Department of Pharmacology and Physiology, The George Washington University, Washington, DC, USA.
Environ Health Perspect. 2012 Sep;120(9):1243-51. doi: 10.1289/ehp.1205056. Epub 2012 Jun 6.
Phthalates are common plasticizers present in medical-grade plastics and other everyday products. They can also act as endocrine-disrupting chemicals and have been linked to the rise in metabolic disorders. However, the effect of phthalates on cardiac metabolism remains largely unknown.
We examined the effect of di(2-ethylhexyl)phthalate (DEHP) on the metabolic profile of cardiomyocytes because alterations in metabolic processes can lead to cell dysfunction.
Neonatal rat cardiomyocytes were treated with DEHP at a concentration and duration comparable to clinical exposure (50-100 μg/mL, 72 hr). We assessed the effect of DEHP on gene expression using microarray analysis. Physiological responses were examined via fatty acid utilization, oxygen consumption, mitochondrial mass, and Western blot analysis.
Exposure to DEHP led to up-regulation of genes associated with fatty acid transport, esterification, mitochondrial import, and β-oxidation. The functional outcome was an increase in myocyte fatty acid-substrate utilization, oxygen consumption, mitochondrial mass, PPARα (peroxisome proliferator-activated receptor α) protein expression, and extracellular acidosis. Treatment with a PPARα agonist (Wy-14643) only partially mimicked the effects observed in DEHP-treated cells.
Data suggest that DEHP exposure results in metabolic remodeling of cardiomyocytes, whereby cardiac cells increase their dependence on fatty acids for energy production. This fuel switch may be regulated at both the gene expression and posttranscription levels. Our findings have important clinical implications because chronic dependence on fatty acids is associated with an accumulation in lipid intermediates, lactate, protons, and reactive oxygen species. This dependence can sensitize the heart to ischemic injury and ventricular dysfunction.
邻苯二甲酸酯是常见的增塑剂，存在于医用塑料和其他日常产品中。它们也可以作为内分泌干扰化学物质，与代谢紊乱的增加有关。然而，邻苯二甲酸酯对心脏代谢的影响在很大程度上仍不清楚。
我们研究了邻苯二甲酸二（2-乙基己基）酯（DEHP）对心肌细胞代谢谱的影响，因为代谢过程的改变可能导致细胞功能障碍。
用与临床暴露相当的浓度和时间（50-100μg/mL，72 小时）用 DEHP 处理新生大鼠心肌细胞。我们使用微阵列分析评估 DEHP 对基因表达的影响。通过脂肪酸利用、耗氧量、线粒体质量和 Western blot 分析来检查 DEHP 的生理反应。
暴露于 DEHP 导致与脂肪酸转运、酯化、线粒体导入和β氧化相关的基因上调。功能结果是肌细胞脂肪酸底物利用、耗氧量、线粒体质量、过氧化物酶体增殖物激活受体α（PPARα）蛋白表达和细胞外酸中毒增加。用 PPARα 激动剂（WY-14643）处理仅部分模拟了 DEHP 处理细胞中观察到的效果。
数据表明，DEHP 暴露导致心肌细胞代谢重塑，使心脏细胞增加对脂肪酸的依赖以产生能量。这种燃料转换可能在基因表达和转录后水平受到调节。我们的发现具有重要的临床意义，因为慢性依赖脂肪酸与脂质中间体、乳酸盐、质子和活性氧的积累有关。这种依赖性会使心脏对缺血性损伤和心室功能障碍敏感。
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