Oxidative stress and inflammation mediate the effect of air pollution on cardio‐ and cerebrovascular disease: A prospective study in nonsmokers

Abstract

Air pollution is associated with a broad range of adverse health effects, including mortality and morbidity due to cardio- and cerebrovascular diseases (CCVD), but the molecular mechanisms involved are not entirely understood. This study aims to investigate the involvement of oxidative stress and inflammation in the causal chain, and to identify intermediate biomarkers that are associated retrospectively with the exposure and prospectively with the disease. We designed a case-control study on CCVD nested in a cohort of 18,982 individuals from the EPIC-Italy study. We measured air pollution, inflammatory biomarkers, and whole-genome DNA methylation in blood collected up to 17 years before the diagnosis. The study sample includes all the incident CCVD cases among former- and never-smokers, with available stored blood sample, that arose in the cohort during the follow-up. We identified enrichment of altered DNA methylation in "ROS/Glutathione/Cytotoxic granules" and "Cytokine signaling" pathways related genes, associated with both air pollution (multiple comparisons adjusted p for enrichment ranging from 0.01 to 0.03 depending on pollutant) and with CCVD risk (P = 0.04 and P = 0.03, respectively). Also, Interleukin-17 was associated with higher exposure to NO (P = 0.0004), NO (P = 0.0005), and CCVD risk (OR = 1.79; CI 1.04-3.11; P = 0.04 comparing extreme tertiles). Our findings indicate that chronic exposure to air pollution can lead to oxidative stress, which in turn activates a cascade of inflammatory responses mainly involving the "Cytokine signaling" pathway, leading to increased risk of CCVD. Inflammatory proteins and DNA methylation alterations can be detected several years before CCVD diagnosis in blood samples, being promising preclinical biomarkers. Environ. Mol. Mutagen. 59:234-246, 2018. © 2017 Wiley Periodicals, Inc.

Long-term effects of air pollution: an exposome meet-in-the-middle approach

“…We detected enrichment of altered DNA methylation in ''ROS/glutathione/cytotoxic granules'' and ''cytokine signalling'' pathways-related genes, associated both with air pollution and with CCVD risk. More specifically, Interleukin-17 was associated with higher exposure to NO 2 , NO x , and CCVD risk (OR = 1.79; CI 1.04-3.11, comparing extreme tertiles) (Fiorito et al 2018). In the subsequent metabolomics investigation (Jeong et al 2018), we observed perturbation of the linoleate metabolism pathway to be associated with both air pollution exposure and two disease outcomes, namely CCVD and asthma.…”

“…From hospital discharge records, we identified all newly diagnosed cases of CCVD and revascularization, which arose during 12.2 years of follow-up on average. For biomarker analyses (inflammatory proteins, genome-wide DNA methylation, metabolites) in prospectively collected and archived blood, we designed a case-control study nested in the cohort (Fiorito et al 2018). We detected enrichment of altered DNA methylation in ''ROS/glutathione/cytotoxic granules'' and ''cytokine signalling'' pathways-related genes, associated both with air pollution and with CCVD risk.…”

A Scoping Review on the Characteristics of Human Exposome Studies

“…Seventeen of the retained studies had a cross-sectional design (21%) [73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89], and twelve were experimental (15%) (i.e., three randomized trials on metabolomic profile alterations [90,91] or clinical health outcomes [92] following administration of the experimental exposure; two open label cross-over trials exploring metabolomic and clinical effects of an experimental (juice) [93,94] or environmental (airborne and grass pollen) intervention [95], and seven experimental non-randomized studies). Five studies were case-control (6%) [94,[96][97][98][99] and three case-control studies nested in cohorts (4%) [100][101][102]. In addition to studies that were based on primary data collection and analysis, some studies utilized secondary data, such as, county-aggregated level data (four studies (5%)) [103][104][105][106], two studies used the National Health and Nutrition Examination Survey (NHANES) database (2%) [107,108] and another one used data collected from numerous occupational disease consultation centers in France (1%) [109].…”

“…On the other hand, a single study (1%) analysed differential gene expression associated with hepatocellular carcinoma in Romania [87]. A "meet-in-the-middle" approach was applied to identify inflammatory pathways associated with cardio-and cerebrovascular disease and exposure to NO 2 , NO x , and PM 2.5 in a study (1%) [101].…”

Predicting Methylation from Sequence and Gene Expression Using Deep Learning with Attention

“…This process has therefore been extensively observed and studied in the context of cancer [24], [15], [41], [29]. While various forms of cancer are central to the discussion on DNA methylation, it has also been linked to other diseases and biological processes such as cardiovascular disease [13] and Alzheimer's Disease [19] as well as gene expression regulation in general [40] and epigenetic editing [35]. Hence, researchers have long been measuring DNA methylation levels.…”