a Department of Pathology and Medical Biology , University of Groningen, University Medical Center Groningen , Hanzeplein 1, EA10, 9713 GZ , Groningen , The Netherlands.
b University of Groningen , University Medical Center Groningen , GRIAC Research Institute , Hanzeplein 1, EA10, 9713 GZ , Groningen , The Netherlands.
Epigenetics. 2017;12(12):1076-1091. doi: 10.1080/15592294.2017.1403691.
The impact of prenatal smoke exposure (PSE) on DNA methylation has been demonstrated in blood samples from children of smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. As the identified differentially methylated genes can be associated with developmental processes, and insulin-like growth factors (IGFs) play a critical role in prenatal tissue growth, we hypothesized that PSE induces fetal programming of Igf1r and Igf1. Using a mouse model of smoking during pregnancy, we show that PSE alters promoter methylation of Igf1r and Igf1 and deregulates their gene expression in lung and liver of fetal (E17.5) and neonatal (D3) mouse offspring. By further comparing female versus male, lung versus liver, or fetal versus neonatal time point, our results demonstrate that CpG site-specific aberrant methylation patterns sex-dependently vary per organ and time point. Moreover, PSE reduces gene expression of Igf1r and Igf1, dependent on organ, sex, and offspring's age. Our results indicate that PSE may be a source of organ-specific rather than general systemic fetal programming. This is exemplified here by gene promoter methylation and mRNA levels of Igf1r and Igf1, together with a sex- and organ-specific naturally established correlation of both parameters that is affected by prenatal smoke exposure. Moreover, the comparison of fetuses with neonates suggests a CpG site-dependent reversibility/persistence of PSE-induced differential methylation patterns.
产前吸烟暴露 (PSE) 对儿童血液样本中的 DNA 甲基化的影响已得到证实，但关于性别依赖性吸烟诱导效应的证据有限。由于已确定的差异甲基化基因与发育过程有关，而胰岛素样生长因子 (IGFs) 在胎儿组织生长中起着关键作用，因此我们假设 PSE 会导致 Igf1r 和 Igf1 的胎儿编程。我们使用怀孕期间吸烟的小鼠模型表明，PSE 改变了 Igf1r 和 Igf1 的启动子甲基化，并在胎儿 (E17.5) 和新生儿 (D3) 小鼠后代的肺和肝中调节其基因表达。通过进一步比较雌性与雄性、肺与肝，或胎儿与新生儿时间点，我们的结果表明，CpG 位点特异性异常甲基化模式在每个器官和时间点都具有性别依赖性差异。此外，PSE 降低了 Igf1r 和 Igf1 的基因表达，这取决于器官、性别和后代的年龄。我们的结果表明，PSE 可能是器官特异性而不是全身性胎儿编程的来源。这里通过 Igf1r 和 Igf1 的基因启动子甲基化和 mRNA 水平，以及这两个参数的性别和器官特异性自然相关性的例子来说明这一点，而这种相关性受到产前吸烟暴露的影响。此外，对胎儿和新生儿的比较表明，CpG 位点依赖性逆转/持续存在 PSE 诱导的差异甲基化模式。
