Urinary 1H NMR Metabolomic Analysis of Prenatal Maternal Stress Due to a Natural Disaster Reveals Metabolic Risk Factors for Non-Communicable Diseases: The QF2011 Queensland Flood Study.

Prenatal stress alters fetal programming, potentially predisposing the ensuing offspring to long-term adverse health outcomes. To gain insight into environmental influences on fetal development, this QF2011 study evaluated the urinary metabolomes of 4-year-old children (n = 89) who were exposed to the 2011 Queensland flood in utero. Proton nuclear magnetic resonance spectroscopy was used to analyze urinary metabolic fingerprints based on maternal levels of objective hardship and subjective distress resulting from the natural disaster. In both males and females, differences were observed between high and low levels of maternal objective hardship and maternal subjective distress groups. Greater prenatal stress exposure was associated with alterations in metabolites associated with protein synthesis, energy metabolism, and carbohydrate metabolism. These alterations suggest profound changes in oxidative and antioxidative pathways that may indicate a higher risk for chronic non-communicable diseases such obesity, insulin resistance, and diabetes, as well as mental illnesses, including depression and schizophrenia. Thus, prenatal stress-associated metabolic biomarkers may provide early predictors of lifetime health trajectories, and potentially serve as prognostic markers for therapeutic strategies in mitigating adverse health outcomes.

Trans- and Multigenerational Maternal Social Isolation Stress Programs the Blood Plasma Metabolome in the F3 Generation.

Metabolic risk factors are among the most common causes of noncommunicable diseases, and stress critically contributes to metabolic risk. In particular, social isolation during pregnancy may represent a salient stressor that affects offspring metabolic health, with potentially adverse consequences for future generations. Here, we used proton nuclear magnetic resonance (1H NMR) spectroscopy to analyze the blood plasma metabolomes of the third filial (F3) generation of rats born to lineages that experienced either transgenerational or multigenerational maternal social isolation stress. We show that maternal social isolation induces distinct and robust metabolic profiles in the blood plasma of adult F3 offspring, which are characterized by critical switches in energy metabolism, such as upregulated formate and creatine phosphate metabolisms and downregulated glucose metabolism. Both trans- and multigenerational stress altered plasma metabolomic profiles in adult offspring when compared to controls. Social isolation stress increasingly affected pathways involved in energy metabolism and protein biosynthesis, particularly in branched-chain amino acid synthesis, the tricarboxylic acid cycle (lactate, citrate), muscle performance (alanine, creatine phosphate), and immunoregulation (serine, threonine). Levels of creatine phosphate, leucine, and isoleucine were associated with changes in anxiety-like behaviours in open field exploration. The findings reveal the metabolic underpinnings of epigenetically heritable diseases and suggest that even remote maternal social stress may become a risk factor for metabolic diseases, such as diabetes, and adverse mental health outcomes. Metabolomic signatures of transgenerational stress may aid in the risk prediction and early diagnosis of non-communicable diseases in precision medicine approaches.