DNA Methylation in Babies Born to Nonsmoking Mothers Exposed to Secondhand Smoke during Pregnancy: An Epigenome-Wide Association Study,Environmental Health Perspectives

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DNA Methylation in Babies Born to Nonsmoking Mothers Exposed to Secondhand Smoke during Pregnancy: An Epigenome-Wide Association Study
Environmental Health Perspectives ( IF 10.1 ) Pub Date : 2021-5-19 , DOI: 10.1289/ehp8099
Bernard F Fuemmeler _{1,

2} , Mikhail G Dozmorov _{3,

4} , Elizabeth K Do _{1,

2} , Junfeng Jim Zhang ₅ , Carole Grenier ₆ , Zhiqing Huang ₆ , Rachel L Maguire _{6,

7} , Scott H Kollins ₈ , Cathrine Hoyo ₇ , Susan K Murphy ₆

Affiliation

Abstract

Background:

Maternal smoking during pregnancy is related to altered DNA methylation in infant umbilical cord blood. The extent to which low levels of smoke exposure among nonsmoking pregnant women relates to offspring DNA methylation is unknown.

Objective:

This study sought to evaluate relationships between maternal prenatal plasma cotinine levels and DNA methylation in umbilical cord blood in newborns using the Infinium HumanMethylation 450K BeadChip.

Methods:

Participants from the Newborn Epigenetics Study cohort who reported not smoking during pregnancy had verified low levels of cotinine from maternal prenatal plasma (0 $ng / mL$ to $less than 4 nanograms per milliliter$ ), and offspring epigenetic data from umbilical cord blood were included in this study ( $lowercase italic n equals 79$ ). Multivariable linear regression models were fit to the data, controlling for cell proportions, age, race, education, and parity. Estimates represent changes in response to any $1 nanogram per milliliter$ unit increase in exposure.

Results:

Multivariable linear regression models yielded 29,049 CpGs that were differentially methylated in relation to increases in cotinine at a 5% false discovery rate. Top CpGs were within or near genes involved in neuronal functioning (PRKG1, DLGAP2, BSG), carcinogenesis (FHIT, HSPC157) and inflammation (AGER). Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggest cotinine was related to methylation of gene pathways controlling neuronal signaling, metabolic regulation, cell signaling and regulation, and cancer. Further, enhancers associated with transcription start sites were enriched in altered CpGs. Using an independent sample from the same study population ( $lowercase italic n equals 115$ ), bisulfite pyrosequencing was performed with infant cord blood DNA for two genes within our top 20 hits (AGER and PRKG1). Results from pyrosequencing replicated epigenome results for PRKG1 (cg17079497, $estimate = - 1.09$ , $standard error equals 0.45$ , $lowercase italic p equals 0.018$ ) but not for AGER (cg09199225; $estimate = - 0.16$ , $standard error equals 0.21$ , $lowercase italic p equals 0.44$ ).

Discussion:

Secondhand smoke exposure among nonsmoking women may alter DNA methylation in regions involved in development, carcinogenesis, and neuronal functioning. These novel findings suggest that even low levels of smoke exposure during pregnancy may be sufficient to alter DNA methylation in distinct sites of mixed umbilical cord blood leukocytes in pathways that are known to be altered in cord blood from pregnant active smokers. https://doi.org/10.1289/EHP8099

中文翻译：

怀孕期间接触二手烟的不吸烟母亲所生婴儿的 DNA 甲基化：一项全表观基因组关联研究

抽象的

背景：

母亲在怀孕期间吸烟与婴儿脐带血中 DNA 甲基化的改变有关。不吸烟孕妇的低水平烟雾暴露与后代 DNA 甲基化的关系尚不清楚。

客观的：

本研究旨在使用 Infinium HumanMmethylation 450K BeadChip 评估母亲产前血浆可替宁水平与新生儿脐带血 DNA 甲基化之间的关系。

方法：

来自新生儿表观遗传学研究队列的参与者报告在怀孕期间不吸烟，已证实母亲产前血浆中的可替宁含量较低（0 $吴 / 毫升$ 到 $less than 4 nanograms per milliliter$ ），并且本研究包括来自脐带血的后代表观遗传数据（ $lowercase italic n equals 79$ ）。多变量线性回归模型适合数据，控制细胞比例、年龄、种族、教育程度和胎次。估计值代表了响应任何变化的变化 $1 nanogram per milliliter$ 曝光量增加单位。

结果：

多变量线性回归模型产生了 29,049 个 CpG，这些 CpG 与可替宁的增加相关，存在差异甲基化，错误发现率为 5%。顶级 CpG 位于涉及神经元功能（ PRKG1 、 DLGAP2 、 BSG ）、癌变（ FHIT 、 HSPC157 ）和炎症（ AGER ）的基因内或附近。京都基因和基因组百科全书 (KEGG) 分析表明，可替宁与控制神经元信号传导、代谢调节、细胞信号传导和调节以及癌症的基因通路甲基化有关。此外，与转录起始位点相关的增强子在改变的 CpG 中富集。使用来自同一研究人群的独立样本（ $lowercase italic n equals 115$ ），使用婴儿脐带血 DNA 对我们排名前 20 的两个基因（ AGER和PRKG1 ）进行亚硫酸氢盐焦磷酸测序。 PRKG1的焦磷酸测序重复表观基因组结果（cg17079497， $估计 = - 1.09$ , $standard error equals 0.45$ , $lowercase italic p equals 0.018$ ）但不适用于 AGER（cg09199225； $估计 = - 0.16$ , $standard error equals 0.21$ , $lowercase italic p equals 0.44$ ）。

讨论：

不吸烟女性接触二手烟可能会改变参与发育、致癌和神经元功能的区域的 DNA 甲基化。这些新发现表明，即使怀孕期间接触低水平的烟雾也可能足以改变混合脐带血白细胞不同位点的 DNA 甲基化，而这些途径已知在怀孕的活跃吸烟者的脐带血中会发生改变。 https://doi.org/10.1289/EHP8099

更新日期：2021-05-19

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