title: Extracellular histones mediate the effects of metal-rich air particles on blood coagulation.
abstract: BACKGROUND
  Epidemiological studies have shown associations of particulate matter (PM) exposure with hypercoagulability and thrombosis. Extracellular circulating histones have recently been identified as novel mediators of inflammatory and procoagulant responses. The potential roles of extracellular histones in PM-related hypercoagulability have yet not been investigated.
  
  
  OBJECTIVE
  In 63 steel workers, we evaluated the effects of exposure to PM and PM metal components on two extracellular histone modifications (H3K4me3 and H3K9ac); and the association of H3K4me3 and H3K9ac with coagulation markers.
  
  
  METHODS
  Extracellular H3K4me3 and H3K9ac were determined in plasma through enzyme-linked immunosorbent assays. Coagulation markers included endogenous thrombin potentials (ETPs), tissue-type plasminogen activator antigen (t-PA) and D-dimer. Exposure to PM with aerodynamic diameters <1 μm (PM1) or <10 μm (PM10) and PM10 metal components were estimated for each participant.
  
  
  RESULTS
  The coagulation marker ETP, measured in the presence of soluble thrombomodulin (ETP TM+), showed significant positive associations with PM1 (β=107.84, p=0.03), PM10 (β=83.06, p=0.02), and zinc (β=75.14, p=0.03); and a marginal association with iron (β=122.58, p=0.07). Additional PM effects were observed on t-PA, D-dimer, and ETP TM+. PM1 exposure was associated with increased plasma H3K4me3 and H3K9ac (β=0.20, p=0.02; β=0.16, p=0.05, respectively). H3K4me3, but not H3K9ac, was associated with zinc (β=0.13, p=0.03) and iron (β=0.32, p=0.01) contained in PM. ETP TM+ was increased in association with higher plasma H3K4me3 (β=0.50, p=0.05) and H3K9ac (β=0.54, p=0.05).
  
  
  CONCLUSIONS
  This observational study suggests potential roles of extracellular histones in PM-induced hypercoagulability. Experimental studies are warranted to further characterize these findings.
authors.affiliation: Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community, Università di Milano and Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Cantone
authors.affiliation: Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community, Università di Milano and Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Angelici
authors.affiliation: Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community, Università di Milano and Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Bollati
authors.affiliation: Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bonzini
authors.affiliation: Occupational Medicine and Industrial Hygiene, University of Brescia, Department of Experimental and Applied Medicine, Brescia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Apostoli
authors.affiliation: Angelo Bianchi-Bonomi Haemophilia and Thrombosis Centre, Department of Medicine and Medical Specialties, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Tripodi
authors.affiliation: Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community, Università di Milano and Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: P A
authors.initials: PA
authors.lastname: Bertazzi
authors.affiliation: Laboratory of Environmental Epigenetics, Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA. Electronic address: abaccare@hsph.harvard.edu.
authors.forename: A A
authors.initials: AA
authors.lastname: Baccarelli
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects*; D019652:Extraction and Processing Industry; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D008670:Metals / Q000633:toxicity*; D008875:Middle Aged; D016273:Occupational Exposure / Q000009:adverse effects; D052638:Particulate Matter / Q000633:toxicity*
chemical_list: D006657:Histones; D008670:Metals; D052638:Particulate Matter
keywords: Blood coagulation; Histones; Metals; Particulate matter; Thrombosis
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