Residential green space in association with the methylation status in a CpG site within the promoter region of the placental serotonin receptor HTR2A

Abstract

Green space exposure could influence cognition in adults and neurodevelopment in children, and is hypothesized to be partly driven by epigenetic modifications. However, it remains unknown whether some of these associations are already evident during foetal development. Developmental processes in the foetal brain and placenta are shaped by similar biological signals. Therefore, we hypothesize that green space exposure can modify epigenetic processes of cognition-related pathways in placental tissue, such as DNA-methylation of the serotonin receptor HTR2A. HTR2A-methylation was determined within 327 placentas from the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort using bisulphite-PCR-pyrosequencing. Total green space exposure was calculated using high-resolution land cover data derived from the Green Map of Flanders in seven buffers (50 m-3 km) and stratified into low (<3 m) and high (≥3 m) vegetation. Residential nature was calculated using the Land use Map of Flanders. We performed multivariate regression models adjusted for several a priori chosen covariables. For an IQR increment in total green space within a 1,000 m, 2,000 m and 3,000 m buffer the methylation of HTR2A increased with 1.47% (95%CI:0.17;2.78), 1.52% (95%CI:0.21;2.83) and 1.42% (95%CI:0.15;2.69), respectively. In addition, we found 3.00% (95%CI:1.09;4.91) and 1.98% (95%CI:0.28;3.68) higher HTR2A methylation when comparing residences with and without the presence of nature in a 50 m and 100 m buffer, respectively. The methylation status of HTR2A in placental tissue is positively associated with maternal green space exposure. Future research is needed to understand better how these epigenetic changes are related to functional modifications in the placenta and the consequent implications for foetal development.

Epigenome-wide analysis of maternal exposure to green space during gestation and cord blood DNA methylation in the ENVIRONAGE cohort

“…In the same population here under study, in a targeted study, Dockx et al (2022) found green space associated with placental methylation of HTR2A, which was also among the cord blood DMRs we identified as linked with green space.…”

“…Finally, we compared meta-EWASs results with associations previously reported in placenta ( Dockx et al, 2022 ), in children ( Lee et al, 2021 ) and in adult studies ( Jeong et al, 2022 ; Xu et al, 2021a ).…”

“…DNA methylation is the epigenetic mechanism most studied and consists of the transfer of a methyl group in the C5 position of the cytosine to form 5-methylcytosine, which can be induced by environmental factors and influence the ability of DNA to regulate gene expression ( Martin and Fry, 2018 ). To date, green space has been associated in adults with DNA methylation ( Jeong et al, 2022 ; Xu et al, 2021a ) and with a validated DNA methylation-based epigenetic mortality risk score ( Ward-Caviness et al, 2020 ), with DNA methylation in children of two years of age ( Lee et al, 2021 ) and with placental DNA methylation of serotonin receptor ( Dockx et al, 2022 ). However, DNA methylation plays a fundamental role in development already in early life, beginning in utero ( Felix and Cecil, 2019 ).…”

Greenspace, stress, and health: how is epigenetics involved?

“…Prenatal greenspace exposure has been associated with reduced odds of autism spectrum disorder and healthier birth weights (16,17). Notably, maternal greenspace exposure has been shown to have a positive association with methylation status of HTR2A in placental tissue which has significant implications for serotonin and child neurodevelopment (18). Maternal prenatal stress results in hormone dysregulation and affects the epigenetic regulation of placental HPA axis (i.e., glucocorticoid) genes that can elevate susceptibility of psychopathology (19).…”

Epigenome-wide association study of pregnancy exposure to green space and placental DNA methylation

“…This essential organ regulates nutrient and oxygen transfer and hormone and immune supply, and may act as a barrier to environmental exposures, playing a key role in foetal growth and development (Griffiths & Campbell, 2015;Mortillo & Marsit, 2022). To date, only a candidate gene study has explored the association between green space and placental DNAm, where the methylation status of the serotonin receptor HTR2A was positively associated with pregnancy green space exposure (Dockx et al, 2022). Thus, it is important to explore the association between maternal green space exposure during pregnancy and DNAm in placenta not only in specific genes but also on a genome-wide scale in relatively large samples sizes.…”