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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.