Univ. Grenoble Alpes, Inserm, CNRS, IAB, 38000 Grenoble, France.
Laboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA - Institut de Biologie François Jacob, Evry, France.
Environ Int. 2018 Sep;118:334-347. doi: 10.1016/j.envint.2018.05.007. Epub 2018 Jun 21.
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.
We investigated whether nitrogen dioxide (NO), particulate matter (PM), temperature and humidity during pregnancy are associated with differences in placental DNA methylation levels.
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.
The candidate genes approach identified nine CpGs mapping to 9 genes associated with prenatal NO and PM exposure [false discovery rate (FDR) p < 0.05]. Among these, the methylation level of 2 CpGs located in ADORA2B remained significantly associated with NO 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.
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.
空气污染暴露对发育中的胎儿构成了重大健康威胁。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还很少受到关注。
我们研究了怀孕期间二氧化氮（NO）、颗粒物（PM）、温度和湿度是否与胎盘 DNA 甲基化水平的差异有关。
使用 Illumina 的 Infinium HumanMethylation450 BeadChip 在 EDEN 队列的 668 名新生儿的胎盘中测量全基因组 DNA 甲基化。我们设计了一种原始策略，使用先验生物学信息来关注胎盘（活跃或沉默）中具有特定表达模式的候选基因，同时结合无偏倚的全基因组关联研究（EWAS）。我们使用稳健的线性回归来识别与短期和长期时间窗口内每种暴露相关的 CpG 和差异甲基化区域（DMR）。
候选基因方法确定了 9 个 CpG 映射到 9 个与产前 NO 和 PM 暴露相关的基因[错误发现率（FDR）p < 0.05]。其中，位于 ADORA2B 中的 2 个 CpG 的甲基化水平在 EWAS 中仍然与第 2 个孕期和整个孕期的 NO 暴露显著相关（FDR p < 0.05）。EWAS 进一步揭示了研究中的环境暴露与其他 4 个 CpG 的 DNA 甲基化变化之间的关联。我们还进一步确定了 27 个与空气污染物暴露显著相关的 DMR（FDR p < 0.05）和 13 个与气象条件相关的 DMR。
ADORA2B 基因的甲基化以前与缺氧和子痫前期有关，这里一致发现其对大气污染物敏感。此外，空气污染物与 DMR 相关，这些 DMR 指向先前与子痫前期、高血压和代谢紊乱有关的基因。这些发现表明，在欧洲人群中常见的水平下暴露于空气污染物与胎盘基因甲基化有关，并为空气污染物对子痫前期的一些报告影响提供了一些机制上的见解。
