DNA methylation and exposure to ambient air pollution in two prospective cohorts

Abstract

Long-term exposure to air pollution has been associated with several adverse health effects including cardiovascular, respiratory diseases and cancers. However, underlying molecular alterations remain to be further investigated. The aim of this study is to investigate the effects of long-term exposure to air pollutants on (a) average DNA methylation at functional regions and, (b) individual differentially methylated CpG sites. An assumption is that omic measurements, including the methylome, are more sensitive to low doses than hard health outcomes.This study included blood-derived DNA methylation (Illumina-HM450 methylation) for 454 Italian and 159 Dutch participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). Long-term air pollution exposure levels, including NO2, NOx, PM2.5, PMcoarse, PM10, PM2.5 absorbance (soot) were estimated using models developed within the ESCAPE project, and back-extrapolated to the time of sampling when possible. We meta-analysed the associations between the air pollutants and global DNA methylation, methylation in functional regions and epigenome-wide methylation. CpG sites found differentially methylated with air pollution were further investigated for functional interpretation in an independent population (EnviroGenoMarkers project), where (N = 613) participants had both methylation and gene expression data available.Exposure to NO2 was associated with a significant global somatic hypomethylation (p-value = 0.014). Hypomethylation of CpG island's shores and shelves and gene bodies was significantly associated with higher exposures to NO2 and NOx. Meta-analysing the epigenome-wide findings of the 2 cohorts did not show genome-wide significant associations at single CpG site level. However, several significant CpG were found if the analyses were separated by countries. By regressing gene expression levels against methylation levels of the exposure-related CpG sites, we identified several significant CpG-transcript pairs and highlighted 5 enriched pathways for NO2 and 9 for NOx mainly related to the immune system and its regulation.Our findings support results on global hypomethylation associated with air pollution, and suggest that the shores and shelves of CpG islands and gene bodies are mostly affected by higher exposure to NO2 and NOx. Functional differences in the immune system were suggested by transcriptome analyses.

Association between ambient air pollution and breast cancer risk: The multiethnic cohort study

“…Methylation may be another potential biologic mechanism as PAH sources have been associated with hypo‐ and hypermethylation at multiple promoter regions in breast tumors and in blood of control women . Two of the ESCAPE cohorts conducted a genome‐wide DNA methylation study in relation to exposure to gaseous and particulate matter pollutants and found an association between global hypomethylation with exposure to NO x ( p = 0.089) and NO 2 ( p = 0.014) but not to exposures of particulate matter . High epigenome‐wide DNA methylation in prediagnostic blood samples has been associated with lower risk of breast cancer .…”

“…35 Two of the ESCAPE cohorts conducted a genome-wide DNA methylation study in relation to exposure to gaseous and particulate matter pollutants and found an association between global hypomethylation with exposure to NO x (p = 0.089) and NO 2 (p = 0.014) but not to exposures of particulate matter. 47 High epigenome-wide DNA methylation in prediagnostic blood samples has been associated with lower risk of breast cancer. 48 Thus, it is a reasonable hypothesis that hypomethylation, often a hallmark of genetic instability, in relation to exposure to traffic-related air pollutants may lead to high risk of breast cancer.…”

Integrating DNA methylation measures to improve clinical risk assessment: are we there yet? The case of BRCA1 methylation marks to improve clinical risk assessment of breast cancer

“…prenatal famine 60 ) as well as environmental conditions later in life (e.g. air pollution 61,62 ). Alterations in DNA methylation might hold great potential as surrogate markers for factors that are not easily measured by questionnaires-for instance, Boyne et al 62 and Johansson et al 63 have found that long-term hormonal exposure can be proxied through DNA methylation signatures.…”

Emerging concepts and challenges in implementing the exposome paradigm in allergic diseases and asthma: a Practall document

“…Genetic polymorphisms also interact with many other environmental stressors to generate asthma phenotypes such as decreased lung function, adult‐onset asthma, or the severe asthma phenotype . Air pollution also induces transcriptomic, epigenomic, and metabolomic responses …”