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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/221201
In utero green space exposure, DNA methylation, and birth size metrics
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[eng] An increasing body of evidence has established health benefits of exposure to green space. Notably, in utero exposure to green space has been linked to a reduced risk of adverse birth outcomes, such as low birth weight (LBW), a critical indicator of long-term heath throughout the life-course. Despite these associations, the biological mechanisms underlying the benefits of green space remain unclear, with epigenetic changes emerging as a potential explanation. The aim of this thesis was to investigate the epigenetic mechanisms, focusing on DNA methylation (DNAm) patterns, associated with green space exposure and birth size metrics. First, we examined the association between green space exposure and DNAm through epigenome-wide association studies (EWAS), focused on two tissue types: blood and placenta. In blood, we analyzed two exposure windows using data from eight European birth cohorts with a total of 2,988 newborns and 1,849 children. After multiple-testing correction, in utero greenness exposure was associated with three differentially methylated regions (DMRs) in cord blood. These regions encompass the SLC6A12, ADAMTS2, and KCNQ1DN genes, with the latter two previously reported in the literature in relation to green space exposure. These genes regulate extracellular matrix organization, blood vessel development, cell growth inhibition, and TGF-beta receptor signaling. The cumulative exposure to greenness from conception to childhood was associated with one DMR in the SDK1 gene, related to immune regulation and neural development. None of the exposure windows was associated with individual differentially methylated positions (DMPs). In the placenta, data from 550 mother-child pairs from the Barcelona Life Study Cohort (BiSC) revealed a significant association between residential greenness and DNAm levels at a DMP located in the SLC25A10 gene. This gene is linked to metabolic processes and body mass index (BMI). Additional suggestive DMPs were identified, related to pathways involving glucocorticoid signaling, inflammatory responses, and oxidative stress. No DMRs were detected after adjusting for multiple testing and additional checks. Second, we explored the association between placental DNAm and birth size metrics, including birth weight (BW), birth length (BL), birth weight-for-length (WLR), and head circumference (HC) in 3,852 neonates from 16 international cohorts. DNAm at 1,106 CpGs was associated with at least one of the birth size metrics, with 1,000 of them being associated with BW. Through positional annotation, promoter-enhancer interactions, and expression quantitative trait methylations (eQTMs), key pathways for placental function and fetal growth were identified, including glucose metabolism, growth and hormonal signaling, immune regulation, vascularization, and hypoxia, as well as enrichment for certain placental transcription factors (TFs). Moreover, sex specific differences in DNAm patterns related to BW were observed, with nine female specific and 38 male-specific DMPs. Additionally, the comparison of the findings with those previously reported for cord blood indicated tissue-specific effects. Furthermore, we identified seven cell-dependent DMPs. The genetic contribution was also assessed, revealing that approximately 20% of the DMPs were influenced by fetal methylation quantitative trait loci acting in cis (cis-mQTLs). To infer causality between the DNAm and BW, bi-directional Mendelian randomization (MR) analyses were conducted, suggesting that DNAm at nine DMPs might affect BW, though further studies are needed to exclude horizontal pleiotropy. Potential causal CpGs were annotated to genes associated with placental development and function as well as obstetric complications (RASSF1, SEMA3F, SIK3, SLC2A4RG). Finally, we investigated whether placental DNAm markers could underlie the association between in utero exposure to green space and BW by applying the meet-in-middle approach. We observed that 37 out of the 1,000 BW-associated DMPs had consistent associations with green space exposure, suggesting a potential mediating role. Experimental or interventional studies are necessary to confirm causality. In summary, this thesis, through international multi-cohort studies, has elucidated placental epigenetic mechanisms involved in fetal growth. It also has pointed to biological pathways that aligned with benefits of green space, such as mental restoration and physical activity. Results, however, should be interpreted cautiously, and future research with more precise exposure assessments, cellular models, and interventional designs will be essential to fully confirm these findings.
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AGUILAR LACASAÑA, Sofía. In utero green space exposure, DNA methylation, and birth size metrics. [consulta: 27 de novembre de 2025]. [Disponible a: https://hdl.handle.net/2445/221201]