensor. Cardiomyocytes were exposed to DEHP (5 – 50 μg/mL), and calcium transients were recorded using a Zeiss confocal imaging system. DEHP exposure (24 – 72 hr) had a negative chronotropic and inotropic effect on cardiomyocytes, increased the minimum threshold voltage required for external pacing, and modified connexin-43 expression. Application of Wy-14,643 (100 μM), an agonist for the peroxisome proliferator-activated receptor alpha, did not replicate DEHP’s effects on calcium transient morphology or spontaneous beating rate. Phthalates can affect the normal physiology of human cardiomyocytes, including DEHP elicited perturbations in cardiac calcium handling and intercellular connectivity. Our findings call for additional studies to clarify the extent by which phthalate exposure can alter cardiac function, particularly in vulnerable patient populations who are at risk for high phthalate exposure.
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