Cumulative Ancestral and Lifetime Adversities Alter Stress Vulnerability in Metabolic Pathways in a Two-Hit Stress Model

Introduction: Chronic prenatal maternal stress (PNMS) usually has an adverse impact on the developing fetus and lifetime health. Preexisting ancestral stress may also raise vulnerability to recurrent stress and failure to cope as adversity accumulates. This study was designed to test the hypothesis that ancestral PNMS can increase the vulnerability to acute or chronic stress with respect to cellular metabolic functions.

Methods: Forty-eight male rats from the third filial generation (F3) were derived from three different lineages: (1) a transgenerational PNMS lineage where only the F0 mother was exposed to stress; (2) a multigenerational PNMS lineage where the mother from each generation was exposed to stress; and (3) a control lineage with no experimental stress exposure. Each of these groups were exposed to both an acute and chronic stressor in adulthood. Blood was then collected, processed, and the metabolomic profiles (spectra) were acquired on a 700 MHz NMR spectrometer. A data reduction step (binning) was employed, and univariate and multivariate statistical testing was applied to the metabolite concentrations. Metabolite identification and pathway analysis were performed in order to interpret the biological relevance of the data.

Results: Identification of the significant bins display separation of the metabolomes among groups at varying levels. The metabolomic variations revealed that each experimental group responded differently to the same stressors. The metabolic pathways of glycine, serine, and threonine, as well as the aminoacyl-tRNA biosynthesis pathway were significantly altered between each pairing of the chronically stressed groups.

Conclusion: The findings from this study suggest that being exposed to multiple hits of stress exacerbates stress sensitivity and vulnerability. A dysfunctional aminoacyl-tRNA synthesis pathway proposes a mechanism for stress-induced protein mistranslation and misfolding with potential pathogenic consequences. The results support the hypothesis that ancestral and lifetime stress cumulatively and differentially affect the metabolic response to stress.