Effects of Particulate Matter on Genomic DNA Methylation Content and iNOS Promoter Methylation

By Tarantini, Letizia; Bonzini, Matteo et al. | Environmental Health Perspectives, February 2009 | Go to article overview

Effects of Particulate Matter on Genomic DNA Methylation Content and iNOS Promoter Methylation


Tarantini, Letizia, Bonzini, Matteo, Apostoli, Pietro, Pegoraro, Valeria, Bollati, Valentina, Marinelli, Barbara, Cantone, Laura, Rizzo, Giovanna, Hou, Lifang, Schwartz, Joel, Bertazzi, Pier Alberto, Baccarelli, Andrea, Environmental Health Perspectives


BACKGROUND: Altered patterns of gene expression mediate the effects of particulate matter (PM) on human health, but mechanisms through which PM modifies gene expression are largely undetermined.

OBJECTIVES: We aimed at identifying short- and long-term effects of PM exposure on DNA methylation, a major genomic mechanism of gene expression control, in workers in an electric furnace steel plant with well-characterized exposure to PM with aerodynamic diameters < 10 [micro]m ([PM.sub.10]).

METHODS: We measured global genomic DNA methylation content estimated in Alu and long interspersed nuclear element-1 (LINE-1) repeated elements, and promoter DNA methylation of iNOS (inducible nitric oxide synthase), a gene suppressed by DNA methylation and induced by PM exposure in blood leukocytes. Quantitative DNA methylation analysis was performed through bisulfite PCR pyrosequencing on blood DNA obtained from 63 workers on the first day of a work week (baseline, after 2 days off work) and after 3 days of work (postexposure). Individual [PM.sub.10] exposure was between 73.4 and 1,220 [micro]g/[m.sup.3].

RESULTS: Global methylation content estimated in Alu and LINE-1 repeated elements did not show changes in postexposure measures compared with baseline. [PM.sub.10] exposure levels were negatively associated with methylation in both Alu [[beta] = -0.19 %5-methylcytosine (%5mC); P = 0.04] and LINE-1 [[beta] = -0.34 %5mC; P = 0.04], likely reflecting long-term P[M.sup.10] effects. iNOS promoter DNA methylation was significantly lower in postexposure blood samples compared with baseline (difference = -0.61 %5mC; p = 0.02).

CONCLUSIONS: We observed changes in global and gene specific methylation that should be further characterized in future investigations on the effects of PM.

KEY WORDS: DNA methylation, epigenetics, etiology, interspersed repetitive sequences, nitric oxide synthase, particulate matter. Environ Health Perspect 117:217-222 (2009). doi:10.1289/ehp.11898 available via http://dx.doi.org/ [Online 26 September 2008]

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Foundry work has been associated in several early investigations with adverse health outcomes, including cardiovascular and respiratory disease as well as increased risk of lung cancer [Andjelkovich et al. 1990; International Agency for research on Cancer (IARC) 1987; Kuo et al. 1999; Xu et al. 1996]. Exposures responsible for the excess in risk have not been clearly identified (IARC 1987). In modern foundry facilities, exposures to chemicals are remarkably lower than in the past (Bergamaschi et al. 2005), but particulate matter (PM) levels are still well above the concentrations found in ambient outdoor air. Ambient PM has also been associated with increased hospitalization and mortality due to cardiorespiratory disease and lung cancer (Brook et al. 2004; Peters 2005; Samet et al. 2000; Vineis and Husgafvel-Pursiainen 2005). Epidemiologic (Brook et al. 2004; Peters 2005; Schulz et al. 2005) and in vivo studies (Chang et al. 2005; Chen and Hwang 2005; Corey et al. 2006) suggest that the transition metal components of PM may be responsible for such effects.

The mechanisms linking PM inhalation to adverse health outcomes have not been completely clarified. Inhaled particulate pollutants have been shown to produce systemic changes in gene expression, which can be detected in peripheral blood of exposed individuals (Wang et al. 2005). Gene expression of human genes is controlled by DNA methylation, which, in mammals, involves the postreplication addition of methyl groups to the 5' position of cytosine ring within the context of CpG dinucleotides to form 5-methylcytosine (5mC). Initial observations of in vitro and animal models have shown that air particles, or air particle components such as toxic metals, can induce changes in DNA methylation (Belinsky et al. 2002; Takiguchi et al. 2003). Whether DNA methylation changes occur in human subjects exposed to PM has never been determined. …

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