Metabolomic Profiling of Biomarkers Indicative of Ancestral and Lifetime Adversity in a Two-Hit Stress Model

Introduction: Chronic prenatal maternal stress (PNMS) can have adverse effects on the developing fetus and lifetime health. The effects depend on the number of stressors individuals are exposed to. Over-activation of the mother’s stress response also potentially triggers epigenetic marks that can be transmitted to several generations of offspring. To date, very little research has focused on how exposure to ancestral PNMS affects an individual’s response to both chronic and acute stress throughout their lifetime. The purpose of this study was to investigate if exposure to ancestral PNMS puts an individual at an evolutionary advantage or disadvantage with respect to their altered stress response. This study utilized a rat model of ancestral PNMS to explore the response of the metabolome to both acute and chronic stress. Methods: Forty-eight male rats from the third filial generation 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 where there was no experimental stress exposure. Each of these groups were split in two; an acute stress group and a chronic stress group. Plasma was collected from each animal, processed to extract the water-soluble metabolites, added to NMR buffer, and pipetted into NMR tubes. NMR spectra were acquired and the data underwent a data reduction step (binning), normalization, scaling, and both univariate and multivariate statistical testing. These tests identified spectral peaks from metabolites that had been significantly altered across comparison groups. Chemometric software was utilized to determine the identity of altered metabolites and pathway topology analysis was performed. Results: Multivariate and univariate statistical tests indicated that exposure to chronic stress in ancestrally stressed rats creates significant alteration in the metabolomic profile when compared to control animals. No differences were observed in the case of acute stress. Conclusions: Our results support the hypothesis that ancestral and lifetime stress cumulatively affect the metabolome. A subset of metabolites can potentially act as biomarkers of stress during pregnancy. This procedure may aid in the development of new predictive and diagnostic strategies in precision medicine approaches. *Indicates presente

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

Urban green space, public health, and environmental justice: The challenge of making cities ‘just green enough’

Urban green space, such as parks, forests, green roofs, streams, and community gardens, provides critical ecosystem services. Green space also promotes physical activity, psychological well-being, and the general public health of urban residents. This paper reviews the Anglo-American literature on urban green space, especially parks, and compares efforts to green US and Chinese cities. Most studies reveal that the distribution of such space often disproportionately benefits predominantly White and more affluent communities. Access to green space is therefore increasingly recognized as an environmental justice issue. Many US cities have implemented strategies to increase the supply of urban green space, especially in park-poor neighborhoods. Strategies include greening of remnant urban land and reuse of obsolete or underutilized transportation infrastructure. Similar strategies are being employed in Chinese cities where there is more state control of land supply but similar market incentives for urban greening. In both contexts, however, urban green space strategies may be paradoxical: while the creation of new green space to address environmental justice problems can make neighborhoods healthier and more esthetically attractive, it also can increase housing costs and property values. Ultimately, this can lead to gentrification and a displacement of the very residents the green space strategies were designed to benefit. Urban planners, designers, and ecologists, therefore, need to focus on urban green space strategies that are 'just green enough' and that explicitly protect social as well as ecological sustainability.Full Tex