Inhalable Metal-rich Air Particles and Histone H3K4 Dimethylation and H3K9 Acetylation in a Cross-sectional Study of Steel Workers.

Environ Health Perspect. 2011 Mar 8. [Epub ahead of print]
Cantone L, Nordio F, Hou L, Apostoli P, Bonzini M, Tarantini L, Angelici L, Bollati V, Zanobetti A, Schwartz J, Bertazzi PA, Baccarelli A.
Università degli Studi di Milano e Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena.
Abstract: BACKGROUND: Epidemiology investigations have linked exposure to ambient and occupational air particles with increased risk of lung cancer. Air particles contain carcinogenic and toxic metals, including arsenic and nickel, which have been shown in in-vitro studies to induce histone modifications that activate gene expression by inducing open-chromatin states. Whether inhalation of metal components of air particles induces histone modifications in human subjects is undetermined. OBJECTIVES: We investigated whether the metal components of air particles determined activating histone modifications in 63 steel workers with well-characterized exposure to metal-rich particles. METHODS: We determined histone H3K4 dimethylation (H3K4me2) and H3K9 acetylation (H3K9ac) on histones from blood leukocytes. Exposure to inhalable metal components (aluminum, manganese, nickel, zinc, arsenic, lead, iron), and to total particulate matter (PM), was estimated for each study subject. RESULTS: Both H3K4me2 and H3K9ac increased in association with years of employment in the plant (p-trend=0.04 and 0.006, respectively). H3K4me2 increased in association with air levels of nickel (β=0.16; %95 CI 0.03 to 0.3), arsenic (β=0.16; %95 CI 0.02 to 0.3), and iron (β=0.14; %95 CI 0.01 to 0.26). H3K9ac showed non-significant positive associations with air levels of nickel (β=0.24; %95 CI -0.02 to 0.51), arsenic (β=0.21; %95 CI -0.06 to 0.48) and iron (β=0.22; %95 CI -0.03 to 0.47). Cumulative exposures to nickel and arsenic, defined as the product of years of employment by metal air levels, were positively correlated with both H3K4me2 (β=0.16; %95 CI 0.01 to 0.3 for nickel; β=0.16; %95 CI 0.03 to 0.29 for arsenic) and H3K9ac (β=0.27; %95 CI 0.01 to 0.54 for nickel; β=0.28; %95 CI 0.04 to 0.51 for arsenic). CONCLUSIONS: Our results indicate histone modifications as a novel epigenetic mechanism induced in human subjects by long-term exposure to inhalable nickel and arsenic.