Academic journal article Environmental Health Perspectives

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

Academic journal article Environmental Health Perspectives

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

Article excerpt

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 (H3 K9ac) on histories 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. [beta]6, respectively). H3K4me2 increased in association with air levels of nickel [p = 0.16; 95% confidence interval (CI), 0.03-0.3], arsenic [beta] = 0.16; 95% CI, 0.02-0.3), and iron [beta] = 0.14; 95% CI, 0.01-0.26). H3K9ac showed nonsignificant positive associations with air levels of nickel [beta] = 0.24; 95% CI, -0.02 to 0.51), arsenic [beta] = 0.21; 95% CI, -0.06 to 0.48), and iron ([beta] = 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: [beta] = 0.16; 95% CI, 0.01-0.3; arsenic: [beta] = 0.16; 95% CI, 0.03-0.29) and H3K9ac (nickel: [beta] = 0.27; 95% CI, 0.01-0.54; arsenic: [beta] = 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.

KEYWORDS: environmental carcinogens, epigenetics, histone modifications, metals, particulate matter. Environ Health Perspect 119:964-969 (2011). doi:10.1289/ehp. 1002955 [Online 8 March 2011]

Ambient and occupational exposure to inhalable particulate matter (PM) has been associated with increased risk of lung cancer (Dockery et al. 1993; Gibb et al. 2000; Kuo et al. 1999). Epidemiologic and in vivo studies suggest that the metal components of PM may be responsible for PM health effects, including lung cancer (Chang et al. 2005; Chen and Hwang 2005; Conroy et al. 2008; Corey et al. 2006; Coyle et al. 2006; Franklin et al. 2008; MacNee and Donaldson 2003; Roller 2009; Wild et al. 2009). Despite the well-recognized carcinogenic potentials of several toxic metals, the molecular mechanisms underlying their associations with cancer risk remain poorly understood. In particular, most carcinogenic metals are weak mutagens and do not induce DNA adduct formation, a key initiating event caused by other carcinogens (Salnikow and Zhitkovich 2008).

Growing evidence indicates that epigenetic dysregulation of gene expression plays a primary role in cancer etiology (Feinberg and Tycko 2004; Ke et al. 2006). Several toxic metals have been shown to bind more avidly to histone proteins than to other biopolymers such as DNA or RNA (Conroy et al. 2008; Zoroddu et al. 2000, 2002). Recent in vitro studies have shown that carcinogenic metals cause posttranslational epigenetic modifications of histone proteins, thus derailing the normal programming of gene expression (Ke et al. 2006; Yan and Boyd 2006; Yan et al. 2003; Zhou X et al. 2009). In lung epithelial cell lines and malignant transformation models, arsenic (Jensen et al. 2009; Zhou X et al. 2009), nickel (Zhou QX et al. 2009), and chromium (Sun et al. 2009; Zhou X et al. 2009) have been linked with specific activating histone modifications, such as H3K4 (histone 3 lysine 4) dimethylation (H3K4me2), that contribute to the formation of a relaxed or "open" chromatin structure permissive for gene transcription (Surralles et al. …

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