Green space and neurodevelopment: exploring biological mechanisms

Abstract

The Developmental Origins of Health and Disease (DOHaD) hypothesis states that early-life exposures can shape the risk of disease in later life. Green space represents one such exposure and has been associated with both physiological and psychological health benefits across the lifespan, including neurodevelopmental outcomes. However, the biological mechanisms underlying these associations remain poorly understood. This dissertation therefore investigates biological pathways through which prenatal and early-life green space exposure may influence neurodevelopment. Specifically, it furthers the examination of telomere length in relation to early-life exposures and neurodevelopment, and explores two additional molecular targets, telomerase reverse transcriptase (TERT) and insulin-like growth factor 1 (IGF1), as potential mediators linking early-life green space exposure to neurodevelopmental outcomes. Telomeres, the protective ends of our chromosomes, are a biological indicator of cellular replicative capacity, lifespan and disease susceptibility. In this thesis, the sensitivity of telomere length to early-life environmental exposures is examined, including prenatal exposure to maternal psychosocial stressors and childhood exposure to environmental factors such as particulate matter < 2.5 μm (PM2.5) and the size of a nearby green space. In addition, the potential relevance of telomere length for neurodevelopment is assessed by investigating associations between infant telomere length and behavioural outcomes from infancy to preschooler years. Besides telomere length, this dissertation focuses on two molecular mechanisms with established relevance for neurodevelopment. TERT is the catalytic subunit of the telomerase enzyme that plays a central role in telomere lengthening. Additionally, TERT exerts several non-canonical effects relating to neuronal survival and development. IGF1 is a neurotrophic factor that is directly involved in neuronal growth and brain development. In this thesis, cord TERT gene expression and IGF1 protein levels are examined as potential mediators of the association between prenatal green space exposure and childhood cognition.

This dissertation consists of two main parts. In Part 1 we investigate the link between telomere length and environmental exposures and neurodevelopment. In Chapter 1, using a European multicohort study of 633 adolescents, socioeconomic status (SES) moderated the association between telomere length attrition and residential exposure to particulate matter ≤ 2.5 μm (PM2.5), while no significant results were present for green space exposure in the form of normalized difference vegetation index (NDVI), nor size of or distance to a nearby green space. Lower socioeconomic status associated with more negative associations between PM2.5 exposure and telomere length attrition. Chapter 2 examined prenatal maternal psychosocial and work-related factors in relation to infant telomere length, as well as associations between infant telomere length and offspring behaviour, in 147 mother–child pairs. No robust associations were observed, although a trend suggested that higher maternal social satisfaction during pregnancy may be associated with longer infant telomere length after accounting for work-related factors. Overall, findings from Part 1 indicate that telomere length is responsive to some environmental exposures in early life, but that these associations are context-dependent and not clearly linked to early neurodevelopmental outcomes. In Part 2 we investigate two potential molecular mediators linking prenatal green space exposure to neurodevelopment. In Chapter 3, cord blood TERT gene expression was examined in 313 newborns as a mediator of the association between prenatal green space and air pollution exposure and childhood cognition. Cord TERT expression partially mediated the association between attention outcomes at 4–6 years of age and both prenatal green space and PM2.5 exposure. In Chapter 4, cord IGF1 protein levels were identified as a similar mediator of the association between childhood cognition and prenatal short vegetation (≤ 3 m in height) exposure.

Taken together, these findings suggest that prenatal exposure to green space exposure may be associated with neurodevelopment partially through modulation of TERT gene expression and IGF1 protein levels. Furthermore, we provide evidence that the type of green space matters in these associations, as particularly vegetation ≤ 3 meters in height appeared to drive the observed associations with TERT gene expression and IGF1.