Harvard University Center for the Environment, Harvard University, Cambridge, MA 02138, USA; Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women׳s Hospital, 221 Longwood Avenue, Boston, MA 02115, USA.
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women׳s Hospital, 221 Longwood Avenue, Boston, MA 02115, USA.
Environ Res. 2014 Aug;133:396-406. doi: 10.1016/j.envres.2014.04.032. Epub 2014 Jun 25.
Genomic imprinting leads to parent-of-origin specific gene expression and is determined by epigenetic modification of genes. The paternally expressed gene insulin-like growth-factor 2 (IGF2) is located about ~100kb from the maternally expressed non-coding gene H19 on human chromosome 11, and both genes play major roles in embryonic and placental growth. Given adverse gestational environments can influence DNA methylation patterns in extra-embryonic tissues, we hypothesized that prenatal exposure to endocrine disrupting chemicals (EDCs) alters H19 and IGF2 methylation in placenta. Our study was restricted to a total of 196 women co-enrolled in the Predictors of Preeclampsia Study and the Harvard Epigenetic Birth Cohort. First trimester urine concentrations of 8 phenols and 11 phthalate metabolites were measured and used to characterize EDC exposure profiles. We assessed methylation of differentially methylated regions (DMRs) by pyrosequencing of H19, IGF2DMR0, and IGF2DMR2 and correlated values with phenol and phthalate metabolites. We also assessed overall expression and allele-specific expression of H19 and IGF2. We found several significant associations between DNA methylation and additive biomarker measurements. A significant decrease in H19 methylation was associated with high levels of the sum (Σ) of phthalate metabolites and metabolites of low molecular weight (LMW) phthalates. Σphthalate and LMW phthalate concentrations were inversely associated with IGF2DMR0 methylation values. Variation in methylation was not associated with changes in allele-specific expression. However increased deviation of allele-specific expression of H19 was associated with Σdi(2-ethylhexyl) phthalate metabolites and high molecular weight phthalates. Neither methylation nor expression of these imprinted regions had a significant impact on birth length or birth weight. Overall, our study provides new insight into an epigenetic mechanism that occurs following EDC exposure.
基因组印迹导致亲本来源特异性基因表达，并由基因的表观遗传修饰决定。父源表达的基因胰岛素样生长因子 2（IGF2）位于人类 11 号染色体上母源表达的非编码基因 H19 约 100kb 处，这两个基因在胚胎和胎盘生长中起主要作用。由于不良的妊娠环境会影响胚胎外组织中的 DNA 甲基化模式，我们假设产前暴露于内分泌干扰化学物质（EDC）会改变胎盘的 H19 和 IGF2 甲基化。我们的研究仅限于总共 196 名同时参加预测子痫前期研究和哈佛表观遗传出生队列的女性。测量了 8 种酚类和 11 种邻苯二甲酸代谢物的第一孕期尿液浓度，并用于描述 EDC 暴露谱。我们通过焦磷酸测序评估了 H19、IGF2DMR0 和 IGF2DMR2 的差异甲基化区域（DMR）的甲基化，并将这些值与酚类和邻苯二甲酸代谢物相关联。我们还评估了 H19 和 IGF2 的整体表达和等位基因特异性表达。我们发现 DNA 甲基化与加性生物标志物测量之间存在一些显著关联。H19 甲基化的显著降低与高水平的邻苯二甲酸代谢物总和（Σ）和低分子量（LMW）邻苯二甲酸代谢物有关。Σ 邻苯二甲酸和 LMW 邻苯二甲酸浓度与 IGF2DMR0 甲基化值呈负相关。甲基化的变化与等位基因特异性表达的变化无关。然而，H19 等位基因特异性表达的偏差增加与 Σ 邻苯二甲酸二（2-乙基己基）代谢物和高分子量邻苯二甲酸有关。这些印迹区域的甲基化或表达都没有对出生长度或出生体重产生显著影响。总的来说，我们的研究提供了关于 EDC 暴露后发生的表观遗传机制的新见解。
