Association between acetaminophen metabolites and CYP2E1 DNA methylation level in neonate cord blood in the Boston Birth Cohort.

IF 5.7 2区 医学 Q1 Medicine
Yijun Li, Xiumei Hong, Liming Liang, Xiaobin Wang, Christine Ladd-Acosta
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引用次数: 0

Abstract

Background: Acetaminophen is a commonly used medication by pregnant women and is known to cross the placenta. However, little is known about the biological mechanisms that regulate acetaminophen in the developing offspring. Cytochrome 2E1 (CYP2E1) is the primary enzyme responsible for the conversion of acetaminophen to its toxic metabolite. Ex vivo studies have shown that the CYP2E1 gene expression in human fetal liver and placenta is largely controlled by DNA methylation (DNAm) at CpG sites located in the gene body of CYP2E1 at the 5' end. To date, no population studies have examined the association between acetaminophen metabolite and fetal DNAm of CYP2E1 at birth.

Methods: We utilized data from the Boston Birth Cohort (BBC) which represents an urban, low-income, racially and ethnically diverse population in Boston, Massachusetts. Acetaminophen metabolites were measured in the cord plasma of newborns enrolled in BBC between 2003 and 2013 using liquid chromatography-tandem mass spectrometry. DNAm at 28 CpG sites of CYP2E1 was measured by Illumina Infinium MethylationEPIC BeadChip. We used linear regression to identify differentially methylated CpG sites and the "DiffVar" method to identify differences in methylation variation associated with the detection of acetaminophen, adjusting for cell heterogeneity and batch effects. The false discovery rate (FDR) was calculated to account for multiple comparisons.

Results: Among the 570 newborns included in this study, 96 (17%) had detectable acetaminophen in cord plasma. We identified 7 differentially methylated CpGs (FDR < 0.05) associated with the detection of acetaminophen and additional 4 CpGs showing a difference in the variation of methylation (FDR < 0.05). These CpGs were all located in the gene body of CYP2E1 at the 5' end and had a 3-6% lower average methylation level among participants with detectable acetaminophen compared to participants without. The CpG sites we identified overlap with previously identified DNase hypersensitivity and open chromatin regions in the ENCODE project, suggesting potential regulatory functions.

Conclusions: In a US birth cohort, we found detection of cord biomarkers of acetaminophen was associated with DNAm level of CYP2E1 in cord blood. Our findings suggest that DNA methylation of CYP2E1 may be an important regulator of acetaminophen levels in newborns.

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波士顿出生队列新生儿脐血中对乙酰氨基酚代谢产物与CYP2E1 DNA甲基化水平的相关性。
背景:对乙酰氨基酚是孕妇常用的药物,已知会穿过胎盘。然而,对发育中的后代中调节对乙酰氨基酚的生物学机制知之甚少。细胞色素2E1(CYP2E1)是负责将对乙酰氨基酚转化为其毒性代谢产物的主要酶。体外研究表明,CYP2E1基因在人类胎儿肝脏和胎盘中的表达在很大程度上受CYP2E1 5’端基因体CpG位点的DNA甲基化(DNAm)控制。到目前为止,还没有群体研究检测对乙酰氨基酚代谢产物与出生时CYP2E1的胎儿DNAm之间的关系。方法:我们使用了波士顿出生队列(BBC)的数据,该队列代表了马萨诸塞州波士顿的城市、低收入、种族和民族多样性人群。2003年至2013年间,使用液相色谱-串联质谱法对英国广播公司登记的新生儿脐带血浆中的对乙酰氨基酚代谢物进行了测量。通过Illumina Infinium MethylationEPIC BeadChip测量CYP2E1 28个CpG位点的DNAm。我们使用线性回归来识别差异甲基化的CpG位点,并使用“DiffVar”方法来识别与检测对乙酰氨基酚相关的甲基化变化的差异,调整细胞异质性和批次效应。计算错误发现率(FDR)是为了考虑多次比较。结果:在纳入本研究的570名新生儿中,96名(17%)的脐带血浆中检测到对乙酰氨基酚。我们鉴定了7个差异甲基化CpG(FDR 结论:在美国出生队列中,我们发现检测对乙酰氨基酚的脐带生物标志物与脐带血中CYP2E1的DNAm水平有关。我们的研究结果表明,CYP2E1的DNA甲基化可能是新生儿对乙酰氨基酚水平的重要调节因子。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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