背景:内分泌干扰化合物(EDC),如邻苯二甲酸酯和酚类,可影响胎盘功能和胎儿健康,可能通过表观遗传修饰。我们调查了从重复尿液采样估计的合成酚和邻苯二甲酸盐与全基因组胎盘DNA甲基化之间的关系。
方法:该研究基于387名胎盘DNA甲基化的女性,使用InfiniumMethlationationEPIC阵列和7种酚进行评估,13邻苯二甲酸酯,以及在怀孕期间两次收集的尿液样本池中测量的两种非邻苯二甲酸酯增塑剂代谢物。我们对单个CpG(EWAS)和差异甲基化区域(DMRs)进行了探索性分析,并对20个先前鉴定的CpG进行了候选分析。还进行了性别分层分析。
结果:在探索性分析中,当两种性别一起研究时,在EWAS中未观察到关联.在性别分层分析中,114个人CpG(男性68,女性中有46人)差异甲基化,包含74个基因(男性36个,女性38个)。我们还在整个队列中确定了28个DMRs,女性为40,男性为42。关联大多为阳性(对于DMRs:整个队列中93%的阳性关联,性别分层分析中的60%),除了双酚和DINCH代谢物呈阴性的几个关联。与大多数DMRs相关的生物标志物是对羟基苯甲酸酯,DEHP,和DiNP代谢物浓度。一些DMRs包含印迹基因,包括APC(与对羟基苯甲酸酯和DiNP代谢物相关),GNAS(双酚),ZIM2;PEG3;MIMT1(对羟基苯甲酸酯,邻苯二甲酸单乙酯),和SGCE;PEG10(对羟基苯甲酸酯,食用代谢物)。与肥胖相关的术语,脂质和葡萄糖代谢,和心血管功能是与差异甲基化CpG相关的富集表型。候选分析确定了一个CpG映射到印迹LGALS8基因,与对羟基苯甲酸乙酯呈负相关。
结论:通过结合改善的暴露评估和广泛的胎盘表观基因组覆盖,我们发现了几个与暴露相关的新基因,可能以特定性别的方式。
BACKGROUND: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation.
METHODS: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed.
RESULTS: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben.
CONCLUSIONS: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.