Academic journal article Environmental Health Perspectives

Sex-Specific Associations between Particulate Matter Exposure and Gene Expression in Independent Discovery and Validation Cohorts of Middle-Aged Men and Women

Academic journal article Environmental Health Perspectives

Sex-Specific Associations between Particulate Matter Exposure and Gene Expression in Independent Discovery and Validation Cohorts of Middle-Aged Men and Women

Article excerpt

Background

Particulate matter (PM) is a complex mixture of small particles and liquid droplets that contains a number of components, including acids, organic chemicals, metals, and soil or dust particles. PM exposure is known to increase overall mortality and morbidity, mainly due to its effect on the cardiorespiratory system (Alfaro-Moreno et al. 2007; Pope et al. 2004). Exposure to PM may disturb normal physiological pathways that maintain homeostasis and this may activate cellular processes that mediate the adverse effects of PM (Kleensang et al. 2014). Gene expression changes play an important role in the activation of pathways of toxicity and gene signatures have the potential to serve as biomarkers of exposure (van Leeuwen et al. 2008; van Breda et al. 2015) and recent reports demonstrate their potential use as biomarkers of effect (La Rocca et al. 2014; Fink et al. 2014). As it has been shown previously that transcriptomic responses to diverse environmental stimuli (i.e., chemical exposure, smoking) can be significantly different between men and women (De Coster et al. 2013; Paul and Amundson 2014), we have opted to perform a sex-specific analysis.

Several studies have suggested that elevated oxidative stress may mediate toxic effects of air pollutants (Donaldson et al. 2005; Nel et al. 2001). The systemic inflammatory response following acute inhalation exposure to PM can induce leukocytosis and monocyte release from the bone marrow (Fujii et al. 2002). Controlled exposure studies of recent diesel exhaust exposure (Pettit et al. 2012) and recent exposure to ultra-fine particles (Huang et al. 2010) have reported evidence of altered gene expression in leukocytes but, to our knowledge, associations between patterns of gene expression and long-term particulate air pollution have not been studied in general populations.

Materials and Methods

Study Design

As our goal was to identify transcriptomic biomarkers of exposure and effect in a healthy adult population, we started by applying microarray analysis in a discovery cohort of 98 adults for which we modelled particulate matter exposure. On the resulting dataset containing significantly modulated genes and pathways, we applied a literature and bio-informatics approach to identify potential exposure effect biomarkers. Subsequently, these were validated using qPCR analysis in an independent cohort with similar characteristics as the discovery population (Figure 1). Study protocols for the discovery and validation cohort were approved by the Institutional Review Board and the Ethical Committee of Antwerp University and informed consent was obtained from all participants.

Study Population

Discovery cohort. The original study population was described previously (van Leeuwen et al. 2008) and consisted of 398 participants from eight different regions of residence in Flanders (Belgium), as part of the first Flemish Environment and Health Survey (FLEHS I) during the period 2001-2006. Participants were recruited in several communities based on random sampling. Inclusion criteria were age 50-65 years, living in Flanders > 5 years, and being able to complete questionnaires in Dutch. Prior to blood collection, informed consent was obtained from all individuals. A subset of 98 samples was selected for microarray analysis based on previously measured exposure levels to several pollutants including cadmium, lead, polychlorinated biphenyls (PCBs) (138, 153, and 180), dioxins, polycyclic aromatic hydrocarbons (PAHs), and benzene. The overall exposure to these pollutants was estimated using a z-score for each pollutant, and study participants with both low- and high- exposure levels were chosen for inclusion. Z-scores were not correlated with long-term [PM.sub.10] exposure ([r.sup.2] = 0.0012). Smokers were excluded from the study population. PAXgene tubes (PreAnalytiX GmbH, Hombrechtikon, Switzerland) were used for RNA collection. …

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