Concentrations of persistent organic pollutants in maternal plasma and epigenome-wide placental DNA methylation
Concentrations of persistent organic pollutants in maternal plasma and epigenome-wide placental DNA methylation
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DOI：
10.1186/s13148-020-00894-6
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发表时间：
2020-07-11
影响因子：
5.7
通讯作者：
Tekola-Ayele, Fasil
中科院分区：
文献类型：
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作者：
Ouidir, Marion;Mendola, Pauline;Tekola-Ayele, Fasil
背景产前母体血浆持久性有机污染物（POP）浓度与新生儿结局相关。然而，其潜在机制仍不清楚。胎盘表观遗传机制可能参与其中，但没有先前的表观基因组范围的研究调查了母体持久性有机污染物对胎盘DNA甲基化的影响。我们研究了来自NICHD胎儿生长研究的260名孕妇在妊娠早期的母体血浆POP浓度与表观基因组范围的胎盘DNA甲基化之间的关联。结果分析对象为80%以上血药浓度超过定量限的持久性有机污染物，包括3种有机氯农药（六氯苯、反式九氯、p，p '-二氯二苯基二氯乙烯）、1多溴二苯醚（PBDE 47）、3多氯联苯（138/158、153、180）和6种多氟烷基和全氟烷基物质（全氟癸酸、全氟己烷磺酸、全氟壬酸、全氟辛烷磺酸、全氟十一烷酸（PFUnDA））。使用5%的错误发现率，POP与总共214个差异甲基化的CpG位点相关（名义值范围为2.61 x 10（-21）至2.11 x 10（-7））。在214个CpG位点中，24个（11%）与21个基因的胎盘表达显著相关。值得注意的是，较高的PFUnDA与TUSC 3注释的3个CpG位点（cg 13996963，cg 12089439，cg 18145877）的甲基化增加相关，并且这3个CpG位点的甲基化增加与胎盘中TUSC 3的表达降低相关。在cg 18145877（TUSC 3）甲基化的增加和TUSC 3的表达减少与出生长度较短相关。在214个CpG位点中，44个CpG位点处的甲基化与至少一种新生儿人体测量测量（即，出生体重、出生身长和头围）。七个CpG位点介导了PBDE 47与新生儿人体测量之间的关联（p值< 0.05）。注释顶部差异甲基化CpG位点的基因在与胚胎细胞分化相关的途径（PBDE 47）和与脑大小和脑形态相关的途径（PFAS）中富集。结论胎盘DNA甲基化改变与母体血浆POP浓度显著相关。研究结果表明，胎盘DNA甲基化和基因表达机制可能参与了持久性有机污染物的产前毒性及其与新生儿人体测量措施的关联。
Background Prenatal maternal plasma persistent organic pollutant (POP) concentrations have been associated with neonatal outcomes. However, the underlying mechanisms remain unknown. Placental epigenetic mechanisms may be involved, but no prior epigenome-wide studies have investigated the impact of maternal POPs on placental DNA methylation. We studied the association between maternal plasma POP concentration in early pregnancy and epigenome-wide placental DNA methylation among 260 pregnant women from the NICHD Fetal Growth Studies. Results Our analysis focused on POPs with more than 80% plasma concentrations above the limit of quantification, including 3 organochlorine pesticides (hexachlorobenzene, trans-nonachlor,p,p'-dichlorodiphenyldichloroethylene), 1 polybrominated diphenyl ether (PBDE 47), 3 polychlorinated biphenyls (138/158, 153, 180), and 6 poly- and perfluorinated alkyl substances (PFASs) (perfluorodecanoic acid, perfluorohexanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluoroundecanoic acid (PFUnDA)). Using 5% false discovery rate, POPs were associated with a total of 214 differentially methylated CpG sites (nominalpvalues ranging from 2.61 x 10(-21)to 2.11 x 10(-7)). Out of the 214 CpG sites, 24 (11%) were significantly correlated with placental expression of 21 genes. Notably, higher PFUnDA was associated with increased methylation at 3 CpG sites (cg13996963, cg12089439, cg18145877) annotated toTUSC3, and increased methylation at those 3 CpG sites was correlated with decreased expression ofTUSC3in the placenta. Increased methylation at cg18145877 (TUSC3) and decreased expression ofTUSC3were correlated with shorter birth length. Out of the 214 CpG sites, methylation at 44 CpG sites was correlated (pvalue < 0.10) with at least one neonatal anthropometry measure (i.e., birth weight, birth length, and head circumference). Seven CpG sites mediated (pvalue < 0.05) the association between PBDE 47 and neonatal anthropometry measures. Genes annotating the top differentially methylated CpG sites were enriched in pathways related to differentiation of embryonic cells (PBDE 47) and in pathways related to brain size and brain morphology (PFASs). Conclusions DNA methylation changes in the placenta were significantly associated with maternal plasma POPs concentration. The findings suggest that placental DNA methylation and gene expression mechanism may be involved in the prenatal toxicity of POPs and their association with neonatal anthropometry measures.