In utero exposure to maternal smoking is associated with DNA methylation alterations and reduced neuronal content in the developing fetal brain.
In utero exposure to maternal smoking is associated with DNA methylation alterations and reduced neuronal content in the developing fetal brain.
复制标题
在子宫内暴露于孕产妇的吸烟与DNA甲基化的改变有关，并且在发育中的胎儿脑中的神经元含量降低。
DOI：
10.1186/s13072-017-0111-y
复制
发表时间：
2017
影响因子：
3.9
通讯作者：
Haghighi F
中科院分区：
文献类型：
--
作者：
Chatterton Z;Hartley BJ;Seok MH;Mendelev N;Chen S;Milekic M;Rosoklija G;Stankov A;Trencevsja-Ivanovska I;Brennand K;Ge Y;Dwork AJ;Haghighi F
宫内暴露于母亲吸烟与后代的执行功能受损和行为问题有关。母亲吸烟与胎儿大脑发育减少和儿童期皮质灰质体积较小有关，表明产前暴露于烟草可能会影响皮质发育并表现为行为问题。细胞发育是由表观遗传修饰的变化介导的，如DNA甲基化，这可能会受到烟草的影响。在这项研究中，我们试图确定母亲在怀孕期间吸烟如何影响全球DNA甲基化谱的发展背外侧前额叶皮层（DLPFC）在妊娠中期。当比较吸烟暴露和未暴露胎儿的DLPFC甲基化谱（通过Illumina，HM 450测定）时，没有差异甲基化区域（DMR）通过错误发现校正（FDR ≤ 0.05）。然而，最显著的DMR是吸烟暴露胎儿的GNA 15和SDHAP 3启动子区域内的低甲基化CpG岛。有趣的是，SDHAP 3 mRNA的发育上调在吸烟暴露的胎儿中被延迟。胎龄和吸烟暴露之间的相互作用分析确定了通过FDR的注释为SYCE 3、C21 orf 56/LSS、SPAG 1和RNU 12/POLDIP 3的显著DMR。此外，利用已建立的方法来估计DNA甲基化的细胞比例，我们发现暴露DLPFC样本中含有较低比例的神经元暴露于母体吸烟的胎儿样本。我们还表明，通过体外实验，尼古丁阻碍独立于细胞死亡的神经元的分化。我们发现证据表明，宫内吸烟暴露改变了DNA甲基化和基因表达的发育模式，并与成熟神经元含量减少有关，这种影响可能是由尼古丁驱动的。本文的在线版本（doi：10.1186/s13072-017-0111-y）包含补充材料，可供授权用户使用。
Intrauterine exposure to maternal smoking is linked to impaired executive function and behavioral problems in the offspring. Maternal smoking is associated with reduced fetal brain growth and smaller volume of cortical gray matter in childhood, indicating that prenatal exposure to tobacco may impact cortical development and manifest as behavioral problems. Cellular development is mediated by changes in epigenetic modifications such as DNA methylation, which can be affected by exposure to tobacco. In this study, we sought to ascertain how maternal smoking during pregnancy affects global DNA methylation profiles of the developing dorsolateral prefrontal cortex (DLPFC) during the second trimester of gestation. When DLPFC methylation profiles (assayed via Illumina, HM450) of smoking-exposed and unexposed fetuses were compared, no differentially methylated regions (DMRs) passed the false discovery correction (FDR ≤ 0.05). However, the most significant DMRs were hypomethylated CpG Islands within the promoter regions of GNA15 and SDHAP3 of smoking-exposed fetuses. Interestingly, the developmental up-regulation of SDHAP3 mRNA was delayed in smoking-exposed fetuses. Interaction analysis between gestational age and smoking exposure identified significant DMRs annotated to SYCE3, C21orf56/LSS, SPAG1 and RNU12/POLDIP3 that passed FDR. Furthermore, utilizing established methods to estimate cell proportions by DNA methylation, we found that exposed DLPFC samples contained a lower proportion of neurons in samples from fetuses exposed to maternal smoking. We also show through in vitro experiments that nicotine impedes the differentiation of neurons independent of cell death. We found evidence that intrauterine smoking exposure alters the developmental patterning of DNA methylation and gene expression and is associated with reduced mature neuronal content, effects that are likely driven by nicotine. The online version of this article (doi:10.1186/s13072-017-0111-y) contains supplementary material, which is available to authorized users.