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Blood hypomethylation of inflammatory genes mediates the effects of metal-rich airborne pollutants on blood coagulation
  1. Letizia Tarantini1,
  2. Matteo Bonzini2,
  3. Armando Tripodi3,
  4. Laura Angelici1,
  5. Francesco Nordio4,
  6. Laura Cantone1,
  7. Pietro Apostoli5,
  8. Pier Alberto Bertazzi1,
  9. Andrea A Baccarelli4
  1. 1Department of Clinical and Community Sciences, Università degli Studi di Milano and IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy
  2. 2Department of Clinical and Experimental Medicine, Epidemiology and Preventive Medicine Research Centre, University of Insubria, Varese, Italy
  3. 3Department of Medicine and Medical Specialties, Angelo Bianchi-Bonomi Haemophilia and Thrombosis Centre, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Milan, Italy
  4. 4Laboratory of Environmental Epigenetics, Exposure Epidemiology and Risk Program, Harvard School of Public Health, Boston, Massachusetts, USA
  5. 5Department of Experimental and Applied Medicine, Occupational Medicine and Industrial Hygiene, University of Brescia, Brescia, Italy
  1. Correspondence to Andrea A Baccarelli, Laboratory of Environmental Epigenetics, Exposure Epidemiology and Risk Program, Harvard School of Public Health, Office—Landmark Center, Rm 415E West, PO-Box 15677, 401 Park Dr, Boston, MA 02215, USA; abaccare{at}hsph.harvard.edu

Abstract

Objectives Recent investigations have associated airborne particulate matter (PM) with increased coagulation and thrombosis, but underlying biological mechanisms are still incompletely characterised. DNA methylation is an environmentally sensitive mechanism of gene regulation that could potentially contribute to PM-induced hypercoagulability.

We aimed to test whether altered methylation mediates environmental effects on coagulation.

Methods We investigated 63 steel workers exposed to a wide range of PM levels, as a work-related condition with well-characterised prothrombotic exposure. We measured personal PM10 (PM≤10 µm in aerodynamic diameter), PM1 (≤1 µm) and air metal components. We determined leukocyte DNA methylation of NOS3 (nitric-oxide-synthase-3) and EDN1 (endothelin-1) through bisulfite-pyrosequencing and we measured ETP as a global coagulation-activation test after standardised triggers.

Results ETP increased in association with PM10 (β=20.0, 95% CI 3.0 to 37.0), PM1 (β=80.8 95% CI 14.9 to 146.7) and zinc (β=51.3, 95% CI 0.01 to 111.1) exposures. NOS3 methylation was negatively associated with PM10 (β=−0.2, 95% CI −0.4 to −0.03), PM1 (β=−0.8, 95% CI −1.4 to −0.1), zinc (β=−0.9, 95% CI −1.4 to −0.3) and iron (β=−0.7, 95% CI −1.4 to −0.01) exposures. Zinc exposure was negatively associated with EDN1 (β=−0.3, 95% CI −0.8 to −0.1) methylation. Lower NOS3 (β=−42.3; p<0.001) and EDN1 (β=−14.5; p=0.05) were associated with higher ETP. Statistical mediation analysis formally confirmed NOS3 and EDN1 hypomethylation as intermediate mechanisms for PM-related coagulation effects.

Conclusions Our study showed for the first time, that gene hypomethylation contributes to environmentally induced hypercoagulability.

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