Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation.
Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation.
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DOI：
10.1186/s13148-015-0060-x
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发表时间：
2015
影响因子：
5.7
通讯作者：
Ewart S
中科院分区：
文献类型：
--
作者：
Wang IJ;Karmaus WJ;Chen SL;Holloway JW;Ewart S
邻苯二甲酸盐可能会增加儿童哮喘的风险。这种联系的内在机制仍有待探讨。本研究评估了邻苯二甲酸酯暴露对表观遗传变化的影响以及表观遗传变化对哮喘的作用。在第一步中，分析了来自儿童环境和过敏性疾病研究（CEAS）的256名儿童的尿液和血液样本。将尿5 OH-MEHP水平定量作为暴露指标，并收集哮喘信息。DNA甲基化（DNA-M）通过定量PCR测量。在步骤1的筛选部分中，在22个血液样本中研究了毒理基因组学数据所建议的21个潜在人类候选基因的DNA-M。然后，在步骤1的测试部分，在256名儿童的更大样本中测试阳性筛选基因，然后通过蛋白质测量进行验证。在第2步中，我们在邻苯二甲酸酯污染食品事件中的54名儿童中复制了邻苯二甲酸酯暴露与基因特异性DNA-M之间的关联。在第3步中，对来自CEAS的256名儿童进行了DNA-M哮喘风险测试，并在来自怀特岛（IOW）出生队列的270名儿童中得到证实。通过筛选鉴定了三个基因（AR、TNFα和IL-4）的差异甲基化。在256名儿童中进行的检测显示，当儿童尿液中的5 OH-MEHP值较高时，TNFα基因启动子的甲基化程度较低（β = −0.138，P = 0.040）。功能验证显示TNFα甲基化与TNFα蛋白水平呈负相关（β = −0.18，P = 0.041）。在另外54名儿童的样本中，我们证实了当尿中5 OH-MEHP浓度较高时，TNFα基因启动子的甲基化较低。最后，我们发现TNFα 5′CGI区低甲基化与256例CEAS儿童的哮喘发病有关（OR = 2.15，95%CI = 1.01 ~ 4.62）。我们在IOW出生队列研究的270名儿童中复制了这一点。当儿童具有TNFα单核苷酸rs 1800610的“AA”或“AG”基因型时，CpG位点cg 10717214的甲基化与哮喘呈负相关。邻苯二甲酸酯暴露对哮喘的影响可能通过DNA甲基化的改变来介导。本文的在线版本（doi：10.1186/s13148-015-0060-x）包含补充材料，可供授权用户使用。
Phthalates may increase the asthma risk in children. Mechanisms underlying this association remain to be addressed. This study assesses the effect of phthalate exposures on epigenetic changes and the role of epigenetic changes for asthma. In the first step, urine and blood samples from 256 children of the Childhood Environment and Allergic diseases Study (CEAS) were analyzed. Urine 5OH-MEHP levels were quantified as an indicator of exposure, and asthma information was collected. DNA methylation (DNA-M) was measured by quantitative PCR. In the screening part of step 1, DNA-M of 21 potential human candidate genes suggested by a toxicogenomic data were investigated in 22 blood samples. Then, in the testing part of step 1, positively screened genes were tested in a larger sample of 256 children and then validated by protein measurements. In step 2, we replicated the association between phthalate exposure and gene-specific DNA-M in 54 children in the phthalate contaminated food event. In step 3, the risk of DNA-M for asthma was tested in 256 children from CEAS and corroborated in 270 children from the Isle of Wight (IOW) birth cohort. Differential methylation in three genes (AR, TNFα, and IL-4) was identified through screening. Testing in 256 children showed that methylation of the TNFα gene promoter was lower when children had higher urine 5OH-MEHP values (β = −0.138, P = 0.040). Functional validation revealed that TNFα methylation was inversely correlated with TNFα protein levels (β = −0.18, P = 0.041). In an additional sample of 54 children, we corroborated that methylation of the TNFα gene promoter was lower when urine 5OH-MEHP concentrations were higher. Finally, we found that a lower methylation of 5′CGI region of TNFα was associated with asthma in 256 CEAS children (OR = 2.15, 95% CI = 1.01 to 4.62). We replicated this in 270 children from the IOW birth cohort study. Methylation of the CpG site cg10717214 was negatively associated with asthma, when children had ‘AA’ or ‘AG’ genotype of the TNFα single nucleotide rs1800610. Effects of phthalate exposure on asthma may be mediated through alterations in DNA methylation. The online version of this article (doi:10.1186/s13148-015-0060-x) contains supplementary material, which is available to authorized users.
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影响因子：
4.4
作者：
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DOI：
10.1016/j.ijheh.2009.08.002
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影响因子：
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