Integrative analysis of miRNA and inflammatory gene expression after acute particulate matter exposure.
ABSTRACT 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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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.Epidemiology (Cambridge, Mass.) 11/2013; 25(1). DOI:10.1097/EDE.0000000000000026 · 6.18 Impact Factor
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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.Biomarkers in Medicine 02/2014; 8(2):161-72. DOI:10.2217/bmm.13.147 · 2.86 Impact Factor
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ABSTRACT: Exposures to environmental toxicants and toxins cause epigenetic changes that likely play a role in the development of diseases associated with exposure. The mechanism behind these exposure-induced epigenetic changes is currently unknown. One commonality between most environmental exposures is that they cause DNA damage either directly or through causing an increase in reactive oxygen species, which can damage DNA. Like transcription, DNA damage repair must occur in the context of chromatin requiring both histone modifications and ATP-dependent chromatin remodeling. These chromatin changes aid in DNA damage accessibility and signaling. Several proteins and complexes involved in epigenetic silencing during both development and cancer have been found to be localized to sites of DNA damage. The chromatin-based response to DNA damage is considered a transient event, with chromatin being restored to normal as DNA damage repair is completed. However, in individuals chronically exposed to environmental toxicants or with chronic inflammatory disease, repeated DNA damage-induced chromatin rearrangement may ultimately lead to permanent epigenetic alterations. Understanding the mechanism behind exposure-induced epigenetic changes will allow us to develop strategies to prevent or reverse these changes. This review focuses on epigenetic changes and DNA damage induced by environmental exposures, the chromatin changes that occur around sites of DNA damage, and how these transient chromatin changes may lead to heritable epigenetic alterations at sites of chronic exposure. Environ. Mol. Mutagen., 2013. © 2013 Wiley Periodicals, Inc.Environmental and Molecular Mutagenesis 04/2014; 55(3). DOI:10.1002/em.21830 · 2.55 Impact Factor