PDF(Pubmed)
Abstract：
To improve outcomes in fetuses with spina bifida (SB), better understanding is needed of the molecular drivers of SB and its comorbidities. Pregnant people carrying a fetus with isolated SB (cases; n = 12) or a fetus with no congenital anomalies (controls; n = 21) were recruited at Mount Sinai Hospital, Toronto, Ontario, Canada. Clinical data and placental samples were collected. Placental transcriptome was sequenced (Clariom D microarray) and a nutrient-focused gene expression analysis pipeline was applied to determine whether fetal SB associates with placental dysfunction. Of the 391 differentially expressed genes (DEGs) in cases, 11% (n = 42) had at least one nutrient cofactor, including B vitamins (n = 7 genes), iron/heme (n = 6), and zinc (n = 11). Cases had dysregulation in genes not previously known to associate with SB, and in placental genes that have known links to SB but have not been previously identified in the placenta. Cases also had downregulated nutrient transport and upregulated branching angiogenesis and immune/inflammatory processes. Five nutrient-dependent transcription regulators, collectively predicted to target 46% of DEGs in cases, were identified and were most commonly dependent on B vitamins (n = 3) and zinc (n = 2). Placental gene expression changes were most acute in cases with poor growth. Placentae from fetuses with SB have dysregulation in several gene networks, including those that are sensitive to multiple micronutrients beyond the well-known folic acid. An improved understanding of placental phenotype in fetuses with SB may help identify novel mechanisms associated with comorbidities in fetuses with SB, and reveal new targets to improve fetal outcomes in this population.
摘要：
为了改善脊柱裂(SB)胎儿的预后，需要更好地了解SB及其合并症的分子驱动因素。西奈山医院招募了携带孤立SB胎儿（病例；n=12）或无先天性异常胎儿（对照；n=21）的孕妇，多伦多。收集临床数据和胎盘样品。对胎盘转录组进行测序（ClariomDTM微阵列），并应用营养集中的基因表达分析流程来确定胎儿SB是否与胎盘功能障碍有关。在病例中的391个差异表达基因(DEGs)中，11%(n=42)有至少一种营养辅因子，包括B族维生素（n=7个基因），铁/血红素（n=6），和锌（n=11）。病例在以前不知道与SB相关的基因中失调，以及已知与SB有联系但先前尚未在胎盘中鉴定的胎盘基因。病例还具有下调的营养转运和上调的分支血管生成和免疫/炎症过程。五种营养依赖性转录调节因子，在病例中，共同预测目标为46%的DEG，被鉴定，最常见的是依赖B族维生素（n=3）和锌（n=2）。在生长不良的情况下，胎盘基因表达变化最严重。来自SB胎儿的胎盘在几个基因网络中有失调，包括那些对多种微量营养素敏感，而不是众所周知的叶酸。改善对SB胎儿胎盘表型的理解可能有助于确定与SB胎儿合并症相关的新机制。并揭示了改善该人群胎儿结局的新目标。
