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Stress transgenerationally programs metabolic pathways linked to altered mental health

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Abstract

Stress is among the primary causes of mental health disorders, which are the most common reason for disability worldwide. The ubiquity of these disorders, and the costs associated with them, lends a sense of urgency to the efforts to improve prediction and prevention. Down-stream metabolic changes are highly feasible and accessible indicators of pathophysiological processes underlying mental health disorders. Here, we show that remote and cumulative ancestral stress programs central metabolic pathways linked to mental health disorders. The studies used a rat model consisting of a multigenerational stress lineage (the great-great-grandmother and each subsequent generation experienced stress during pregnancy) and a transgenerational stress lineage (only the great-great-grandmother was stressed during pregnancy). Urine samples were collected from adult male F4 offspring and analyzed using 1H NMR spectroscopy. The results of variable importance analysis based on random variable combination were used for unsupervised multivariate principal component analysis and hierarchical clustering analysis, as well as metabolite set enrichment analysis (MSEA) and pathway analysis. We identified distinct metabolic profiles associated with the multigenerational and transgenerational stress phenotype, with consistent upregulation of hippurate and downregulation of tyrosine, threonine, and histamine. MSEA and pathway analysis showed that these metabolites are involved in catecholamine biosynthesis, immune responses, and microbial host interactions. The identification of metabolic signatures linked to ancestral programming assists in the discovery of gene targets for future studies of epigenetic regulation in pathogenic processes. Ultimately, this research can lead to biomarker discovery for better prediction and prevention of mental health disorders.

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Acknowledgments

The authors acknowledge the assistance and expertise of Michael Opyr in coding some of the MATLAB scripts used for data analysis. This research was supported by the Alberta Innovates-Health Solutions (AI-HS) Interdisciplinary Team Grant #200700595 “Preterm Birth and Healthy Outcomes” (GM); the Norlien/Palix Foundation, Alberta Family Wellness Initiative and the Alberta Centre for Child, Family and Community Research (GM); Natural Sciences and Engineering Research Council of Canada (GM), the Canadian Institutes of Health Research #102652 (GM); and the University of Lethbridge Health Research Accelerator Fund (HRAF; GM and TM).

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  1. Department of Neuroscience, University of Lethbridge, 4401 University Drive, Lethbridge, AB, T1K 3M4, Canada

    Douglas Kiss, Mirela Ambeskovic & Gerlinde A. S. Metz

  2. Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, AB, T1K 3M4, Canada

    Tony Montina

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  1. Douglas Kiss
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Correspondence to Tony Montina or Gerlinde A. S. Metz.

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Kiss, D., Ambeskovic, M., Montina, T. et al. Stress transgenerationally programs metabolic pathways linked to altered mental health. Cell. Mol. Life Sci. 73, 4547–4557 (2016). https://doi.org/10.1007/s00018-016-2272-4

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