雌性小鼠血浆和卵巢对慢性应激的代谢组学反应。

Plasma and ovarian metabolomic responses to chronic stress in female mice.

作者信息

Lin Nan, Huang Tianyi, Patel Chirag J, Poole Elizabeth M, Clish Clary B, Armaiz-Pena Guillermo N, Nagaraja Archana S, Eliassen A Heather, Shutta Katherine H, Balasubramanian Raji, Kubzansky Laura D, Hankinson Susan E, Zeleznik Oana A, Sood Anil K, Tworoger Shelley S

机构信息

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Departments of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

出版信息

Metabolomics. 2025 Jul 1;21(4):99. doi: 10.1007/s11306-025-02287-3.

DOI:10.1007/s11306-025-02287-3

PMID:40593273

Abstract

INTRODUCTION

Chronic stress has been linked with higher risk of ovarian cancer and one posited pathway is through altered metabolism of amino acids, lipids, and other small molecule metabolites. However, the types of alterations that occur may not be uniform across tissue types.

OBJECTIVES

We aim to examine and compare the impacts of chronic stress on metabolomic changes in circulation and ovarian tissue.

METHODS

Twelve-week-old, healthy, female, C57 black mice were randomly assigned to three-week of chronic stress using daily restraint (2-hours/day; n = 9) or normal care (n = 10). Metabolomic profiling was conducted on plasma and ovarian tissues via mass spectrometry. We utilized Wilcoxon Rank Tests, Metabolite Set Enrichment Analysis, Differential Network Analysis and a previously derived metabolite-based distress score to identify metabolomic alterations under restraint stress. We used the false discovery rate to account for testing multiple correlated comparisons.

RESULTS

In plasma, individual lysophosphatidylcholines and the metabolite class carnitines were positively associated while diacylglycerols and triacylglycerols were inversely associated with restraint stress (adjusted-p < 0.2). In contrast, in ovarian tissue, diacylglycerols and triacylglycerols were positively associated while carnitines were inversely associated with restraint stress (adjusted-p < 0.2). Other metabolites (cholesteryl esters, phosphatidylcholines/ phosphatidylethanolamines plasmalogens and multiple amino acids) were inversely associated with restraint stress in both plasma and ovarian tissue (adjusted-p < 0.2). A previously developed human metabolite-based distress score was higher in restraint stress mice compared to controls, with a larger difference observed in ovarian tissue than in plasma.

CONCLUSION

These findings suggest research to understand the metabolic impact of chronic stress needs to consider both systemic and tissue-specific alterations.

摘要

引言

慢性应激与卵巢癌风险升高有关，一种假定的途径是通过氨基酸、脂质和其他小分子代谢物的代谢改变。然而，发生的改变类型在不同组织类型中可能并不一致。

目的

我们旨在研究和比较慢性应激对循环和卵巢组织代谢组变化的影响。

方法

将12周龄、健康的雌性C57黑鼠随机分为两组，一组进行为期三周的每日束缚慢性应激（每天2小时；n = 9），另一组给予正常护理（n = 10）。通过质谱对血浆和卵巢组织进行代谢组分析。我们利用Wilcoxon秩和检验、代谢物集富集分析、差异网络分析以及先前推导的基于代谢物的应激评分来识别束缚应激下的代谢组改变。我们使用错误发现率来处理多个相关比较的检验。

结果

在血浆中，个别溶血磷脂酰胆碱和肉碱类代谢物与束缚应激呈正相关，而二酰甘油和三酰甘油与束缚应激呈负相关（校正P < 0.2）。相比之下，在卵巢组织中，二酰甘油和三酰甘油与束缚应激呈正相关，而肉碱与束缚应激呈负相关（校正P < 0.2）。其他代谢物（胆固醇酯、磷脂酰胆碱/磷脂酰乙醇胺缩醛磷脂和多种氨基酸）在血浆和卵巢组织中均与束缚应激呈负相关（校正P < 0.2）。与对照组相比，束缚应激小鼠中先前开发的基于人类代谢物的应激评分更高，在卵巢组织中观察到的差异比血浆中更大。