Abstract LB-180: Metabolomic changes in response to chronic stress in healthy mice
Authors: Tworoger Shelley S. , Poole Elizabeth M. , Armaiz Pena Guillermo , Kubzansky Laura , Hankinson Susan E. , Sood Anil K. , Patel Chirag , Clish Clary 
Published: August 2015

Abstract
Background: Animal models of ovarian cancer suggest that chronic stress and subsequent prolonged distress can increase tumor aggressiveness. While specific stress hormones, such as norepinephrine, appear to have a direct influence on tumors, chronic stress may cause other metabolic perturbations important for cancer development. Here, we searched for potential metabolic biomarkers associated with chronic stress using preclinical models.
Methods: We induced stress with a daily restraint protocol, and assessed the impact of daily restraint versus control in 19 healthy, female C57 black mice on plasma and ovarian tissue metabolomic profiles. At 12 weeks old, mice were randomly assigned to three weeks of daily restraint (2 hr/day; n = 10) or normal care (n = 9). At the end of the experiment, a necropsy was performed and plasma and ovarian tissues were obtained. Metabolomic profiling was conducted using LC-MS-MS, and resulted in peak information for 248 identified metabolites and over 18,000 unidentified peaks.
Results: For the identified metabolites, a Q-Q plot showed a significant deviation from the expected p-value distribution under the null hypothesis for both plasma and tissue when comparing stressed versus non-stressed animals. Triacylglycerols (TAGs), as a group, differed between stressed versus non-stressed animals in both ovary and plasma, although the specific TAGs that were altered and the direction of association appeared to differ by tissue type. Putrescine was significantly higher in stressed versus non-stressed animals in both plasma and tissue. Further, multiple phosphatidylcholines (PCs) and their downstream metabolites, lyso-PCs, differed in plasma of stressed versus non-stressed animals. When considering metabolites that significantly differed in plasma between conditions (FDR&lt;5%), stressed and non-stressed animals clustered together with the exception of one non-stressed animal that clustered with the stressed animals. Similar results were observed for tissue, with 2 stressed and 1-non-stressed animals clustering with the other group. The median correlation between tissue and plasma metabolites was -0.01 for stressed animals and 0.21 for control animals.
Conclusions: Our results suggest that lipid metabolism, which is often dysregulated in cancer cells, may be altered by exposure to stress in healthy animals. Putrescine, which is created by the breakdown of amino acids and is important for cell proliferation, was increased by stress. Overall, our results suggest that chronic stress can lead to metabolic changes at a macro (plasma) and tissue specific level. Additional analyses will characterize specific metabolites altered by stress, detail relationships between tissue and plasma metabolites, and assess correlations with corticosterone.
Citation Format: Shelley S. Tworoger, Elizabeth M. Poole, Guillermo Armaiz Pena, Laura Kubzansky, Susan E. Hankinson, Anil K. Sood, Chirag Patel, Clary Clish. Metabolomic changes in response to chronic stress in healthy mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-180. doi:10.1158/1538-7445.AM2015-LB-180