Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium; Department of Public Health & Primary Care, Leuven University, Leuven, Belgium.
Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium.
Environ Int. 2018 May;114:231-241. doi: 10.1016/j.envint.2018.02.034. Epub 2018 Mar 7.
In mammals, a central clock maintains the daily rhythm in accordance with the external environment. At the molecular level, the circadian rhythm is maintained by epigenetic regulation of the Circadian pathway. Here, we tested the role of particulate matter with an aerodynamic diameter ≤ 2.5 μm (PM) exposure during gestational life on human placental Circadian pathway methylation, as an important molecular target for healthy development. In 407 newborns, we quantified placental methylation of CpG sites within the promoter regions of the following genes: CLOCK, BMAL1, NPAS2, CRY1-2 and PER1-3 using bisulfite-PCR-pyrosequencing. Daily PM exposure levels were estimated for each mother's residence, using a spatiotemporal interpolation model. We applied mixed-effects models to study the methylation status of the Circadian pathway genes and in utero PM exposure, while adjusting for a priori chosen covariates. In a multi-gene model, placental Circadian pathway methylation was positively and significantly (p < 0.0001) associated with 3rd trimester PM exposure. Consequently, the single-gene models showed relative methylation differences [Log(fold change)] in placental NPAS2 (+0.16; p = 0.001), CRY1 (+0.59; p = 0.0023), PER2 (+0.36; p = 0.0005), and PER3 (+0.42; p = 0.0008) for an IQR increase (8.9 μg/m) in 3rd trimester PM exposure. PM air pollution, an environmental risk factor leading to a pro-inflammatory state of the mother and foetus, is associated with the methylation pattern of genes in the Circadian pathway. The observed alterations in the placental CLOCK epigenetic signature might form a relevant molecular mechanism through which fine particle air pollution exposure might affect placental processes and foetal development.
在哺乳动物中，中央时钟根据外部环境维持日常节律。在分子水平上，生物钟节律通过生物钟途径的表观遗传调控来维持。在这里，我们测试了在生命的妊娠期间暴露于空气动力学直径≤2.5μm 的颗粒物（PM）对人胎盘生物钟途径甲基化的作用，作为健康发育的重要分子靶标。在 407 名新生儿中，我们使用亚硫酸氢盐-PCR-焦磷酸测序定量了以下基因启动子区域内 CpG 位点的胎盘甲基化：CLOCK、BMAL1、NPAS2、CRY1-2 和 PER1-3。使用时空插值模型为每位母亲的住所估计每日 PM 暴露水平。我们应用混合效应模型来研究生物钟途径基因的甲基化状态与宫内 PM 暴露之间的关系，同时调整了预先选择的协变量。在多基因模型中，胎盘生物钟途径的甲基化与 3 期 PM 暴露呈正相关且具有统计学显著意义（p<0.0001）。因此，单基因模型显示胎盘 NPAS2（+0.16；p=0.001）、CRY1（+0.59；p=0.0023）、PER2（+0.36；p=0.0005）和 PER3（+0.42；p=0.0008）的相对甲基化差异[对数（倍变化）]与 3 期 PM 暴露的 IQR 增加（8.9μg/m）相关。PM 空气污染是导致母亲和胎儿炎症状态的环境风险因素，与生物钟途径基因的甲基化模式有关。观察到的胎盘 CLOCK 表观遗传特征的改变可能是一个相关的分子机制，通过该机制，细颗粒物空气污染暴露可能会影响胎盘过程和胎儿发育。
