Gene expression profiling of DEHP-treated cardiomyocytes reveals potential causes of phthalate arrhythmogenicity.
Gene expression profiling of DEHP-treated cardiomyocytes reveals potential causes of phthalate arrhythmogenicity.
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DOI：
10.1016/j.tox.2010.09.007
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发表时间：
2011-01-11
期刊：
影响因子：
4.5
通讯作者：
Sarvazyan, Narine
中科院分区：
文献类型：
--
作者：
Posnack, Nikki Gillum;Lee, Norman H.;Brown, Ronald;Sarvazyan, Narine
邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种广泛使用的增塑剂，可赋予聚氯乙烯柔韧性。我们最近报道，临床相关浓度的DEHP可影响心肌细胞之间的电耦合，导致显著的节律紊乱。这种影响的根本原因目前尚不清楚。使用全球mRNA表达数据作为工具，揭示导致DEHP致癌效应的可能途径。用50 μg/mL DEHP处理乳鼠心肌细胞72 h。将提取的RNA样品杂交到Affyssin Rat Gene 1.0 ST阵列上。通过qRT-PCR验证基因子集的mRNA表达。在第二组实验中，以浓度依赖性方式处理细胞，以鉴定受低DEHP浓度影响的基因。DEHP暴露与mRNA表达的总体变化相关，差异表达基因在47个基因本体分类中过度表达。检测到与细胞电活动、钙处理、粘附和微管转运相关的基因的修饰表达。对于许多关键蛋白质，包括驱动蛋白、TGFβ2、α-微管蛋白和α1和β1整联蛋白，mRNA水平的变化在蛋白质表达水平上得到证实。许多与细胞粘附和电活动相关的基因被确定为早期DEHP目标，因为它们受到低至1 μg/mL浓度的影响。新生大鼠心肌细胞暴露于临床相关DEHP浓度导致mRNA表达的整体变化。这些变化有助于解释邻苯二甲酸酯对这些细胞的致瘤作用。
Di-(2-ethylhexyl)-phthalate (DEHP) is a widely used plasticizer that imparts flexibility to polyvinyl chloride. We have recently reported that clinically relevant concentrations of DEHP can affect electrical coupling between cardiac myocytes causing significant rhythm disturbances. The underlying causes for this effect are currently unknown. To use data on global mRNA expression as a tool to reveal possible pathways leading to arrhythmogenic effects of DEHP. Rat neonatal cardiomyocyte were treated with 50 μg/mL DEHP for 72h. Extracted RNA samples were hybridized onto Affymetrix Rat Gene 1.0 ST arrays. The mRNA expression of a subset of genes was validated by qRT-PCR. In a second set of experiments, cells were treated in a concentration dependent manner to identify genes affected by low DEHP concentrations. DEHP exposure is associated with global changes in mRNA expression, with differentially expressed genes overrepresented in 47 Gene Ontology categories. Modified expression was detected for genes associated with cell electrical activity, calcium handling, adhesion and microtubular transport. For a number of key proteins, including kinesin, TGFβ2, α-tubulin, and α1 & β1 integrins, changes in mRNA levels were confirmed on the level of the protein expression. A number of genes associated with cell adhesion and electrical activity were identified as early DEHP targets as they were affected by concentrations as low as 1 μg/mL. Exposure of neonatal rat cardiomyocytes to clinically relevant DEHP concentrations leads to global changes in mRNA expression. These changes help to explain arrhythmogenic effects of phthalates on these cells.
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DOI：
10.1152/ajpheart.00924.2006
发表时间：
2007-05-01
影响因子：
4.8
作者：
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