PDF(Pubmed)
Abstract：
Maternal stress before, during and after pregnancy has profound effects on the development and lifelong function of the infant\'s neurocognitive development. We hypothesized that the programming of the central nervous system (CNS), hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) induced by prenatal stress (PS) is reflected in electrophysiological and epigenetic biomarkers. In this study, we aimed to find noninvasive epigenetic biomarkers of PS in the newborn salivary DNA.
A total of 728 pregnant women were screened for stress exposure using Cohen Perceived Stress Scale (PSS), 164 women were enrolled, and 114 dyads were analyzed. Prenatal Distress Questionnaire (PDQ) was also administered to assess specific pregnancy worries. Transabdominal fetal electrocardiograms (taECG) were recorded to derive coupling between maternal and fetal heart rates resulting in a \'Fetal Stress Index\' (FSI). Upon delivery, we collected maternal hair strands for cortisol measurements and newborn\'s saliva for epigenetic analyses. DNA was extracted from saliva samples, and DNA methylation was measured using EPIC BeadChip array (850 k CpG sites). Linear regression was used to identify associations between PSS/PDQ/FSI/Cortisol and DNA methylation. We found epigenome-wide significant associations for 5 CpG with PDQ and cortisol at FDR < 5%. Three CpGs were annotated to genes (Illumina Gene annotation file): YAP1, TOMM20 and CSMD1, and two CpGs were located approximately lay at 50 kb from SSBP4 and SCAMP1. In addition, two differentiated methylation regions (DMR) related to maternal stress measures PDQ and cortisol were found: DAXX and ARL4D.
Genes annotated to these CpGs were found to be involved in secretion and transportation, nuclear signaling, Hippo signaling pathways, apoptosis, intracellular trafficking and neuronal signaling. Moreover, some CpGs are annotated to genes related to autism, post-traumatic stress disorder (PTSD) and schizophrenia. However, our results should be viewed as hypothesis generating until replicated in a larger sample. Early assessment of such noninvasive PS biomarkers will allow timelier detection of babies at risk and a more effective allocation of resources for early intervention programs to improve child development. A biomarker-guided early intervention strategy is the first step in the prevention of future health problems, reducing their personal and societal impact.
A total of 728 pregnant women were screened for stress exposure using Cohen Perceived Stress Scale (PSS), 164 women were enrolled, and 114 dyads were analyzed. Prenatal Distress Questionnaire (PDQ) was also administered to assess specific pregnancy worries. Transabdominal fetal electrocardiograms (taECG) were recorded to derive coupling between maternal and fetal heart rates resulting in a \'Fetal Stress Index\' (FSI). Upon delivery, we collected maternal hair strands for cortisol measurements and newborn\'s saliva for epigenetic analyses. DNA was extracted from saliva samples, and DNA methylation was measured using EPIC BeadChip array (850 k CpG sites). Linear regression was used to identify associations between PSS/PDQ/FSI/Cortisol and DNA methylation. We found epigenome-wide significant associations for 5 CpG with PDQ and cortisol at FDR < 5%. Three CpGs were annotated to genes (Illumina Gene annotation file): YAP1, TOMM20 and CSMD1, and two CpGs were located approximately lay at 50 kb from SSBP4 and SCAMP1. In addition, two differentiated methylation regions (DMR) related to maternal stress measures PDQ and cortisol were found: DAXX and ARL4D.
Genes annotated to these CpGs were found to be involved in secretion and transportation, nuclear signaling, Hippo signaling pathways, apoptosis, intracellular trafficking and neuronal signaling. Moreover, some CpGs are annotated to genes related to autism, post-traumatic stress disorder (PTSD) and schizophrenia. However, our results should be viewed as hypothesis generating until replicated in a larger sample. Early assessment of such noninvasive PS biomarkers will allow timelier detection of babies at risk and a more effective allocation of resources for early intervention programs to improve child development. A biomarker-guided early intervention strategy is the first step in the prevention of future health problems, reducing their personal and societal impact.
摘要：
母亲的压力之前，怀孕期间和之后对婴儿神经认知发育的发育和终身功能有深远的影响。我们假设中枢神经系统（CNS）的编程，产前应激（PS）诱导的下丘脑-垂体-肾上腺（HPA）轴和自主神经系统（ANS）反映在电生理和表观遗传生物标志物中。在这项研究中,我们旨在在新生儿唾液DNA中寻找PS的非侵袭性表观遗传生物标志物.
使用科恩感知压力量表（PSS）对728名孕妇进行了压力暴露筛查，164名妇女报名参加，并对114个二元组合进行了分析。还进行了产前痛苦问卷（PDQ）以评估特定的妊娠忧虑。记录经腹胎儿心电图（taECG）以得出母体和胎儿心率之间的耦合，从而产生“胎儿应激指数”（FSI）。交付时，我们收集母体的发束进行皮质醇测量，并收集新生儿的唾液进行表观遗传学分析。从唾液样本中提取DNA,使用EPICBeadChip阵列（850kCpG位点）测量DNA甲基化。线性回归用于鉴定PSS/PDQ/FSI/皮质醇与DNA甲基化之间的关联。我们发现在FDR<5%时，5CpG与PDQ和皮质醇的表观全基因组显著关联。三个CpG被注释到基因(Illumina基因注释文件):YAP1、TOMM20和CSMD1,并且两个CpG被定位为大约位于SSBP4和SCAMP1的50kb处。此外,发现了两个与母体应激指标PDQ和皮质醇相关的分化甲基化区（DMR）：DAXX和ARL4D。
发现这些CpG注释的基因参与分泌和运输，核信号，河马信号通路,凋亡，细胞内运输和神经元信号传导。此外，一些CpG被注释与自闭症相关的基因，创伤后应激障碍（PTSD）和精神分裂症。然而,我们的结果应该被视为假设产生，直到在更大的样本中复制。对此类非侵入性PS生物标志物的早期评估将允许更及时地检测处于危险中的婴儿，并为早期干预计划更有效地分配资源以改善儿童发育。生物标志物指导的早期干预策略是预防未来健康问题的第一步，减少个人和社会影响。
使用科恩感知压力量表（PSS）对728名孕妇进行了压力暴露筛查，164名妇女报名参加，并对114个二元组合进行了分析。还进行了产前痛苦问卷（PDQ）以评估特定的妊娠忧虑。记录经腹胎儿心电图（taECG）以得出母体和胎儿心率之间的耦合，从而产生“胎儿应激指数”（FSI）。交付时，我们收集母体的发束进行皮质醇测量，并收集新生儿的唾液进行表观遗传学分析。从唾液样本中提取DNA,使用EPICBeadChip阵列（850kCpG位点）测量DNA甲基化。线性回归用于鉴定PSS/PDQ/FSI/皮质醇与DNA甲基化之间的关联。我们发现在FDR<5%时，5CpG与PDQ和皮质醇的表观全基因组显著关联。三个CpG被注释到基因(Illumina基因注释文件):YAP1、TOMM20和CSMD1,并且两个CpG被定位为大约位于SSBP4和SCAMP1的50kb处。此外,发现了两个与母体应激指标PDQ和皮质醇相关的分化甲基化区（DMR）：DAXX和ARL4D。
发现这些CpG注释的基因参与分泌和运输，核信号，河马信号通路,凋亡，细胞内运输和神经元信号传导。此外，一些CpG被注释与自闭症相关的基因，创伤后应激障碍（PTSD）和精神分裂症。然而,我们的结果应该被视为假设产生，直到在更大的样本中复制。对此类非侵入性PS生物标志物的早期评估将允许更及时地检测处于危险中的婴儿，并为早期干预计划更有效地分配资源以改善儿童发育。生物标志物指导的早期干预策略是预防未来健康问题的第一步，减少个人和社会影响。
