Background

Air pollution exposure represents a major health threat to the developing foetus. DNA methylation is one of the most well-known molecular determinants of the epigenetic status of cells. Blood DNA methylation has been proven sensitive to air pollutants, but the molecular impact of air pollution on new-borns has so far received little attention.

Objectives

We investigated whether nitrogen dioxide (NO₂), particulate matter (PM₁₀), temperature and humidity during pregnancy are associated with differences in placental DNA methylation levels.

Methods

Whole-genome DNA-methylation was measured using the Illumina's Infinium HumanMethylation450 BeadChip in the placenta of 668 newborns from the EDEN cohort. We designed an original strategy using a priori biological information to focus on candidate genes with a specific expression pattern in placenta (active or silent) combined with an agnostic epigenome-wide association study (EWAS). We used robust linear regression to identify CpGs and differentially methylated regions (DMR) associated with each exposure during short- and long-term time-windows.

Results

The candidate genes approach identified nine CpGs mapping to 9 genes associated with prenatal NO₂ and PM₁₀ exposure [false discovery rate (FDR) p < 0.05]. Among these, the methylation level of 2 CpGs located in ADORA2B remained significantly associated with NO₂ exposure during the 2nd trimester and whole pregnancy in the EWAS (FDR p < 0.05). EWAS further revealed associations between the environmental exposures under study and variations of DNA methylation of 4 other CpGs. We further identified 27 DMRs significantly (FDR p < 0.05) associated with air pollutants exposure and 13 DMRs with meteorological conditions.

Conclusions

The methylation of ADORA2B, a gene whose expression was previously associated with hypoxia and pre-eclampsia, was consistently found here sensitive to atmospheric pollutants. In addition, air pollutants were associated to DMRs pointing towards genes previously implicated in preeclampsia, hypertensive and metabolic disorders. These findings demonstrate that air pollutants exposure at levels commonly experienced in the European population are associated with placental gene methylation and provide some mechanistic insight into some of the reported effects of air pollutants on preeclampsia.

中文翻译：

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怀孕暴露于大气污染和气象条件以及胎盘DNA甲基化

背景

空气污染暴露是对发育中的胎儿的主要健康威胁。DNA甲基化是细胞表观遗传状态最著名的分子决定因素之一。血液DNA甲基化已被证明对空气污染物敏感，但迄今为止，空气污染对新生儿的分子影响一直未引起关注。

目标

我们调查了怀孕期间二氧化氮（NO ₂ ），颗粒物（PM ₁₀），温度和湿度是否与胎盘DNA甲基化水平的差异有关。

方法

使用Illumina的Infinium HumanMethylation450 BeadChip在来自EDEN队列的668名新生儿的胎盘中测量了全基因组DNA甲基化。我们设计了一种原始策略，利用先验生物学信息将重点放在胎盘中具有特定表达模式的候选基因上（主动或沉默），并结合不可知的表观基因组范围的关联研究（EWAS）。我们使用稳健的线性回归来确定与短期和长期时间窗内的每次暴露相关的CpG和差异甲基化区域（DMR）。

结果

候选基因方法确定了9个CpG，它们映射到与产前NO ₂和PM ₁₀暴露相关的9个基因[错误发现率（FDR）p  <0.05]。其中，位于ADORA2B中的2个CpG的甲基化水平仍然与EWAS的第2孕期和整个妊娠期间的NO ₂暴露显着相关（FDR p  <0.05）。EWAS进一步揭示了所研究的环境暴露与其他4种CpG的DNA甲基化变化之间的关联。我们进一步确定了 与空气污染物暴露显着相关的27个DMR（FDR p <0.05）和具有气象条件的13个DMR。

结论

ADORA2B的甲基化是一个以前与低氧和先兆子痫有关的基因，一直在这里发现它对大气污染物敏感。此外，空气污染物与DMR相关，指向先前与先兆子痫，高血压和代谢性疾病有关的基因。这些发现表明，在欧洲人口中普遍经历的空气污染物暴露水平与胎盘基因甲基化有关，并为一些据报道的空气污染物对先兆子痫的影响提供了一些机械的见解。