Table_1_Placental transcriptional signatures associated with cerebral white matter damage in the neonate.XLSX

Cerebral white matter is the most common anatomic location of neonatal brain injury in preterm newborns. Factors that predispose preterm newborns to white matter damage are understudied. In relation to studies of the placenta-brain-axis, dysregulated placental gene expression may play a role in preterm brain damage given its implication in programming early life origins of disease, including neurological disorders. There is a critical need to investigate the relationships between the placental transcriptome and white matter damage in the neonate. In a cohort of extremely low gestational age newborns (ELGANs), we aimed to investigate the relationship between the placental transcriptome and white matter damage as assessed by neonatal cranial ultrasound studies (echolucency and/or ventriculomegaly). We hypothesized that genes involved in inflammatory processes would be more highly expressed in placentas of ELGANs who developed ultrasound-defined indicators of white matter damage. Relative to either form of white matter damage, 659 placental genes displayed altered transcriptional profiles. Of these white matter damage-associated genes, largely distinct patterns of gene expression were observed in the study (n = 415/659 genes). Specifically, 381 genes were unique to echolucency and 34 genes were unique to ventriculomegaly. Pathways involved in hormone disruption and metabolism were identified among the unique echolucency or ventriculomegaly genes. Interestingly, a common set of 244 genes or 37% of all genes was similarly dysregulated in the placenta relative to both echolucency and ventriculomegaly. For this common set of white matter damage-related genes, pathways involved in inflammation, immune response and apoptosis, were enriched. Among the white matter damage-associated genes are genes known to be involved in Autism Spectrum Disorder (ASD) and endocrine system disorders. These data highlight differential mRNA expression patterning in the placenta and provide insight into potential etiologic factors that may predispose preterm newborns to white matter damage. Future studies will build upon this work to include functional measures of neurodevelopment as well as measures of brain volume later in life.

脑白质是早产儿脑损伤最常见的解剖部位。目前，早产儿脑白质损伤的易感因素尚未得到充分研究。针对胎盘-脑轴（placenta-brain-axis）的相关研究表明，胎盘基因表达失调可能参与早产儿脑损伤的发生——鉴于其在调控包括神经系统疾病在内的疾病早期生命起源程序中发挥的重要作用。目前亟需探究新生儿胎盘转录组与脑白质损伤之间的关联。本研究纳入极早早产儿（extremely low gestational age newborns, ELGANs）队列，旨在通过新生儿颅脑超声检查（以透回声异常和/或脑室扩大作为评估指标），探究胎盘转录组与脑白质损伤的关联。本研究假设，在出现超声定义的脑白质损伤指标的极早早产儿胎盘中，参与炎症过程的基因表达水平会更高。相较于未发生脑白质损伤的个体，共有659个胎盘基因的转录谱发生了显著失调。在这些与脑白质损伤相关的基因中，本研究观察到了显著分化的基因表达模式（共涉及659个基因中的415个）：其中381个基因仅与透回声异常相关，34个基因仅与脑室扩大相关。仅与透回声异常相关或仅与脑室扩大相关的基因，其富集通路涉及激素紊乱与代谢调控过程。有趣的是，有244个基因（占全部差异基因的37%）在透回声异常与脑室扩大两种情况下均出现了表达失调，且失调模式一致。针对这组与脑白质损伤相关的共有基因，其富集通路涉及炎症反应、免疫应答与细胞凋亡过程。在与脑白质损伤相关的基因中，还包含了已知与孤独症谱系障碍（Autism Spectrum Disorder, ASD）及内分泌系统疾病相关的基因。本研究数据揭示了胎盘中mRNA表达模式的差异，为阐明可能导致早产儿易发生脑白质损伤的潜在病因学因素提供了新的见解。后续研究将基于本工作基础，纳入神经发育功能评估指标以及晚年脑体积测量数据。