The impact of first trimester phthalate and phenol exposure on IGF2/H19 genomic imprinting and birth outcomes.
The impact of first trimester phthalate and phenol exposure on IGF2/H19 genomic imprinting and birth outcomes.
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DOI：
10.1016/j.envres.2014.04.032
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发表时间：
2014-08
影响因子：
8.3
通讯作者：
Michels, Karin B.
中科院分区：
文献类型：
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作者：
LaRocca, Jessica;Binder, Alexandra M.;McElrath, Thomas F.;Michels, Karin B.
基因组印记导致亲本特异性基因表达，并由基因的表观遗传修饰决定。父亲表达的胰岛素样生长因子2 （IGF2）基因位于人类11号染色体上，距离母亲表达的非编码基因H19约100 kb，这两个基因在胚胎和胎盘生长中起重要作用。鉴于不利的妊娠环境会影响胚胎外组织的DNA甲基化模式，我们假设产前暴露于内分泌干扰化学物质（EDCs）会改变胎盘中H19和IGF2的甲基化。我们的研究被限制在总共196名女性中，她们同时加入了子痫前期预测研究和哈佛表观遗传出生队列。测定了孕早期尿中8种酚类和11种邻苯二甲酸酯代谢物的浓度，并用于表征EDC暴露概况。我们通过对H19、IGF2DMR0和IGF2DMR2的焦磷酸测序，以及与苯酚和邻苯二甲酸盐代谢物的相关值，评估了差异甲基化区域（DMRs）的甲基化程度。我们还评估了H19和IGF2的总体表达和等位基因特异性表达。我们发现DNA甲基化和添加性生物标志物测量之间存在一些显著的关联。H19甲基化的显著降低与高水平的邻苯二甲酸酯代谢物和低分子量（LMW）邻苯二甲酸酯代谢物的总和（Σ）有关。Σphthalate和LMW邻苯二甲酸盐浓度与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偏差的增加与Σ二（2-乙基己基）邻苯二甲酸酯代谢物和高分子量邻苯二甲酸酯有关。这些印迹区域的甲基化和表达对出生长度或出生体重都没有显著影响。总的来说，我们的研究为EDC暴露后发生的表观遗传机制提供了新的见解。
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 ∼100 kb 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 level 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 Σ di(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.
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影响因子：
--
作者：
Koch, HM;Preuss, R;Angerer, J
通讯作者：
Angerer, J
女性生殖系统中邻苯二甲酸酯毒性的机制。
影响因子：
10.4
作者：
Lovekamp-Swan, T;Davis, BJ
通讯作者：
Davis, BJ
影响因子：
8.8
作者：
Irvin, Elizabeth Ann;Calafat, Antonia M.;Naeher, Luke P.
通讯作者：
Naeher, Luke P.
影响因子：
10.4
作者：
Calafat AM;Ye X;Wong LY;Reidy JA;Needham LL
通讯作者：
Needham LL
影响因子：
3.4
作者：
Markham, Julie A.;Koenig, James I.
通讯作者：
Koenig, James I.