Susceptibility to particle health effects, miRNA and exosomes: rationale and study protocol of the SPHERE study

Abstract

BackgroundDespite epidemiological findings showing increased air pollution related cardiovascular diseases (CVD), the knowledge of the involved molecular mechanisms remains moderate or weak. Particulate matter (PM) produces a local strong inflammatory reaction in the pulmonary environment but there is no final evidence that PM physically enters and deposits in blood vessels. Extracellular vesicles (EVs) and their miRNA cargo might be the ideal candidate to mediate the effects of PM, since they could be potentially produced by the respiratory system, reach the systemic circulation and lead to the development of cardiovascular effects.The SPHERE (“Susceptibility to Particle Health Effects, miRNAs and Exosomes”) project was granted by ERC-2011-StG 282413, to examine possible molecular mechanisms underlying the effects of PM exposure in relation to health outcomes.Methods/designThe study population will include 2000 overweight (25 < BMI < 30 kg/cm2) or obese (BMI ≥ 30 kg/cm2) subjects presenting at the Center for Obesity and Work (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy).Each subject donates blood, urine and hair samples. Extensive epidemiological and clinical data are collected. Exposure to PM is assigned to each subject using both daily PM10 concentration series from air quality monitors and pollutant levels estimated by the FARM (Flexible air Quality Regional Model) modelling system and elaborated by the Regional Environmental Protection Agency.The recruitment period started in September 2010 and will continue until 2015. At December 31, 2013 we recruited 1250 subjects, of whom 87% lived in the province of Milan.Primary study outcomes include cardiometabolic and respiratory health effects. The main molecular mechanism we are investigating focuses on EV-associated microRNAs.DiscussionSPHERE is the first large study aimed to explore EVs as a novel potential mechanism of how air pollution exposure acts in a highly susceptible population. The rigorous study design, the availability of banked biological samples and the potential to integrate epidemiological, clinical and molecular data will also furnish a powerful base for investigating different complementary molecular mechanisms. Our findings, if confirmed, could lead to the identification of potentially reversible alterations that might be considered as possible targets for new diagnostic and therapeutic interventions.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2458-14-1137) contains supplementary material, which is available to authorized users.

Particulate matter exposure is associated with inflammatory gene methylation in obese subjects

“…(Bollati, 2014a, Bollati et al, 2014b) The study subjects were predominantly female (80% of the population), 122 were obese (66%) and 64 were overweight (34%), with a mean age of 51 years.…”

“…Epidemiological studies have shown that obesity may confer greater susceptibility to the adverse effects of PM exposure, since adipocytes have increased particle accumulation (Bollati et al, 2014b; Dubowsky et al, 2006) A positive correlation between exhaled nitric oxide, a marker of pulmonary inflammation, and BMI has been shown in healthy adults (De Winter-de Groot et al, 2005) Moreover, a differential autonomic cardiac response (measured as heart rate variability) to metal particles has been observed between obese and non-obese individuals (Chen et al, 2007). Obesity represents a pro-inflammatory state (Jacobsen et al, 2016, Karkeni et al, 2016) which itself may increase susceptibility to air pollution by increasing the response to inflammatory stimuli.…”

“…These subjects were the first 186 subjects consecutively enrolled in the context of the larger study SPHERE (ERC-2011-StG 282413), (Bollati et al, 2014b) which was aimed at examining the possible molecular mechanisms underlying the effects of PM exposure in relation to health. Each participant signed a written informed consent, approved by the Ethic Committee of the Fondazione Ca’Granda – Ospedale Maggiore Policlinico (Approval no.…”

MicroRNAs are associated with blood-pressure effects of exposure to particulate matter: Results from a mediated moderation analysis

“…Obese individuals were chosen for this study due to their increased susceptibility to the effects of air pollution (due to a higher particle accumulation rate) (Bennett and Zeman, 2004, Bollati et al, 2014). We identified and validated a distinct signature of nine miRNAs (miR-145, miR-197, miR-30b, miR-345, miR-26a, miR-425–5p, miR-331, miR-140–3p, and miR-101) in the peripheral blood, which were associated with PM 10 exposure levels 48 h after exposure.…”

“…Ninety overweight and obese subjects were recruited at the Center for Obesity and Work (Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico in Milan, Lombardia, Italy) from September 2010 to January 2011 as part of the cross-sectional SPHERE study (Bollati et al, 2014). Each participant provided written informed consent before inclusion in the study, which was approved by the Ethics Committee of Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico (approval number 1425).…”