Integrative Analysis of miRNA and Inflammatory Gene Expression After Acute Particulate Matter Exposure
Exposure, Epidemiology and Risk Program, Department of Environmental Health, Laboratory of Environmental Epigenetics, Harvard School of Public Health, 665 Huntington Avenue, KRESGE Building 1, Boston, MA 02115, USA. Phone: (617) 432-0666. Fax: (617) 384-8859.Toxicological Sciences (Impact Factor: 3.85). 01/2013; 132(2). DOI: 10.1093/toxsci/kft013
MicroRNAs are environmentally-sensitive inhibitors of gene expression that may mediate the effects of metal-rich particulate matter (PM) and toxic metals on human individuals. Previous environmental miRNA studies have investigated a limited number of candidate miRNAs and have not yet evaluated functional effects on gene expression. In this study we want to identify PM-sensitive miRNAs using microarray profiling on matched baseline and post-exposure RNA from foundry workers with well-characterized exposure to metal-rich PM; and to characterize miRNA relations with expression of candidate inflammatory genes.We applied microarray analysis of 847 human miRNAs and Real-Time PCR analysis of 18 candidate inflammatory genes on matched blood samples collected from foundry workers at baseline and after three days of work (post-exposure). We identified differentially-expressed miRNAs (Fold Change [FC]>2 and p<0.05) and correlated their expression with the inflammatory associated genes. We performed in-silico network analysis in MetaCore v6.9 to characterize the biological pathways connecting miRNA-mRNA pairs.Microarray analysis identified four miRNAs that were differentially-expressed in post-exposure compared to baseline samples, including miR-421 (FC=2.81, p-value<0.001), miR146a (FC=2.62, p-value=0.007), miR-29a (FC=2.91, p-value<0.001), and let-7g (FC=2.73, p-value=0.019). Using FDR adjustment for multiple comparisons, we found 11 miRNA-mRNA correlated pairs involving the four differentially-expressed miRNAs and candidate inflammatory genes. In-silico network analysis with MetaCore database identified biological interactions for all the 11 miRNA-mRNA pairs, which ranged from direct mRNA targeting to complex interactions with multiple intermediates.Acute PM exposure may affect gene-regulation through PM-responsive miRNAs that directly or indirectly control inflammatory gene expression.
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- "The investigation of short term effects of metal-rich PM on miRNA expression in pre-and post-exposure samples from steel production plant workers, highlighted 4 up-regulated miRNA in post-exposure compared with baseline samples (Motta et al., 2013). Concomitant mRNA analysis provided evidence on the impact of acute PM exposure on gene regulation through novel PMresponsive miRNA that may directly or indirectly control inflammatory gene expression (Motta et al., 2013). Subsequently, Fossati and collaborators analyzed the association between PM exposure and miRNA deregulation in elderly men; they found a down-regulation in candidate miRNA involved in processes related to PM exposure, including inflammation, endothelial dysfunction, and coagulation (Fossati et al., 2014). "
ABSTRACT: DNA sequence and genetic factors alone cannot fully explain the many processes implicated in diseases initiation and development. It is now well understood that additional factors are involved in a final resulting phenotype. Epigenetic modifications, heritable changes not affecting the DNA sequence, are a key phenomenon at the basis of normal growth and differentiation. However, these can be defective leading to diseases, such as cancer. An increasing body of literature reports the environmental and occupational exposure to a mixture of natural and man-produced substances leading to epigenetic alterations. The identification of key genetic and/or epigenetic events involved in chemical carcinogenesis is an important step towards the discovery of biomarkers that can be used to evaluate the exposure, predict biological effects, and prevent adverse health consequences. Here, we focus on epidemiological studies to review the most recent advances in understanding genetic and epigenetic factors in relation to particulate matter, benzene and polycyclic aromatic hydrocarbons exposure.
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ABSTRACT: Ambient particulate matter (PM) has been associated with mortality and morbidity for cardiovascular disease. MicroRNAs control gene expression at a posttranscriptional level. Altered microRNA expression has been reported in processes related to cardiovascular disease and PM exposure, such as systemic inflammation, endothelial dysfunction, and atherosclerosis. Polymorphisms in microRNA-related genes could influence response to PM. We investigated the association of exposure to ambient particles in several time windows (4-hour to 28-day moving averages) and blood leukocyte expression changes in 14 candidate microRNAs in 153 elderly males from the Normative Aging Study (examined 2005-2009). Potential effect modification by six single nucleotide polymorphisms (SNPs) in three microRNA-related genes was investigated. Fine PM (PM2.5), black carbon, organic carbon, and sulfates were measured at a stationary ambient monitoring site. Linear regression models, adjusted for potential confounders, were used to assess effects of particles and SNP-by-pollutant interaction. An in silico pathway analysis was performed on target genes of microRNAs associated with the pollutants. We found a negative association for pollutants in all moving averages and miR-1, -126, -135a, -146a, -155, -21, -222, and -9. The strongest associations were observed with the 7-day moving averages for PM2.5 and black carbon and with the 48-hour moving averages for organic carbon. The association with sulfates was stable across the moving averages. The in silico pathway analysis identified 18 pathways related to immune response shared by at least two microRNAs; in particular, the "high-mobility group protein B1/advanced glycosylation end product-specific receptor signaling pathway" was shared by miR-126, -146a, -155, -21, and -222. No important associations were observed for miR-125a-5p, -125b, -128, -147, -218, and -96. We found significant SNP-by-pollutant interactions for rs7813, rs910925, and rs1062923 in GEMIN4 and black carbon and PM2.5 for miR-1, -126, -146a, -222, and -9, and for rs1640299 in DGCR8 and SO4 for miR-1 and -135a. Exposure to ambient particles could cause a downregulation of microRNAs involved in processes related to PM exposure. Polymorphisms in GEMIN4 and DGCR8 could modify these associations.
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ABSTRACT: The complex miRNA regulatory network plays an important role in diverse biological activities of physiopathological processes. In addition to the discovery of and research on the extracellular miRNAs detected in multiple biofluids, the properties of tissue specificity and high stability underlie the great potential of these small miRNAs to serve as translational biomarkers for various diseases in the clinical setting, including in drug-induced liver injury. In this review, we describe the major technologies currently used and challenges in miRNA measurement and provide information on major bioinformatics resources available for current miRNA research. We also discuss novel findings in liver disease and highlight the potential of miRNAs for clinical and basic research as translational biomarkers for drug-induced liver injury.
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