Targeted metabolomics reveals reduced levels of polyunsaturated choline plasmalogens and a smaller dimethylarginine/arginine ratio in the follicular fluid of patients with a diminished ovarian reserve
Targeted metabolomics reveals reduced levels of polyunsaturated choline plasmalogens and a smaller dimethylarginine/arginine ratio in the follicular fluid of patients with a diminished ovarian reserve
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DOI：
10.1093/humrep/dex303
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发表时间：
2017-11-01
影响因子：
6.1
通讯作者：
May-Panloup, P.
中科院分区：
文献类型：
--
作者：
de la Barca, J. M. Chao;Boueilh, T.;May-Panloup, P.
研究问题：卵巢储备功能下降（DOR）患者的卵泡液（FF）代谢组学特征与卵巢储备功能正常（NOR）患者不同吗？总结回答：FF的代谢组学特征揭示了DOR患者中多不饱和胆碱缩醛磷脂和甲基精氨酸转移酶活性的显著降低，与NOR patients.What是已知的：FF的组成反映了在其获得配子能力期间卵母细胞与其微环境之间的交换。FF的研究已经允许鉴定影响卵母细胞质量的各种病理学中涉及的生物标志物和代谢途径，但是迄今为止还没有在卵巢老化和DOR的背景下进行大代谢组学分析。这是一项对在法国昂热大学医院接受体外受精的57名妇女的FF进行的观察性研究，从2015年11月到2016年9月。这些妇女被分为两组：一组包括28名DOR患者，另一组包括29名NOR患者，作为对照组。一旦卵母细胞被分离用于受精和培养，将FF合并并离心用于分析。使用高效液相色谱-串联质谱法和Biocrates Absolute IDQ p180试剂盒进行靶向定量代谢组学分析。FF水平的188代谢物和几个总和和代谢的显着性比率进行了评估，通过多变量和单变量analysis.Main结果和机会的作用：共136代谢物进行了准确的定量和用于计算23总和和比率。样本被随机分为训练集和验证集。训练集允许使用投影监督方法构建多变量统计模型，即正交偏最小二乘判别分析（OPLS-DA），应用于代谢物的全集，或惩罚最小绝对收缩和选择算子与逻辑回归（LASSO-LR），应用于代谢物的比率和总和。这两个多变量模型显示出良好的预测性能时，应用于验证集。最终的惩罚模型保留了三个最显著的变量，即总二甲基精氨酸与精氨酸的比率（总DMA/精氨酸）、多不饱和胆碱缩醛磷脂（PUFA ae）的总和和患者的年龄。总DMA/精氨酸和PUFA ae的负系数表明，这些FF变量在DOR患者中的值低于NOR patient.LARGE SCALE DATA：N/A。首先，通过这种靶向代谢组学分析，我们仅探索了FF代谢组的有限部分。其次，虽然发现的签名是非常显着的，潜在的功能障碍的机制仍然undetermined.WIDER的影响的调查结果：在卵巢老化的机制暗示的理解是必不可少的，为受影响的妇女渴望怀孕提供充分的反应。我们的研究提出了一种新的签名，可能会为实现这一目标开辟新的道路。
STUDY QUESTION: Does the metabolomic profile of the follicular fluid (FF) of patients with a diminished ovarian reserve (DOR) differ from that of patients with a normal ovarian reserve (NOR)?SUMMARY ANSWER: The metabolomic signature of the FF reveals a significant decrease in polyunsaturated choline plasmalogens and methyl arginine transferase activity in DOR patients compared to NOR patients.WHAT IS KNOWN ALREADY: The composition of the FF reflects the exchanges between the oocyte and its microenvironment during its acquisition of gametic competence. Studies of the FF have allowed identification of biomarkers and metabolic pathways involved in various pathologies affecting oocyte quality, but no large metabolomic analysis in the context of ovarian ageing and DOR has been undertaken so far.STUDY DESIGN, SIZE, DURATION: This was an observational study of the FF retrieved from 57 women undergoing in vitro fertilization at the University Hospital of Angers, France, from November 2015 to September 2016. The women were classified in two groups: one including 28 DOR patients, and the other including 29 NOR patients, serving as controls.PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were enrolled in the morning of oocyte retrieval after ovarian stimulation. Once the oocytes were isolated for fertilization and culture, the FF was pooled and centrifuged for analysis. A targeted quantitative metabolomic analysis was performed using high-performance liquid chromatography coupled with tandem mass spectrometry, and the Biocrates Absolute IDQ p180 kit. The FF levels of 188 metabolites and several sums and ratios of metabolic significance were assessed by multivariate and univariate analyses.MAIN RESULTS AND THE ROLE OF CHANCE: A total of 136 metabolites were accurately quantified and used for calculating 23 sums and ratios. Samples were randomly divided into training and validation sets. The training set, allowed the construction of multivariate statistical models with a projection-supervised method, i.e. orthogonal partial least squares discriminant analysis (OPLS-DA), applied to the full set of metabolites, or the penalized least absolute shrinkage and selection operator with logistic regression (LASSO-LR), applied to the ratios and sums of the metabolites. Both multivariate models showed good predictive performances when applied to the validation set. The final penalized model retained the three most significant variables, i.e. the total dimethylarginine-to-arginine ratio ( Total DMA/Arginine), the sum of the polyunsaturated choline plasmalogens (PUFA ae), and the patient's age. The negative coefficients of Total DMA/Arginine and PUFA ae indicated that these FF variables had lower values in DOR patients than in NOR patients.LARGE SCALE DATA: N/A.LIMITATIONS REASONS FOR CAUTION: This study presents two limitations. First, with this targeted metabolomics analysis, we have explored only a limited portion of the FF metabolome. Second, although the signature found was highly significant, the mechanism underlying the dysfunction remains undetermined.WIDER IMPLICATIONS OF THE FINDINGS: The understanding of the mechanisms implied in ovarian ageing is essential for providing an adequate response to affected women desiring pregnancy. Our study proposes an incoming signature that may open new paths towards this goal.