Hsieh Ya-Ju, Chang Yao-Lung, Wu Yi-Hsin, Hung Cheng-Yu, Li Liang, Yu Jau-Song, Chang Chih-Hsiang, Tu Wei-Ju, Chen Yi-Ting
Molecular and Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Metabolomics. 2025 Aug 11;21(5):106. doi: 10.1007/s11306-025-02298-0.
Down syndrome, caused by the triplication of human chromosome 21 (trisomy 21 [T21]) or its distal segment, is the most prevalent chromosomal anomaly associated with intellectual disability in newborns.
To investigate the relationship between T21 and hydrops by analyzing metabolomic alterations, identifying correlations, and exploring pathway regulation mechanisms. This study goes beyond biomarker discovery, aiming to elucidate the pathogenesis of T21 and to explore the underlying mechanism.
We developed a C-/C-isotope dansylation labeling LC-MS workflow to profile amine/phenol-based metabolomic differences in amniotic fluid (AF) between T21 and euploid fetuses.
This workflow enabled the classification of AF specimens, revealing 138 increased and 116 decreased out of 2351 detected metabolites in T21 AF specimens. Metabolite identities were confirmed via LC-MS/MS spectral analysis using authentic standards. Dysregulated metabolites in T21 AF included markers of oxidative regulation and glutathione metabolism as well as those linked to fetal development. Further subgroup analysis identified 31 T21-associated metabolites, including significantly elevated androsterone sulfate in T21 AF both with and without hydrops. Among 30 hydrops-associated metabolites, most were reduced in hydrops AF, while hyaluronic acid (HA) was notably elevated only in T21 hydrops cases. Correlation analyses highlighted negative associations between HA and metabolites like kynurenine and homovanillic acid, suggesting potential roles in immune modulation and neuronal development in the fetal microenvironment.
This study identifies T21-associated metabolites that may serve as early diagnostic markers or therapeutic targets, offering insights into the metabolic landscape of Down syndrome and a foundation for exploring fetal therapeutic strategies.
唐氏综合征由人类21号染色体三体（21三体 [T21]）或其远端片段的三倍体引起，是新生儿中与智力残疾相关的最常见染色体异常。
通过分析代谢组学改变、确定相关性以及探索通路调节机制，研究T21与水肿之间的关系。本研究超越了生物标志物的发现，旨在阐明T21的发病机制并探索潜在机制。
我们开发了一种C-/C-同位素丹磺酰化标记液相色谱 - 质谱工作流程，以分析T21胎儿和整倍体胎儿羊水（AF）中基于胺/酚的代谢组学差异。
该工作流程能够对AF样本进行分类，在T21 AF样本中检测到的2351种代谢物中，有138种增加，116种减少。通过使用标准品进行液相色谱 - 串联质谱光谱分析确认了代谢物的身份。T21 AF中失调的代谢物包括氧化调节和谷胱甘肽代谢的标志物以及与胎儿发育相关的标志物。进一步的亚组分析确定了31种与T21相关的代谢物，包括无论有无水肿的T21 AF中硫酸雄酮均显著升高。在30种与水肿相关的代谢物中，大多数在水肿AF中减少，而透明质酸（HA）仅在T21水肿病例中显著升高。相关性分析突出了HA与犬尿氨酸和高香草酸等代谢物之间的负相关，表明其在胎儿微环境中的免疫调节和神经元发育中可能发挥作用。
本研究确定了与T21相关的代谢物，这些代谢物可能作为早期诊断标志物或治疗靶点，为唐氏综合征的代谢格局提供了见解，并为探索胎儿治疗策略奠定了基础。
