Neonatal Intensive Care Unit, Department of Womens' and Childrens' Health, University Hospital of Padua, Padova, Italy.
Institute of Pediatric Research (IRP), Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, Italy.
PLoS One. 2022 Aug 16;17(8):e0273175. doi: 10.1371/journal.pone.0273175. eCollection 2022.
Perinatal asphyxia (PA) still occurs in about three to five per 1,000 deliveries in developed countries; 20% of these infants show hypoxic-ischemic encephalopathy (HIE) on brain magnetic resonance imaging (MRI). The aim of our study was to apply metabolomic analysis to newborns undergoing therapeutic hypothermia (TH) after PA to identify a distinct metabotype associated with the development of HIE on brain MRI. We enrolled 53 infants born at >35 weeks of gestation with PA: 21 of them showed HIE on brain MRI (the "HIE" group), and 32 did not (the "no HIE" group). Urine samples were collected at 24, 48 and 72 hours of TH. Metabolomic data were acquired using high-resolution mass spectrometry and analyzed with univariate and multivariate methods. Considering the first urines collected during TH, untargeted analysis found 111 relevant predictors capable of discriminating between the two groups. Of 35 metabolites showing independent discriminatory power, four have been well characterized: L-alanine, Creatine, L-3-methylhistidine, and L-lysine. The first three relate to cellular energy metabolism; their involvement suggests a multimodal derangement of cellular energy metabolism during PA/HIE. In addition, seven other metabolites with a lower annotation level (proline betaine, L-prolyl-L-phenylalanine, 2-methyl-dodecanedioic acid, S-(2-methylpropionyl)-dihydrolipoamide-E, 2,6 dimethylheptanoyl carnitine, Octanoylglucuronide, 19-hydroxyandrost-4-ene-3,17-dione) showed biological consistency with the clinical picture of PA. Moreover, 4 annotated metabolites (L-lysine, L-3-methylhistidine, 2-methyl-dodecanedioic acid, S-(2-methylpropionyl)-dihydrolipoamide-E) retained a significant difference between the "HIE" and "no HIE" groups during all the TH treatment. Our analysis identified a distinct urinary metabotype associated with pathological findings on MRI, and discovered 2 putative markers (L-lysine, L-3-methylhistidine) which may be useful for identifying neonates at risk of developing HIE after PA.
围产期窒息（PA）在发达国家每 1000 例分娩中仍会发生 3 至 5 例；其中 20%的婴儿在脑磁共振成像（MRI）上显示出缺氧缺血性脑病（HIE）。我们的研究目的是应用代谢组学分析对接受治疗性低温（TH）后发生 PA 的新生儿进行分析，以确定与脑 MRI 上 HIE 发展相关的独特代谢表型。我们纳入了 53 名胎龄大于 35 周的发生 PA 的婴儿：其中 21 名在脑 MRI 上显示 HIE（“HIE”组），32 名未显示 HIE（“无 HIE”组）。在 TH 治疗的 24、48 和 72 小时采集尿液样本。使用高分辨率质谱法采集代谢组学数据，并使用单变量和多变量方法进行分析。考虑到在 TH 期间采集的第一批尿液，非靶向分析发现了 111 个能够区分两组的相关预测因子。在具有独立区分能力的 35 种代谢物中，有 4 种已经得到很好的表征：L-丙氨酸、肌酸、L-3-甲基组氨酸和 L-赖氨酸。前三种与细胞能量代谢有关；它们的参与表明在 PA/HIE 期间细胞能量代谢存在多模式紊乱。此外，其他七种代谢物的注释水平较低（脯氨酸甜菜碱、L-脯氨酰-L-苯丙氨酸、2-甲基十二烷二酸、S-（2-甲基丙酰基）-二氢硫辛酸-E、2,6-二甲基庚酰肉碱、辛酰葡萄糖醛酸、19-羟基雄甾-4-烯-3,17-二酮），与 PA 的临床情况具有生物学一致性。此外，在整个 TH 治疗过程中，4 种注释代谢物（L-赖氨酸、L-3-甲基组氨酸、2-甲基十二烷二酸、S-（2-甲基丙酰基）-二氢硫辛酸-E）在“HIE”和“无 HIE”组之间仍保持显著差异。我们的分析确定了与 MRI 上病理发现相关的独特尿代谢表型，并发现了 2 种可能的标志物（L-赖氨酸、L-3-甲基组氨酸），它们可能有助于识别发生 PA 后发生 HIE 的风险新生儿。
