Plasma and ovarian metabolomic responses to chronic stress in female mice

Background Chronic stress may affect metabolism of amino acids, lipids, and other small molecule metabolites, but these alterations may differ depending on tissue evaluated. We examined metabolomic changes in plasma and ovarian tissue samples from female mice due to chronic stress exposure. Methods At 12 weeks old, healthy, female, C57 black mice were randomly assigned to three weeks 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. Using the Wilcoxon Rank Test, Metabolite Set Enrichment Analysis, and Differential Network Analysis we identified metabolomic alterations occurring in response to restraint stress. All p-values were corrected for multiple testing using the false discovery rate approach. Results In plasma, individual lysophosphatidylcholines (positively) and the metabolite classes carnitines (positively), diacylglycerols and triacylglycerols (inversely) were associated with restraint stress (adjusted-p’s<0.2). In contrast, diacylglycerols and triacylglycerols were increased while carnitines were decreased in ovarian tissue from stressed mice (adjusted-p’s<0.2). However, several metabolites (cholesteryl esters, phosphatidylcholines/ phosphatidylethanolamines plasmalogens and multiple amino acids) were consistently inversely associated with restraint stress in plasma and ovarian tissue (adjusted-p’s<0.2). Conclusion We identified differences in multiple lipid and amino acid metabolites in plasma and ovarian tissue of female mice after exposure to chronic stress. Some affected metabolites (primarily triacylglycerols and diacylglycerols) exhibited opposite associations with chronic stress in plasma (a marker of systemic influences) versus in ovarian tissue (representing local changes), suggesting research to understand the biological impact of chronic stress needs to consider both systemic and tissue-specific alterations. ### Competing Interest Statement O.A.Z., T.H., C.J.P., E.M.P., C.B.C., G.N.A.P., A.S.N., A.H.E., K.H.S., R.B., L.D.K., and S.E.H. have nothing to disclose. A.K.S. a consultant for KIYATEC, Merck, and AstraZeneca, has received research funding from M-Trap, and is a BioPath Holdings shareholder. S.S.T. has received research grant funding from the National Institutes of Health, Department of Defense, State of Florida, and BMS. S.S.T. has received honoraria from Ponce School of Medicine, Ovarian Cancer Research Alliance, and American Association of Cancer Research.