Perkeybile Allison M, Kenkel William M, Yee Jason R, Waugh Rebecca E, Lillard Travis S, Ferris Craig F, Carter C Sue, Connelly Jessica J
Department of Psychology, University of Virginia, Charlottesville, VA, USA.
Department of Psychological and Brain Sciences, University of Delaware, Newark, DE, USA.
BMC Pregnancy Childbirth. 2025 Jul 19;25(1):777. doi: 10.1186/s12884-025-07868-7.
To date, nearly one in three births in the United States occurs after a labor induced with synthetic oxytocin. Despite how common this intervention is, little is known about its long-term consequences for maternal health. Existing work has identified a link between labor induction with synthetic oxytocin and increased risk for postpartum depression. For some women, the link between labor induction and postpartum depression risk may be altered functioning of the oxytocin system, including epigenetic modification of the oxytocin receptor gene, OXTR. Here we use the prairie vole to understand how pregnancy and birth impact epigenetic control of Oxtr, and how a labor induced with synthetic oxytocin may alter this control.
In an unmanipulated birth model, we measured Oxtr DNA methylation levels in the brain of virgin females, at term pregnancy, and 90 min postpartum using targeted pyrosequencing at four CpG sites in the Oxtr promotor region that are conserved from the human OXTR. We used RT-PCR to assess Oxtr gene expression levels in the brains of these same subjects. These same methods were next used in a model of labor induction with exogenous oxytocin. In both models, brain regions targeted for analysis included the nucleus accumbens, amygdala, and medial preoptic area. These regions all use oxytocin system activity in regulating aspects of maternal behaviors. 2-way ANOVA, unpaired two-tailed t-tests, and Pearson's and Spearman's correlations were used for analyses.
Results identify a regulatory switch in Oxtr from term pregnancy to early postpartum that is facilitated in part by oxytocin. Oxtr DNA methylation in virgins is negatively associated with Oxtr gene expression at all four conserved CpG sites in the nucleus accumbens. At term pregnancy, there is no relationship between these markers. Immediately postpartum, this relationship shifts back to a pre-pregnancy state. Administration of increasing doses of exogenous oxytocin, modeling labor induction, shifts the methylation-expression relationship toward a negative state in the nucleus accumbens, mimicking a postnatal brain but at a prenatal time point.
Findings show epigenetic control of Oxtr is dynamic across pregnancy and birth and is sensitive to exogenous oxytocin. Results indicate a need to better understand how common birth interventions impact Oxtr regulation in the maternal brain.
迄今为止，在美国，近三分之一的分娩是在使用合成催产素引产之后发生的。尽管这种干预措施很常见，但对于其对孕产妇健康的长期影响却知之甚少。现有研究已经确定了使用合成催产素引产与产后抑郁症风险增加之间的联系。对于一些女性来说，引产与产后抑郁症风险之间的联系可能是催产素系统功能的改变，包括催产素受体基因OXTR的表观遗传修饰。在这里，我们利用草原田鼠来了解怀孕和分娩如何影响Oxtr的表观遗传控制，以及合成催产素引产如何改变这种控制。
在一个未干预的分娩模型中，我们使用靶向焦磷酸测序技术，在Oxtr启动子区域中与人类OXTR保守的四个CpG位点，测量了未孕雌性、足月妊娠和产后90分钟雌性大脑中Oxtr的DNA甲基化水平。我们使用逆转录聚合酶链反应（RT-PCR）来评估这些相同受试者大脑中Oxtr基因的表达水平。接下来，我们在一个外源性催产素引产模型中使用了相同的方法。在这两个模型中，用于分析的脑区包括伏隔核、杏仁核和内侧视前区。这些区域都利用催产素系统活动来调节母性行为的各个方面。使用双向方差分析、非配对双尾t检验以及Pearson和Spearman相关性分析。
结果确定了从足月妊娠到产后早期Oxtr的一种调节转换，催产素在一定程度上促进了这种转换。在伏隔核中，未孕雌性的Oxtr DNA甲基化与所有四个保守CpG位点的Oxtr基因表达呈负相关。在足月妊娠时，这些标志物之间没有关系。产后立即，这种关系又回到了孕前状态。给予递增剂量的外源性催产素，模拟引产，会使伏隔核中的甲基化-表达关系向负状态转变，在产前时间点模拟产后大脑。
研究结果表明，Oxtr的表观遗传控制在怀孕和分娩过程中是动态的，并且对外源性催产素敏感。结果表明有必要更好地了解常见的分娩干预措施如何影响母体大脑中Oxtr的调节。
