title: Susceptibility to particle health effects, miRNA and exosomes: rationale and study protocol of the SPHERE study.
abstract: BACKGROUND
  Despite 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
  The 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.
  
  
  CONCLUSIONS
  SPHERE 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.
authors.affiliation: Molecular Epidemiology and Environmental Epigenetics Laboratory, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy. valentina.bollati@unimi.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bollati
authors.forename: Simona
authors.initials: S
authors.lastname: Iodice
authors.forename: Chiara
authors.initials: C
authors.lastname: Favero
authors.forename: Laura
authors.initials: L
authors.lastname: Angelici
authors.forename: Benedetta
authors.initials: B
authors.lastname: Albetti
authors.forename: Raquel
authors.initials: R
authors.lastname: Cacace
authors.forename: Laura
authors.initials: L
authors.lastname: Cantone
authors.forename: Michele
authors.initials: M
authors.lastname: Carugno
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cavalleri
authors.forename: Barbara
authors.initials: B
authors.lastname: De Giorgio
authors.forename: Laura
authors.initials: L
authors.lastname: Dioni
authors.forename: Silvia
authors.initials: S
authors.lastname: Fustinoni
authors.forename: Mirjam
authors.initials: M
authors.lastname: Hoxha
authors.forename: Barbara
authors.initials: B
authors.lastname: Marinelli
authors.forename: Valeria
authors.initials: V
authors.lastname: Motta
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Patrini
authors.forename: Laura
authors.initials: L
authors.lastname: Pergoli
authors.forename: Luciano
authors.initials: L
authors.lastname: Riboldi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Rizzo
authors.forename: Federica
authors.initials: F
authors.lastname: Rota
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sucato
authors.forename: Letizia
authors.initials: L
authors.lastname: Tarantini
authors.forename: Amedea Silvia
authors.initials: AS
authors.lastname: Tirelli
authors.forename: Luisella
authors.initials: L
authors.lastname: Vigna
authors.forename: Pieralberto
authors.initials: P
authors.lastname: Bertazzi
authors.forename: Angela Cecilia
authors.initials: AC
authors.lastname: Pesatori
mesh_terms: D000393:Air Pollutants / Q000032:analysis; D000397:Air Pollution / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology* / Q000652:urine; D004198:Disease Susceptibility; D004784:Environmental Monitoring; D055354:Exosomes / Q000737:chemistry; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D035683:MicroRNAs / Q000032:analysis; D008875:Middle Aged; D008962:Models, Theoretical; D009765:Obesity; D012140:Respiratory Tract Diseases / Q000097:blood / Q000209:etiology* / Q000652:urine
chemical_list: D000393:Air Pollutants; D035683:MicroRNAs