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

Abstract

Background: Epidemiology investigations have linked exposure to ambient and occupational air particulate matter (PM) with increased risk of lung cancer. PM contains 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 PM induces histone modifications in human subjects is undetermined.Objectives: We investigated whether the metal components of PM determined activating histone modifications in 63 steel workers with well-characterized exposure to metal-rich PM.Methods: We determined histone 3 lysine 4 dimethylation (H3K4me2) and histone 3 lysine 9 acetylation (H3K9ac) on histones from blood leukocytes. Exposure to inhalable metal components (aluminum, manganese, nickel, zinc, arsenic, lead, iron) and to total 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% confidence interval (CI), 0.03–0.3], arsenic (β = 0.16; 95% CI, 0.02–0.3), and iron (β = 0.14; 95% CI, 0.01–0.26). H3K9ac showed nonsignificant 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 (nickel: β = 0.16; 95% CI, 0.01–0.3; arsenic: β = 0.16; 95% CI, 0.03–0.29) and H3K9ac (nickel: β = 0.27; 95% CI, 0.01–0.54; arsenic: β = 0.28; 95% CI, 0.04–0.51).Conclusions: Our results indicate histone modifications as a novel epigenetic mechanism induced in human subjects by long-term exposure to inhalable nickel and arsenic.

Quantitative Mass Spectrometry Reveals Changes in Histone H2B Variants as Cells Undergo Inorganic Arsenic-Mediated Cellular Transformation

“…A number of studies have demonstrated that iAs exposure induces global and gene-specific post-translational histone modifications such as reduction of acetylation in histone H3 and H4: loss of H4Lys 16 10 and H2AX phosphorylation, and decreases in H2B ubiquitination (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Ambient Particulate Air Pollution, Environmental Tobacco Smoking, and Childhood Asthma: Interactions and Biological Mechanisms

“…Alveolar epithelial and pulmonary endothelial cells (9) and fibroblasts (10) from the lungs of patients with emphysema exhibit shorter telomeres, compared with those from subjects without emphysema. Recent data also indicate that telomeres in circulating leukocytes from patients with COPD are shorter, compared with control subjects in any age range (11,12).…”

“…Conversely, the levels and timing of expression of gene products-including mRNA and proteinsare highly sensitive to environmental challenges. In addition, recent investigations have identified changes in epigenetic mechanisms, including DNA methylation (6-10) and histone modifications (11), that control gene expression. The epigenome, together with microRNAs (miRNAs) (12, 13)-an emerging class of inhibitors of gene expression-appears exquisitely sensitive to environmental exposures and may also contribute to mediate rapid changes in gene expression (14,15), as well as in protein activities and metabolite levels, that may parallel the fluctuating phenotypes typical of patients with asthma.…”

Exposure to Nano-Sized Particles and the Emergence of Contemporary Diseases with a Focus on Epigenetics

“…(Chang, 2010;Costa & Dreher, 1997) As will be demonstrated in the following section, long-term exposure to elevated levels of PM mixed with inhalable nickel and arsenic vapors induces also epigenetic changes in human subjects. (Cantone et al, 2011) Thus, the information due to conditioning of the immune system leads to memorization of long-term exposure events at cellular level and is somatically passed on to progeny cells via epigenetic means. As will be exemplified, this also enables cells to leave marks on reproductive cells so that these events can be passed on the filial generation.…”

“…Both acetylation of the histone H3K9 and demethylation of H3K4 increased by about 15% after a >21 year exposure near the smelter. (Cantone et al, 2011) Another key concept for the developmental origin of diseases comprises a transfer of the acquired predisposition onto subsequent generations without further environmental impacts (see Figure 10). Such trans-generational epigenetic inheritance is responsible for wider effects, such as a fast-track pathway of adaptation to environmental stress.…”