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Ambient Particulate Air Pollution and MicroRNAs in Elderly Men
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.
... Certain miRNAs classified as inflammation regulating miRNAs most likely because of their influence on the expression regulation of proinflammatory genes [216,217] include miR-222, miR-21, miR-146a, miR-26a, miR-187, miR135a and miR-155 [192,218,219]. Some of these ncRNAs were associated with regulation of inflammation and target pro-inflammatory genes among children exposed to particulate matter [220]. ...
... Contrary to these observations, elevated time-weighted PM 2.5 concentration was associated with downregulation of miR-21-5p and miR-146a-5p [218] in young adults. Also, in elderly men, miR-21-5p and miR-146a-5p was negatively associated with PM 2.5 exposure [219]. No significant relationship between PM exposure and miR-21-5p and miR-146a-5p in the study reported by Bollati et al. [192]. ...
This study emphasizes the importance of considering the metabolic and toxicity mechanisms of environmental concern chemicals in real-life exposure scenarios. Furthermore, environmental chemicals may require metabolic activation to become toxic, and competition for binding sites on receptors can affect the severity of toxicity. The multicomplex process of chemical toxicity is reflected in the activation of multiple pathways during toxicity of which AhR activation is major. Real-life exposure to a mixture of concern chemicals is common, and the composition of these chemicals determines the severity of toxicity. Nutritional essential elements can mitigate the toxicity of toxic heavy metals, while the types and ratio of composition of PAH can either increase or decrease toxicity. The epigenetic mechanisms of heavy metals and PAH toxicity involves either down-regulation or up-regulation of some non-coding RNAs (ncRNAs) whereas specific small RNAs (sRNAs) may have dual role depending on the tissue and circumstance of expression. Similarly, decrease DNA methylation and histone modification are major players in heavy metals and PAH mediated toxicity and FLT1 hypermethylation is a major process in PAH induced carcinogenesis. Overall, this review provides the understanding of the metabolism of environmental concern chemicals, emphasizing the importance of considering mixed compositions and real-life exposure scenarios in assessing their potential effects on human health and diseases development as well as the dual mechanism of toxicity via genetic or epigenetic axis.
... However, in a cohort of 153 elderly males, an inverse relationship was found between eight leukocyte miRNAs, including miR-21 and miR-222, and PM 2.5 exposure. According to the authors, considering the activity of the predicted target mRNAs, this negative association should result in increased inflammation, endothelial dysfunction, and atherosclerosis [189]. The contradictory results could be due to differences in the methodologies used by the two research teams, the particle composition, the time of exposure and/or the characteristics of the participants. ...
... EVs showed a reduced expression of these miRNAs, promoting apoptotic cell clearance [156] Exposure to cigarette smoke lncRNA SCAL1 Reduced levels of miRNAs and increase of the targeted cytokines, which are involved in inflammation, coagulation, and endothelial dysfunction [189] Coronary artery disease, cardiac hypertrophy, and heart failure Three-day exposure to PM miR-128 and miR-302 from circulating microvesicles miRNAs overexpression and possible positive correlation with CVD development [190] Exposure to metal-rich PM miR-29a-3p, miR-146a-5p, miR-421, and let-7 g-5p ...
Air pollution has increased over the years, causing a negative impact on society due to the many health-related problems it can contribute to. Although the type and extent of air pollutants are known, the molecular mechanisms underlying the induction of negative effects on the human body remain unclear. Emerging evidence suggests the crucial involvement of different molecular mediators in inflammation and oxidative stress in air pollution-induced disorders. Among these, non-coding RNAs (ncRNAs) carried by extracellular vesicles (EVs) may play an essential role in gene regulation of the cell stress response in pollutant-induced multiorgan disorders. This review highlights EV-transported ncRNAs’ roles in physiological and pathological conditions, such as the development of cancer and respiratory, neurodegenerative, and cardiovascular diseases following exposure to various environmental stressors.
... The association of PM 2.5 exposure with miRNAs has been shown in previous studies (Cheng et al., 2020;Fossati et al., 2014;Mancini et al., 2020). An association study based on the Normative Aging Study including 153 elderly males found negative associations between 4-h to 28-day PM 2.5 exposure and miR-1, miR-9, miR-222, miR-126, miR-155, miR-135a, and miR-146a (Fossati et al., 2014). ...
... The association of PM 2.5 exposure with miRNAs has been shown in previous studies (Cheng et al., 2020;Fossati et al., 2014;Mancini et al., 2020). An association study based on the Normative Aging Study including 153 elderly males found negative associations between 4-h to 28-day PM 2.5 exposure and miR-1, miR-9, miR-222, miR-126, miR-155, miR-135a, and miR-146a (Fossati et al., 2014). Another study of 143 participants from 4 European countries indicated that the expression of circulating miR-24-3p, miR-425-5p, miR-4454, miR-4763-3p, miR-502-5p, miR-505-3p, and let-7d-5p was correlated with 24-h PM 2.5 personal exposure, suggesting that miRNAs could be used as novel biomarkers for PM 2.5 exposure-associated health risk assessment (Mancini et al., 2020). ...
The effect of PM2.5 exposure on lung function reduction has been well-documented, but the underlying mechanism remains unclear. MiR-4301 may be involved in regulating pathways related to lung injury/repairment, and this study aimed to explore the potential role of miR-4301 in PM2.5 exposure-associated lung function reduction. A total of 167 Wuhan community nonsmokers were included in this study. Lung function was measured and personal PM2.5 exposure moving averages were evaluated for each participant. Plasma miRNA was determined by real-time polymerase chain reaction. A generalized linear model was conducted to assess the relationships among personal PM2.5 moving average concentrations, lung function, and plasma miRNA. The mediation effect of miRNA on the association of personal PM2.5 exposure with lung function reduction was estimated. Finally, we performed pathway enrichment analysis to predict the underlying pathways of miRNA in lung function reduction from PM2.5 exposure. We found that each 10 μg/m3 increase in the 7-day personal PM2.5 moving average concentration (Lag0-7) was related to a 46.71 mL, 1.15%, 157.06 mL/s, and 188.13 mL/s reductions in FVC, FEV1, PEF, and MMF, respectively. PM2.5 exposure was negatively associated with plasma miR-4301 expression levels in a dose‒response manner. Additionally, each 1% increase in miR-4301 expression level was significantly associated with a 0.36 mL, 0.01%, 1.14 mL/s, and 1.28 mL/s increases in FEV1, FEV1/FVC, MMF, and PEF, respectively. Mediation analysis further revealed that decreased miR-4301 mediated 15.6% and 16.8% of PM2.5 exposure-associated reductions in FEV1/FVC and MMF, respectively. Pathway enrichment analyses suggested that the wingless related-integration site (Wnt) signaling pathway might be one of the pathways regulated by miR-4301 in the reduction of lung function from PM2.5 exposure. In brief, personal PM2.5 exposure was negatively associated with plasma miR-4301 or lung function in a dose‒response manner. Moreover, miR-4301 partially mediated the lung function reduction associated with PM2.5 exposure.
... MicroRNAs (miRNAs) are small endogenous noncoding RNAs that play a crucial role in the regulation of gene expression (Fossati et al., 2014;Duroux-Richard et al., 2019). They participate in numerous biological processes such as inflammation, cell proliferation, oxidative stress, differentiation, angiogenesis, and apoptosis (Fossati et al., 2014;Duroux-Richard et al., 2019;Condorelli et al., 2010). ...
... MicroRNAs (miRNAs) are small endogenous noncoding RNAs that play a crucial role in the regulation of gene expression (Fossati et al., 2014;Duroux-Richard et al., 2019). They participate in numerous biological processes such as inflammation, cell proliferation, oxidative stress, differentiation, angiogenesis, and apoptosis (Fossati et al., 2014;Duroux-Richard et al., 2019;Condorelli et al., 2010). More recent data suggest that miRNA signalling may be an active part of the cellular response to a variety of chemical substances including air pollutants (Sima et al., 2021). ...
Chronic exposure to PM2.5 contributes to the pathogenesis of numerous disorders, although the underlying mechanisms remain unknown. The study investigated whether exposure of human monocytes to PM2.5 is associated with alterations in miRNAs. Monocytes were exposed in vitro to PM2.5 collected during winter and summer, followed by miRNA isolation from monocytes. Additionally, in 140 persons chronically exposed to air pollution, some miRNA patterns were isolated from serum seasonally. Between-season differences in chemical PM2.5 composition were observed. Some miRNAs were expressed both in monocytes and in human serum.
MiR-34c-5p and miR-223-5p expression was more pronounced in winter. Bioinformatics analyses showed that selected miRNAs were involved in the regulation of several pathways. The expression of the same miRNA species in monocytes and serum suggests that these cells are involved in the production of miRNAs implicated in the development of disorders mediated by inflammation, oxidative stress, proliferation, and apoptosis after exposure to PM2.5.
... In addition, specific micro RNAs (miRNAs) are influenced by PM exposure and can be measured, especially when protected in the extracellular environment through microvesicles or exosomes [38]. Amongst them are miR-146a and miR-222, both shown to be responsive to PM exposure in adults [39][40][41][42]. They could be interesting biomarkers to measure in exosome-containing fluids, such as saliva, during the monitoring of air pollution exposure. ...
... Moreover, extracellular non-coding RNAs are thought to have stable and similar expression profiles throughout different fluids [67]. In this study, miR-222 and miR-146a were investigated, two potential biomarkers that are responsive to PM exposure in adults [39][40][41][42]. The selected methods included commercial kits and assays which were successfully used in previous studies involving other biofluids, such as blood and sweat [68,69]. ...
Air pollution exposure can lead to exacerbation of respiratory disorders in children. Using sensitive biomarkers helps to assess the impact of air pollution on children’s respiratory health and combining protein, genetic and epigenetic biomarkers gives insights on their interrelatedness. Most studies do not contain such an integrated approach and investigate these biomarkers individually in blood, although its collection in children is challenging. Our study aimed at assessing the feasibility of conducting future integrated larger-scale studies evaluating respiratory health risks of air pollution episodes in children, based on a qualitative analysis of the technical and logistic aspects of a small-scale field study involving 42 children. This included the preparation, collection and storage of non-invasive samples (urine, saliva), the measurement of general and respiratory health parameters and the measurement of specific biomarkers (genetic, protein, epigenetic) of respiratory health and air pollution exposure. Bottlenecks were identified and modifications were proposed to expand this integrated study to a higher number of children, time points and locations. This would allow for non-invasive assessment of the impact of air pollution exposure on the respiratory health of children in future larger-scale studies, which is critical for the development of policies or measures at the population level.
... 142 Increasing numbers of studies have explored the associations between ambient air pollution and change in ncRNAs in human. [143][144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159][160][161] Most of these studies have focused on miRNA, a kind of small ncRNA (20-24 nucleotides) that regulates the expression of one third of human genes. 162 There are more than 2000 miRNAs that have been found in humans and they regulate gene expression mainly through cleavage of mRNA, suppression of translation or mRNA degradation. ...
... 162 There are more than 2000 miRNAs that have been found in humans and they regulate gene expression mainly through cleavage of mRNA, suppression of translation or mRNA degradation. 142,162 However, there are only about 150 miRNAs that have been found to be associated with ambient air pollution, [143][144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159][160][161] and only 24 of them have been identified in at least two studies (Table 4). After excluding studies based on the same population (e.g., Refs. ...
This chapter summarized the existing epidemiological evidence about the association between exposure to ambient air pollution and human epigenetic modifications, including DNA methylation (global DNA methylation, gene-specific DNA methylation, DNA methylation-based biomarkers, mitochondrial DNA methylation), non-coding RNAs, and histone modifications. We found that most of existing studies on this topic focused on DNA methylation. They showed generally consistent finding about the inverse association between ambient air pollution and global DNA methylation. A total of 150 micro RNAs and the methylation status of over 4240 genes have been found to be associated with ambient air pollution, but few of them have been replicated by different studies. Evidence about mitochondrial DNA methylation, DNA methylation-based biomarkers, long non-coding RNAs, and histone modifications remain scarce or inconsistent. We highlighted the value of twin and family study in this rapidly growing field, in terms of adjusting for familial confounding effects and making causal inference.
... Two studies focused on miRNA expression associated with air pollution in elderly men originating from the Normative Aging Study [91,104]. In a small group of 22 subjects, exposure to PM2.5 was linked with increased blood pressure and positively associated with miR-199a/b and miR-223-3p expression in extracellular vesicles. ...
... The strongest link was found for 7-day moving averages of PM2.5 and black carbon, and 48-h moving averages for organic carbon. The deregulated miRNAs most likely participate in HMGB1/RAGE signaling pathway that is associated with the enhanced expression of proinflammatory cytokines [104]. ...
Small non-coding RNA molecules (miRNAs) play an important role in the epigenetic regulation of gene expression. As these molecules have been repeatedly implicated in human cancers, they have been suggested as biomarkers of the disease. Additionally, miRNA levels have been shown to be affected by environmental pollutants, including airborne contaminants. In this review, we searched the current literature for miRNAs involved in lung cancer, as well as miRNAs deregulated as a result of exposure to air pollutants. We then performed a synthesis of the data and identified those molecules commonly deregulated under both conditions. We detected a total of 25 miRNAs meeting the criteria, among them, miR-222, miR-21, miR-126-3p, miR-155 and miR-425 being the most prominent. We propose these miRNAs as biomarkers of choice for the identification of human populations exposed to air pollution with a significant risk of developing lung cancer.
... Other studies have confirmed significant associations of PM exposure and the cellular levels of miR-222, which has a function in cell cycle and vascular biology, as well as miR-146a which plays an important role in inflammation, in adults (Fossati et al., 2014;Motta et al., 2013). The first study reporting extracellular miRNAs in association to air pollution identified miR-222 to positively correlate with UFP levels in the saliva of school children (Vriens et al., 2016). ...
... We validated the response of 2 miRNAs, namely hsa-miR-222 and hsa-miR-146a, that have been extensively studied in humans upon longterm exposure to PM (Fossati et al., 2014;Motta et al., 2013;Vriens et al., 2016). Both have been positively correlated with the mixture of TRAP and the individual compounds UFP, NO, NO 2 and CO in the present study. ...
Traffic-related air pollution (TRAP) is a complex mixture of compounds that contributes to the pathogenesis of many diseases including several types of cancer, pulmonary, cardiovascular and neurodegenerative diseases, and more recently also diabetes mellitus. In search of an early diagnostic biomarker for improved environmental health risk assessment, recent human studies have shown that certain extracellular miRNAs are altered upon exposure to TRAP. Here, we present a global circulating miRNA analysis in a human population exposed to different levels of TRAP. The cross-over study, with sampling taking place during resting and physical activity in two different exposure scenarios, included for each subject personal exposure measurements of PM 10 ,PM 2.5 , NO, NO 2 , CO, CO 2 , BC and UFP. Next-generation sequencing technology was used to identify global circulating miRNA levels across all subjects. We identified 8 miRNAs to be associated with the mixture of TRAP and 27 miRNAs that were associated with the individual pollutants NO, NO 2 , CO, CO 2 , BC and UFP. We did not find significant associations between miRNA levels and PM 10 or PM 2.5. Integrated network analysis revealed that these circulating miRNAs are potentially involved in processes that are implicated in the development of air pollution-induced diseases. Altogether, this study demonstrates that signatures consisting of circulating miRNAs present a potential novel biomarker to be used in health risk assessment.
... Fine particulate matter (PM2.5) is a well-recognized risk factor for health and has been found to be associated with multiple adverse health outcomes such as cardiovascular disease and respiratory disease 5,6 . Previous studies suggested that PM2.5 has potential immunotoxicity and could be a risk factor for infection [7][8][9] . Various studies have found a positive association between PM2.5 exposure and risk for respiratory infections [10][11][12][13] . ...
The association between PM2.5 and non-respiratory infections is unclear. Using data from Medicare beneficiaries and high-resolution datasets of PM2.5 and its constituents across 39,296 ZIP codes in the U.S between 2000 and 2016, we investigated the associations between annual PM2.5, PM2.5 constituents, source-specific PM2.5, and hospital admissions from non-respiratory infections. Each standard deviation (3.7-μg m−3) increase in PM2.5 was associated with a 10.8% (95%CI 10.8–11.2%) increase in rate of hospital admissions from non-respiratory infections. Sulfates (30.8%), Nickel (22.5%) and Copper (15.3%) contributed the largest weights in the observed associations. Each standard deviation increase in PM2.5 components sourced from oil combustion, coal burning, traffic, dirt, and regionally transported nitrates was associated with 14.5% (95%CI 7.6–21.8%), 18.2% (95%CI 7.2–30.2%), 20.6% (95%CI 5.6–37.9%), 8.9% (95%CI 0.3–18.4%) and 7.8% (95%CI 0.6–15.5%) increases in hospital admissions from non-respiratory infections. Our results suggested that non-respiratory infections are an under-appreciated health effect of PM2.5.
... miRNA expression is tissue-specific [21], and it is affected by irritants and other materials [22]. However, single omics analyses of miRNA-mRNA and protein-protein interactions reflecting the harmful effects of air pollutants on the respiratory tract have been insufficient to identify disease biomarkers [23,24]. ...
Air pollutants are associated with exacerbations of asthma, chronic bronchitis, and airway inflammation. Diesel exhaust particles (DEPs) can induce and worsen lung diseases. However, there are insufficient data to guide polymerase chain reaction (PCR) array proteomics studies regarding the impacts of DEPs on respiratory diseases. This study was performed to identify genes and proteins expressed in normal human bronchial epithelial (NHBE) cells. MicroRNAs (miRNAs) and proteins expressed in NHBE cells exposed to DEPs at 1 μg/cm2 for 8 h and 24 h were identified using PCR array analysis and 2D PAGE/LC-MS/MS, respectively. YWHAZ gene expression was estimated using PCR, immunoblotting, and immunohistochemical analyses. Genes discovered through an overlap analysis were validated in DEP-exposed mice. Proteomics approaches showed that exposing NHBE cells to DEPs led to changes in 32 protein spots. A transcriptomics PCR array analysis showed that 6 of 84 miRNAs were downregulated in the DEP exposure groups compared to controls. The mRNA and protein expression levels of YWHAZ, β-catenin, vimentin, and TGF-β were increased in DEP-treated NHBE cells and DEP-exposed mice. Lung fibrosis was increased in mice exposed to DEPs. Our combined PCR array–omics analysis demonstrated that DEPs can induce airway inflammation and lead to lung fibrosis through changes in the expression levels of YWHAZ, β-catenin, vimentin, and TGF-β. These findings suggest that dual approaches can help to identify biomarkers and therapeutic targets involved in pollutant-related respiratory diseases.
... In addition, PM can stimulate the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. It is also associated with systemic inflammatory responses and atherosclerosis [49][50][51][52][53][54]. Women with cardiovascular diseases have suboptimal cardiac adaptation during pregnancy compared to healthy women. ...
Although preterm birth (PTB), a birth before 34 weeks of gestation accounts for only less than 3% of total births, it is a critical cause of various perinatal morbidity and mortality. Several studies have been conducted on the association between maternal exposure to PM and PTB, but the results were inconsistent. Moreover, no study has analyzed the risk of PM on PTB among women with cardiovascular diseases, even though those were thought to be highly susceptible to PM considering the cardiovascular effect of PM. Therefore, we aimed to evaluate the effect of PM10 on early PTB according to the period of exposure, using machine learning with data from Korea National Health Insurance Service (KNHI) claims. Furthermore, we conducted subgroup analysis to compare the risk of PM on early PTB among pregnant women with cardiovascular diseases and those without. A total of 149,643 primiparous singleton women aged 25 to 40 years who delivered babies in 2017 were included. Random forest feature importance and SHAP (Shapley additive explanations) value were used to identify the effect of PM10 on early PTB in comparison with other well-known contributing factors of PTB. AUC and accuracy of PTB prediction model using random forest were 0.9988 and 0.9984, respectively. Maternal exposure to PM10 was one of the major predictors of early PTB. PM10 concentration of 5 to 7 months before delivery, the first and early second trimester of pregnancy, ranked high in feature importance. SHAP value showed that higher PM10 concentrations before 5 to 7 months before delivery were associated with an increased risk of early PTB. The probability of early PTB was increased by 7.73%, 10.58%, or 11.11% if a variable PM10 concentration of 5, 6, or 7 months before delivery was included to the prediction model. Furthermore, women with cardiovascular diseases were more susceptible to PM10 concentration in terms of risk for early PTB than those without cardiovascular diseases. Maternal exposure to PM10 has a strong association with early PTB. In addition, in the context of PTB, pregnant women with cardiovascular diseases are a high-risk group of PM10 and the first and early second trimester is a high-risk period of PM10.
... These include studies of outcomes such as DNA methylation, telomere length, and inflammatory biomarkers (Baccarelli et al., 2009;Chuang et al., 2007;Plusquin et al., 2017;Rider and Carlsten, 2019;Wang et al., 2022;Xia et al., 2015). One area of relatively newer interest has been the relationship between air pollution and microRNAs (Bollati et al., 2015;Chen et al., 2013;Danesh Yazdi et al., 2023;Fossati et al., 2014a;Mancini et al., 2020;Pergoli et al., 2017). ...
Background:
The molecular effects of intermediate and long-term exposure to air pollution and temperature, such as those on extracellular microRNA (ex-miRNA) are not well understood but may have clinical consequences.
Objectives:
To assess the association between exposure to ambient air pollution and temperature and ex-miRNA profiles.
Methods:
Our study population consisted of 734 participants in the Normative Aging Study (NAS) between 1999 and 2015. We used high-resolution models to estimate four-week, eight-week, twelve-week, six-month, and one-year moving averages of PM2.5, O3, NO2, and ambient temperature based on geo-coded residential addresses. The outcome of interest was the extracellular microRNA (ex-miRNA) profile of each participant over time. We used a longitudinal quantile regression approach to estimate the association between the exposures and each ex-miRNA. Results were corrected for multiple comparisons and ex-miRNAs that were still significantly associated with the exposures were further analyzed using KEGG pathway analysis and Ingenuity Pathway Analysis.
Results:
We found 151 significant associations between levels of PM2.5, O3, NO2, and ambient temperature and 82 unique ex-miRNAs across multiple quantiles. Most of the significant results were associations with intermediate-term exposure to O3, long-term exposure to PM2.5, and both intermediate and long-term exposure to ambient temperature. The exposures were most often associated with the 75th and 90th percentile of the outcomes. Pathway analyses of significant ex-miRNAs revealed their involvement in biological pathways involving cell function and communication as well as clinical diseases such as cardiovascular disease, respiratory disease, and neurological disease.
Conclusion:
Our results show that intermediate and long-term exposure to all our exposures of interest were associated with changes in the ex-miRNA profile of study participants. Further studies on environmental risk factors and ex-miRNAs are warranted.
... In detail, the alteration of the expression of some noncoding RNAs (ncRNAs) caused by PM 2.5 or its components or extracts, as a type of epigenetic change, might be involved in some of the five aforementioned mechanisms, such as inflammatory reactions, and is associated with human diseases. According to present studies, three main types of ncRNAs have been found to be related to human diseases affected by PM 2.5 : microRNAs (miRNAs), long noncoding RNAs (lncRNAs) as well as circular RNAs (circRNAs) (Chao et al., 2017;Fossati et al., 2014;Huang et al., 2017;Jeong et al., 2017;Li et al., 2017Liu et al., 2015;Rodosthenous et al., 2016;Wang et al., 2019aWang et al., , 2021bZarch et al., 2023). miRNA is a type of ncRNA with an approximate length of 22 nt, lncRNA is a type of ncRNA with a length of more than 200 nt, and circRNA is a covalently closed, endogenous single-stand RNA (Kour et al., 2022;Liu et al., 2022b;Qu et al., 2015;Wang and Cen, 2020b;Yang et al., 2022b;Zammit et al., 2018;Zhou et al., 2020b). ...
PM2.5 is a type of particulate matter with an aerodynamic diameter smaller than 2.5 µm, and exposure to PM2.5 can adversely damage human health. PM2.5 may impair health through oxidative stress, inflammatory reactions, immune function alterations and chromosome or DNA damage. Through increasing in-depth studies, researchers have found that noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs), circular RNAs (circRNAs) as well as long noncoding RNAs (lncRNAs), might play significant roles in PM2.5-related human diseases via some of the abovementioned mechanisms. Therefore, in this review, we mainly discuss the regulatory function of ncRNAs altered by PM2.5 in human diseases and summarize the potential molecular mechanisms. The findings reveal that these ncRNAs might induce or promote diseases via inflammation, the oxidative stress response, cell autophagy, apoptosis, cell junction damage, altered cell proliferation, malignant cell transformation, disruption of synaptic function and abnormalities in the differentiation and status of immune cells. Moreover, according to a bioinformatics analysis, the altered expression of potential genes caused by these ncRNAs might be related to the development of some human diseases. Furthermore, some ncRNAs, including lncRNAs, miRNAs and circRNAs, or processes in which they are involved may be used as biomarkers for relevant diseases and potential targets to prevent these diseases. Additionally, we performed a meta-analysis to identify more promising diagnostic ncRNAs as biomarkers for related diseases.
... For example, exposure to metalrich particles significantly altered the miRNA expression profile among steel production workers [164]. Furthermore, miRNAs that actively participate in inflammation, endothelial dysfunction and coagulation are significantly altered in subjects exposed to environmental black carbon, organic carbon, PM2.5 and sulfates [165]. Subchronic exposure to cigarette smoke also affected miRNA expression in rat lungs [166]. ...
Complex molecular mechanisms define our responses to environmental stimuli. Beyond the DNA sequence itself, epigenetic machinery orchestrates changes in gene expression induced by diet, physical activity, stress and pollution, among others. Importantly, nutrition has a strong impact on epigenetic players and, consequently, sustains a promising role in the regulation of cellular responses such as oxidative stress. As oxidative stress is a natural physiological process where the presence of reactive oxygen-derived species and nitrogen-derived species overcomes the uptake strategy of antioxidant defenses, it plays an essential role in epigenetic changes induced by environmental pollutants and culminates in signaling the disruption of redox control. In this review, we present an update on epigenetic mechanisms induced by environmental factors that lead to oxidative stress and potentially to pathogenesis and disease progression in humans. In addition, we introduce the microenvironment factors (physical contacts, nutrients, extracellular vesicle-mediated communication) that influence the epigenetic regulation of cellular responses. Understanding the mechanisms by which nutrients influence the epigenome, and thus global transcription, is crucial for future early diagnostic and therapeutic efforts in the field of environmental medicine.
... Further research into the association between PM exposure and miRNA expression in peripheral blood leukocytes (PBLs) revealed that miRNAs, including miR-126, miR-135a, miR-146a, miR-155, miR-21, miR-222, and miR-9 were all linked to PM exposure [63]. This relationship between the expression of miRNAs and PM exposures was found to be affected by polymorphisms in the RNA processing genes GEMIN4 and DGCR8 (Table 2) [75]. ...
Nearly 2.4 billion people globally (one-third of the world's population) use solid biomass fuels as their primary energy source for cooking which is a major cause of household air pollution. According to sustainable development goal 7, women primarily responsible for household cooking bear a significant health burden by using solid biomass-based stoves that often does not meet emission targets. As an imperative source of total suspended particulate matter, polycyclic aromatic hydrocarbons, and volatile organic compounds, biomass fumes exposure is associated with significant morbidity and mortality. Long-term use of solid fuel in household cooking may lead to epigenetic reprogramming, including changes in the expression patterns of noncoding RNAs (ncRNAs) intimately linked to increased breast cancer (BC) risk. Currently, no specific non-invasive epigenetic markers are available to diagnose BC at an early stage. Cell-free circulating epigenomic signatures such as miRNAs, lncRNAs, and mRNAs regulate intrinsic molecular signaling pathways in breast cancer. Therefore, it is indispensable to assess the feasibility of establishing miRNAs, lncRNAs, and mRNAs as combinatorial triad biomarkers for the early risk assessment and effective management of breast cancer in vulnerable populations. Here, we critically examined various facets entailed in miRNAs-lncRNAs-mRNAs deregulation that might enhance our knowledge of the molecular mechanisms underlying breast cancer risk associated with biomass fumes exposure.
... Particulate matter (PM2.5 and PM10) is reported to be the major factor of air pollution which is termed as carcinogenic (Anenberg et al., 2014;Zhanget al., 2020). Previous studies revealed an increasing case of lung cancer due to pollutants such as PM2.5 and PM10 (Fossati et al., 2014;Tao et al., 2014) and relatively, the world health organization reported that 2.4 million people die annually from causes directly attributable to air pollution (Meo et al., 2013). Human activity (anthropogenic) such as the burning of fossil fuels, coal combustion, power plants and various industrial processes (including cement plants) largely contributes to the suspended particulates in the environment while volcanic eruptions, dust storms, forest and grasslands fires are well known natural sources of particulate matter (Omidvarborna et al., 2015). ...
This study investigated the concentration level of thoracic and inhalable sizes particulate matter (PM2.5 and PM10) present in the air released from a cement company located at Obajana, Kogi State, Nigeria. The collection of ambient air particulates within and outside the cement factory was carried out using the SKC deployable ambient air sampler. The duration considered during sampling was between 8 and 12 hr per day (1 month 2 weeks) and the equipment was operated at 7 and 10 L/min using filter sizes of 2.5 µm and 10 µm. Findings reveal a maximum mean value of PM10 recorded as 364.82±80.19 µg/Nm 3 at the cement mill section, followed by 292.77 µg/Nm 3 at the raw mill area with, the flow rate of 7 L/min for 12 hr and 10 L/min for 12 hr. The highest value of PM2.5 recorded was 744.44±2.5 µg/Nm 3 at the cement mill and 809.9±68.95 µg/Nm 3 at the raw mill section with a flow rate of 7 L/min for 12 hr respectively. It is suggestive that people living within the Obajana community are not safe based on the comparison with standards such as the World Health Organization, and the Nigerian Federal Ministry of Environment (FMEnv).
... In investigating the impact of PM exposure on the cardiac, the modulation of microRNAs (miRNAs) has become one of the risk factors to be investigated on. This is especially critical when involved in systemic inflammation, endothelial dysfunction and atherosclerosis (74,75). ...
Environmental issues such as environmental pollutions and climate change are the impacts of globalization and become debatable issues among academics and industry key players. One of the environmental issues which is air pollution has been catching attention among industrialists, researchers, and communities around the world. However, it has always neglected until the impacts on human health become worse, and at times, irreversible. Human exposure to air pollutant such as particulate matters, sulfur dioxide, ozone and carbon monoxide contributed to adverse health hazards which result in respiratory diseases, cardiorespiratory diseases, cancers, and worst, can lead to death. This has led to a spike increase of hospitalization and emergency department visits especially at areas with worse pollution cases that seriously impacting human life and health. To address this alarming issue, a predictive model of air pollution is crucial in assessing the impacts of health due to air pollution. It is also critical in predicting the air quality index when assessing the risk contributed by air pollutant exposure. Hence, this systemic review explores the existing studies on anticipating air quality impact to human health using the advancement of Artificial Intelligence (AI). From the extensive review, we highlighted research gaps in this field that are worth to inquire. Our study proposes to develop an AI-based integrated environmental and health impact assessment system using federated learning. This is specifically aims to identify the association of health impact and pollution based on socio-economic activities and predict the Air Quality Index (AQI) for impact assessment. The output of the system will be utilized for hospitals and healthcare services management and planning. The proposed solution is expected to accommodate the needs of the critical and prioritization of sensitive group of publics during pollution seasons. Our finding will bring positive impacts to the society in terms of improved healthcare services quality, environmental and health sustainability. The findings are beneficial to local authorities either in healthcare or environmental monitoring institutions especially in the developing countries.
... Another epidemiological study showed that short-term exposure to ambient PM 10 was associated with altered expression of circulating miRNAs including miR-1537, miR-548, miR-200a, miR-520-3p, miR-155, and miR-501-3p between truck drivers and office workers (Hou et al. 2016). Fossati and colleagues reported that exposure to ambient air pollution, including PM 2.5 , black carbon, organic carbon, and sulfates, downregulated the expression of miR-1, miR-126, miR-135a, miR-146a, miR-155, miR-21, miR-222, and miR-9 in blood leukocytes in 153 elderly male participants in the Normative Aging Study (Fossati et al. 2014). The same group later expanded the sample size to 533 participants with repeated measurements and showed an association between black carbon and changes in miR-9 and miR-96 expression, leading to variations in single-nucleotide polymorphisms (Colicino et al. 2016). ...
Air pollution is a global environmental and public health issue. Exposure to air pollution is associated with elevated risk of morbidity and mortality from respiratory, cardiovascular, and neurological diseases. Following exposure to air pollution, the lung and other organ systems mount a variety of physiological and pathological responses that can promote either homeostasis or disease. There is compelling evidence for epigenetic regulation of these biological responses by small, approximately 22-nucleotide-long microRNAs (miRNA). MiRNAs released from cells can act as intercellular messengers, relaying biological signals to nearby or systemic tissues or cells through posttranscriptional regulation, leading to biological changes. Because they are accessible for sampling from biological fluids, extracellular miRNAs can be leveraged as biomarkers for mechanistic investigation of air-pollution-induced health effects. In addition, specific environmental challenges or disease states present unique profiles of extracellular miRNAs, which may provide a sensitive indicator of air pollution exposure as well as disease outcomes. Thus, it is possible to utilize extracellular miRNAs as biomarkers for exposure assessment, mechanistic investigation, and disease outcome prediction of air pollution exposure. This chapter delves into the current literature and discusses miRNA measurement methods, air-pollutant-specific effects on miRNA expression, miRNA’s role in air-pollution-induced health effects, and the possibility of miRNAs as markers of air pollution exposure.
... MiR-NAs-mediated repression or degradation of target mRNA transcripts is gradually one of the primary modes of posttranscriptional regulation. Numerous previous studies elucidated that the miRNAs' expression could be altered in human tissues/cells exposed to ambient PMs (Fossati et al. 2014;Li et al. 2016;Jeong et al. 2017), may stimulate lung carcinogenesis. Another study had shown that in human respiratory cells exposed to PM 2.5 , miR-222, miR-101, and miR-34a expression was significantly upregulated, and these miRNAs correlated with DNA damage response (Veerappan et al. 2019). ...
Fine particulate matter (PM2.5) has been demonstrated to threaten public health and increase lung cancer risk. DNA damage is involved in the pathogenesis of lung cancer. However, the mechanisms of epigenetic modification of lung DNA damage are still unclear. This study developed a real-world air PM2.5 inhalation system and exposed rats for 1 and 2 months, respectively, and investigated rat lungs pathological changes, inflammation, oxidative stress, and DNA damage effects. OGG1 and MTH1 expression was measured, along with their DNA methylation status and related miRNAs expression. The results showed that PM2.5 exposure led to pathological injury, influenced levels of inflammatory cytokines and oxidative stress factors in rat lungs. Of note, 2-month PM2.5 exposure aggravated pathological injury. Besides, PM2.5 significantly elevated OGG1 expression and suppressed MTH1 expression, which was correlated to oxidative stress and partially mediated by reducing OGG1 DNA methylation status and increasing miRNAs expression related to MTH1 in DNA damage with increases of γ-H2AX, 8-OHdG and GADD153. PM2.5 also activated c-fos and c-jun levels and inactivated PTEN levels in rat lungs. These suggested that epigenetic modification was probably a potential mechanism by which PM2.5-induced genotoxicity in rat lungs.
... Inflammation can also occur through changes in microRNA (miRNA) expression caused by PM. Several studies have reported that PM can modulate miRNAs involved in inflammation, endothelial dysfunction, and atherosclerosis (45)(46)(47). ...
Exposure to environmental particulate matter (PM), outdoor air pollution in particular, has long been associated with adverse health effects. Today, PM has widely been accepted as a systemic toxicant showing adverse effects beyond the lungs. There are numerous studies, from those in vitro to epidemiological ones, suggesting various direct and indirect PM toxicity mechanisms associated with cardiovascular risks, including inflammatory responses, oxidative stress, changes in blood pressure, autonomic regulation of heart rate, suppression of endothelium-dependent vasodilation, thrombogenesis, myocardial infarction, and fibrinolysis. In addition to these and other health risks, considerations about air quality standards should include individual differences, lifestyle, and vulnerable populations such as children. Urban air pollution has been a major environmental issue for Turkey, and this review will also address current situation, research, and measures taken in our country.
... In a study of elderly men exposed to environmental particulate matter for different periods of time, Serena and his colleagues found that PM 2.5 was significantly negatively correlated with miR-1, miR-126, miR-146a, miR-222, and miR-9. It is worth noting that this effect is most obvious on the 7th day, suggesting that short-term exposure to air particles can cause rapid changes in miRNA [62]. Previous studies have shown that miR-1, miR-126, and miR-222 regulate important biological pathways in the cardiovascular system and participate in the occurrence and development of atherosclerosis and other CVD [63,64]. ...
Cardiovascular disease (CVD) has become the leading cause of death worldwide, which seriously threatens human life and health. Epidemiological studies have confirmed the occurrence and development of CVD are closely related to air pollution. In particular, fine particulate matter (PM 2.5 ) is recognized as an important environmental factor contributing to increased morbidity, mortality and hospitalization rates among adults and children. However, the underlying mechanism by which PM 2.5 promotes CVD development remains unclear. With the development of epigenetics, recent studies have shown that PM 2.5 exposure may induce or aggravate CVD through epigenetic changes. In order to better understand the potential mechanisms, this paper reviews the epigenetic changes of CVD caused by PM 2.5 . We summarized the epigenetic mechanisms of PM 2.5 causing cardiovascular pathological damage and functional changes, mainly involving DNA methylation, non-coding RNA, histone modification and chromosome remodeling. It will provide important clues for exploring the biological mechanisms affecting cardiovascular health.
... For example, PM 2.5 exposure significantly dysregulated the miR-331 and miR-146e3p expression, which contributes to human airway epithelial cell inflammation following PM 2.5 exposure Zhong et al., 2019). Multiple epidemiologic studies also observed the negative correlation between PM 2.5 exposure and the expression of miRNAs, such as miR-146a, miR-21, miR-222, miR-21e5p, and miR-187e3p Fossati et al., 2014). However, our understanding of the biological significance of miRNAs in response to PM 2.5 exposure is still the tip of the iceberg. ...
PM2.5 (particles matter smaller aerodynamic diameter of 2.5 μm) exposure, a major environmental risk factor for the global burden of diseases, is associated with high risks of respiratory diseases. Heme-oxygenase 1 (HMOX1) is one of the major molecular antioxidant defenses to mediate cytoprotective effects against diverse stressors, including PM2.5-induced toxicity; however, the regulatory mechanism of HMOX1 expression still needs to be elucidated. In this study, using PM2.5 as a typical stressor, we explored whether microRNAs (miRNAs) might modulate HMOX1 expression in lung cells. Systematic bioinformatics analysis showed that seven miRNAs have the potentials to target HMOX1 gene. Among these, hsa-miR-760 was identified as the most responsive miRNA to PM2.5 exposure. More importantly, we revealed a “non-conventional” miRNA function in hsa-miR-760 upregulating HMOX1 expression, by targeting the coding region and interacting with YBX1 protein. In addition, we observed that exogenous hsa-miR-760 effectively elevated HMOX1 expression, reduced the reactive oxygen agents (ROS) levels, and rescued the lung cells from PM2.5-induced apoptosis. Our results revealed that hsa-miR-760 might play an important role in protecting lung cells against PM2.5-induced toxicity, by elevating HMOX1 expression, and offered new clues to elucidate the diverse functions of miRNAs.
... We assume that the observed changes in miRNA expression may be attributed to the PM associated activation of various redox sensitive mechanisms. Such alterations in PM exposed subjects may trigger a cascade of events that are closely associated with the disturbances in various complex biological processes including inflammation, endothelial dysfunction, and coagulation ( Fossati et al., 2014 ). However, there is far less understanding about the miRNA associated complex molecular networks in individuals exposed to PM. ...
Epigenetic modifications act as an important bridge to regulate the complex network of gene-environment interaction. As these mechanisms determines the gene-expression patterns via regulating the transcriptomic machinery, environmental stress induced epigenetic modifications may interrupt distinct cellular functions resulting into generation of diseased phenotypes. In the present study, we used a multi-city approach to compare the epigenomic signatures of individuals living in two tiers of Indian cities categorized as low-risk and high-risk air pollution zones. The high-risk group reported marked changes in the expression levels of epigenetic modifiers (DNMT1, DNMT3a, EZH2, EHMT2 and HAT), that maintains the levels of specific epigenetic marks essential for appropriate gene functioning. These results also coincided with the observed alterations in the levels of DNA methylation (LINE-1 and % 5mC), and histone modifications (H3 and H4), among the high-risk group. In addition, higher degree of changes reported in the expression profile of a selected miRNA panel in the high-risk group indicated the probability of deregulated transcriptional machinery. This was further confirmed by the analysis of a target gene panel involved in various signalling pathways, which revealed differential expression of the gene transcripts regulating cell cycle, inflammation, cell survival, apoptosis and cell adhesion. Together, our results provide first insights of epigenetic modifications among individuals living in different high and low levels of air pollution zones of India. However, further steps to develop a point-of-care epigenomic assay for human bio-monitoring may be immensely beneficial to reduce the health burden of air pollution especially in lower-middle-income countries.
... For instance, PM rich in transition metal components increase miR-222 and miR-21 in peripheral blood leukocytes [60]. miR-1, -9, -135a and -222 are associated with PM exposure, whereas miR-223 and -375 has been systemically regulate airway inflammation [61][62][63]. Therefore, miRs may also play a pivotal role in regulating the barrier integrity following UFP ingestion. ...
Epidemiological studies have linked exposure to ambient particulate matter (PM) with gastrointestinal (GI) diseases. Ambient ultrafine particles (UFP) are the redox-active sub-fraction of PM2.5, harboring elemental and polycyclic aromatic hydrocarbons from urban environmental sources including diesel and gasoline exhausts. The gut-vascular barrier (GVB) regulates paracellular trafficking and systemic dissemination of ingested microbes and toxins. Here, we posit that acute UFP ingestion disrupts the integrity of the intestinal barrier by modulating intestinal Notch activation. Using zebrafish embryos, we performed micro-gavage with the fluorescein isothiocynate (FITC)-conjugated dextran (FD10, 10 kDa) to assess the disruption of GVB integrity upon UFP exposure. Following micro-gavage, FD10 retained in the embryonic GI system, migrated through the cloaca. Conversely, co-gavaging UFP increased transmigration of FD10 across the intestinal barrier, and FD10 fluorescence occurred in the venous capillary plexus. Ingestion of UFP further impaired the mid-intestine morphology. We performed micro-angiogram of FD10 to corroborate acute UFP-mediated disruption of GVB. Transient genetic and pharmacologic manipulations of global Notch activity suggested Notch regulation of the GVB. Overall, our integration of a genetically tractable embryonic zebrafish and micro-gavage technique provided epigenetic insights underlying ambient UFP ingestion disrupts the GVB.
... Emerging researches suggested that the changes in miRNAs' expression and their posttranscriptional regulator function are linked to many human diseases [19,20]. Researchers have shown that fine particular can alter miRNAs expression in recent years [21,22]. Our pervious study indicated 10 differential miRNAs between PM2.5 exposure and control mice, including miR-146, miR-139 and miR-340 [23]. ...
PM2.5 was closely linked to lung cancer worldwide. However, the mechanism involved in PM2.5 induced lung cancer is still largely unknown. In this study, we performed chronic PM2.5 stimulation animal and cells model to investigate the carcinogenetic mechanisms of PM2.5 by targeting EMT through Notch1 signal pathway. Next, we focused on the miRNA involved in PM2.5 induced Notch1 pathway activation. We found chronic PM2.5 could induce EMT event in vivo and in vitro, while reducing miR-139-5p expression and activating Notch1 pathway meanwhile. And blocking Notch1 signal pathway by specific small molecule inhibitor could reverse PM2.5 induced EMT. Then, overexpression of miR-139-5p downregulated the expression of Notch1 protein in untreated 16HBE cells. Importantly, overexpression of miR-139-5p blocked Notch1 pathway activation and inhibited EMT event in PM2.5 treated cells. These results indicate that PM2.5 induces EMT event through Notch1 signal pathway and miR-139-5p is a novel regulator of PM2.5-induced EMT by targeting Notch1. Our conclusion is that overexpression of miR-139-5p can down-regulate the expression of Notch1 and reverse the occurrence of malignant lung events induced by chronic exposure to PM2.5.
... miR-1, -9, 21,-126, -135a, -146a, -155, and -222) and PM 2.5 exposure. As the authors stated, this negative correlation was estimated to amplify inflammation, endothelial dysfunction, and atherosclerosis [43]. It is to mention that there are some substantial differences as regards the methodology of the two abovementioned studies. ...
The association between air pollution and a wide-ranging spectrum of acute and chronic disorders—including cardiovascular diseases—is widely acknowledged. Exposure to airborne pollutants triggers harmful mechanisms such as oxidative stress and systemic inflammation, which lead to increased incidence of myocardial infarction, arterial hypertension, stroke, and heart failure. Sustained efforts have been made in recent years to discover how environmental exposures affect human health through epigenetic phenomena, such as DNA methylation, histone modifications and non-coding RNA-mediated gene regulation. This review summarizes the current evidences on the relationship between air pollution exposure, epigenetic alterations and cardiovascular impact, in view of present implications and future perspectives.
... Previous studies identified that exposure to a concentration of PM of 10 micrometers or less in diameter (PM10) and PM of 2.5 micrometers (PM2.5) may cause serious cardiovascular and respiratory diseases [2][3][4][5], skin diseases [6], and many types of cancer [7][8][9][10][11][12]. They also report that it has particularly adverse impacts on children [13,14], the elderly [15,16], and pregnant women [17,18]. ...
Seoul, a city in South Korea, experiences high particulate matter (PM) levels well above the recommended standards suggested by the World Health Organization. As concerns about public health and everyday lives are being raised, this study investigates the effects of land use on PM levels in Seoul. Specifically, it attempts to identify which land use types increase or decrease PM10 and PM2.5 levels and compare the effects between high and low seasons using two sets of land use classifications: one coarser and the other finer. A series of partial least regression models identifies that industrial land use increases the PM levels in all cases. It is also reported that residential and commercial land uses associated with lower density increase these levels. Other uses, such as green spaces and road, show mixed or unclear effects. The findings of this study may inform planners and policymakers about how they can refine future land use planning and development practice in cities that face similar challenges.
... However, adjusting to the confounding factors (age, BMI, smoking status and seniority), a significant decrease for miR-21, as well as a decrease at the limit of significance for miR-155 were recorded. The decrease in miR-21 was reported in other environmental exposures studies 1 3 (Fossati et al. 2014;Louwies et al. 2016). While Bollati et al. (2010) reported an increase in miR-21 (blood) concentration after 3 days of exposure to metal-rich particles in 63 workers in an electric furnace steel plant. ...
Purpose
A cross-sectional study was conducted in a group of Algerian welders to study the relationship between the exposure to metal particles from welding fumes and the concentration of three circulating miRNAs, miR-21, miR-146a and miR-155, as markers of renal function injury.
Methods
Characteristics of the subjects and the curriculum laboris were determined by questionnaires. We measured the concentrations of metals in blood and urine samples using ICP-MS. The three circulating miRNAs studied were measured by quantitative PCR. Associations between miRNAs and internal exposure markers were assessed by simple and multiple regression analyses.
Results
miR-21 was significantly lower among welders (p = 0.017), compared with controls, adjusted for age, body mass index, smoking status and seniority. Significant adjusted associations were observed between miR-21 or miR-155 and urinary chromium (p = 0.005 or p = 0.041, respectively), miR-146a and urinary nickel (p = 0.019). The results of the multivariate analysis showed that duration of employment was the main factor responsible for the variation of miRNAs among welders.
Conclusion
In conclusion, a recent exposure to certain metals, mainly chromium and nickel, appears to be associated to a decrease in plasma expression of miR-21, miR-146a and miR-155. Further larger studies would help to determine the mechanisms of action of metal particles on miRNA expression.
... Toxicology in Vitro 60 (2019) 187-202 death 4 protein). miR-21 was also positively correlated with 8-OHdG (8-hydroxy-2′ -deoxyguanosine) expression in carcinogenesis and simultaneous increase in ROS levels Tu et al., 2014) and miR-21 expression in humans is also influenced by inhalation of diesel exhaust particles (PM 2.5 , black carbon and organic carbon) exposure (Fossati et al., 2014). Published data suggest that miR-21 may be involved in the HMGB1/RAGE signaling pathway through the modification of transcription factor NF-kappa B thus playing a role in mechanisms related to particulate matter toxicological responses such as inflammation and endothelial dysfunction. ...
The release of nanoparticles to the environment can affect health of the exposed organisms. MicroRNAs have been suggested as potential toxicology biomarkers, however the information about use of microRNA in aquatic organisms exposed to nanoparticles (NP) is limited. In silico analysis from publicly available gene expression data was performed. Data selection for the analysis was based on reported biological and pathological outcomes of NP induced toxicity in zebrafish. After identifying relevant genes, we constructed six miRNA-mRNA regulatory networks involved in nanoparticle induced toxicological responses in zebrafish. Based on our prediction and selection criteria we selected six miRNAs that overlapped in constructed networks with remarkable prediction score, and were validated by previous mammalian and zebrafish microRNA profiling studies: dre-miR-124, -144, -148, -155, -19a, -223. The results of this in silico analysis indicate that several highly conserved miRNAs likely have a regulatory role of organismal responses to nanoparticles, and can possibly be used as biomarkers of nanotoxicity in studies using zebrafish as model organism One health approaches.
Exposure to PM2.5 is the most significant air pollutant for health risk. The testosterone level in male is vulnerable to environmental toxicants. In the past, researchers focused more attention on the impacts of PM2.5 on respiratory system, cardiovascular system, and nervous system, and few researchers focused attention on the reproductive system. Recent studies have reported that PM2.5 involved in male testosterone biosynthesis disruption, which is closely associated with male reproductive health. However, the underlying mechanisms by which PM2.5 causes testosterone biosynthesis disruption are still not clear. To better understand its potential mechanisms, we based on the existing scientific publications to critically and comprehensively reviewed the role and potential mechanisms of PM2.5 that are participated in testosterone biosynthesis in male. In this review, we summarized the potential mechanisms of PM2.5 triggering the change of testosterone level in male, which involve in oxidative stress, inflammatory response, ferroptosis, pyroptosis, autophagy and mitophagy, microRNAs (miRNAs), endoplasmic reticulum (ER) stress, and N6-methyladenosine (m6A) modification. It will provide new suggestions and ideas for prevention and treatment of testosterone biosynthesis disruption caused by PM2.5 for future research.
Introduction:
MicroRNAs are epigenetic regulatory factors capable of silencing the expression of target genes and might mediate the effects of air pollution on health. The objective of the present population-based study was to investigate the association between microRNA expression and long-term, residential exposure to atmospheric PM10 and NO2.
Method:
We included 998 non-smoking adult participants from the cross-sectional ELISABET survey (2010-2014) in the Lille urban area of France. The mean residential annual pollution levels were estimated with an atmospheric dispersion modelling system. Ten microRNAs were selected on the basis of the literature data, together with two housekeeping microRNAs (miR-93-5p and miR-191-5p) and were quantified with RT-qPCRs. Multivariate linear regression models were used to study the association between microRNAs and air pollution. The threshold for statistical significance (after correction for the FDR) was set to p < 0.1.
Results:
The mean annual exposure between 2011 and the year of inclusion was 26.4 ± 2.0 µg/m3 for PM10 and 24.7 ± 5.1 µg/m3 for NO2. Each 2 µg/m3 increment in PM10 exposure was associated with an 8.6% increment (95%CI [3.1; 14.3]; pFDR = 0.019) in miR-451a expression. A 5 µg/m3 increment in NO2 exposure was associated with a 5.3% increment ([0.7; 10]; pFDR = 0.056) in miR451a expression, a 3.6% decrement (95%CI [-6.1; -1.1]; pFDR = 0.052) in miR-223-3p expression, a 3.8% decrement (95%CI[-6.8; -0.7]; pFDR = 0.079) in miR-28-3p expression, a 4.3% decrement (95%CI [-7.7; -0.8]; pFDR = 0.055) in miR-146a-5p expression, and a 4.0% decrement (95% CI[-7.4; -0.4]; pFDR = 0.059) in miR-23a-5p expression. The difference between the two housekeeping microRNAs miR-93-5p and miR-191-5p was also associated with PM10 and NO2 exposure.
Conclusion:
Our results suggest that circulating miRNAs are potentially valuable biomarkers of the effects of air pollution.
Ambient air pollution, and especially particulate matter (PM) air pollution <2.5 μm in diameter (PM2.5), has clearly emerged as an important yet often overlooked risk factor for atherosclerosis and ischemic heart disease (IHD). In this review, we examine the available evidence demonstrating how acute and chronic PM2.5 exposure clinically translates into a heightened coronary atherosclerotic burden and an increased risk of acute ischemic coronary events. Moreover, we provide insights into the pathophysiologic mechanisms underlying PM2.5-mediated atherosclerosis, focusing on the specific biological mechanism through which PM2.5 exerts its detrimental effects. Further, we discuss about the possible mechanisms that explain the recent findings reporting a strong association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, increased PM2.5 exposure, and morbidity and mortality from IHD. We also address the possible mitigation strategies that should be implemented to reduce the impact of PM2.5 on cardiovascular morbidity and mortality, and underscoring the strong need of clinical trials demonstrating the efficacy of specific interventions (including both PM2.5 reduction and/or specific drugs) in reducing the incidence of IHD. Finally, we introduce the emerging concept of the exposome, highlighting the close relationship between PM2.5 and other environmental exposures (i.e.: traffic noise and climate change) in terms of common underlying pathophysiologic mechanisms and possible mitigation strategies.
Primary membranous nephropathy (PMN), is an autoimmune glomerular disease and the main reason of nephrotic syndrome in adults. Studies have confirmed that the incidence of PMN increases yearly and is related to fine air pollutants particulate matter 2.5 (PM2.5) exposure. These imply that PM2.5 may be associated with exposure to PMN-specific autoantigens, such as the M-type receptor for secretory phospholipase A2 (PLA2R1). Emerging evidence indicates that Th17/Treg turns to imbalance under PM2.5 exposure, but the molecular mechanism of this process in PMN has not been elucidated. As an important indicator of immune activity in multiple diseases, Th17/Treg immune balance is sensitive to antigens and cellular microenvironment changes. These immune pathways play an essential role in the disease progression of PMN. Also, microRNAs (miRNAs) are susceptible to external environmental stimulation and play link role between the environment and immunity. The contribution of PM2.5 to PMN may induce Th17/Treg imbalance through miRNAs and then produce epigenetic affection. We summarize the pathways by which PM2.5 interferes with Th17/Treg immune balance and attempt to explore the intermediary roles of miRNAs, with a particular focus on the changes in PMN. Meanwhile, the mechanism of PM2.5 promoting PLA2R1 exposure is discussed. This review aims to clarify the potential mechanism of PM2.5 on the pathogenesis and progression of PMN and provide new insights for the prevention and treatment of the disease.
Particulate matter (PM) is associated with the incidence, exacerbation, and mortality of variable respiratory diseases. However, the molecular mechanisms of PM10-mediated inflammation are unclear. In a previous study, we identified microRNAs (miRNAs) and target mRNAs related to the inflammatory response in PM10-exposed bronchial epithelial cells using next-generation sequencing. Here, we investigated the role of miR-6515-5p in PM10-induced inflammation in human bronchial epithelial BEAS-2B cells. miR-6515-5p expression was downregulated in PM10-exposed cells. In addition, miR-6515-5p regulated the production of pro-inflammatory cytokines (IL-6 and IL-8) and the expression of inflammatory genes (IL-1β, IL-6, IL-8, TNF-α, CXCL-1, and MCP-1); overexpression of miR-6515-5p using a mimic inhibited PM10-induced inflammatory responses, whereas downregulation of miR-6515-5p via an inhibitor significantly increased inflammation in PM10-exposed cells. Furthermore, we confirmed the association between miR-6515-5p and CSF3 using TargetScanHuman and a luciferase assay, and found that mRNA and protein levels of CSF3 were negatively regulated by miR-6515-5p. Inhibition of CSF3 by small interfering RNA significantly reduced the expression and production of inflammatory markers in PM10-exposed cells. Therefore, we suggest that miR-6515-5p regulates PM10-induced inflammatory responses by targeting CSF3 in bronchial epithelial cells.
Here, we investigated the use of breath-borne volatile organic compounds (VOCs) for rapid monitoring of air pollution health effects on humans. Forty-seven healthy college students were recruited, and their exhaled breath samples (n = 235) were collected and analyzed for VOCs before, on, and after two separate haze pollution episodes using gas chromatography-ion mobility spectrometry (GC-IMS). Using a paired t-test and machine learning model (Gradient Boosting Machine, GBM), six exhaled VOC species including propanol and isoprene were revealed to differ significantly among pre-, on-, and post-exposure in both haze episodes, while none was found between clean control days. The GBM model was shown capable of differentiating between pre- and on-exposure to haze pollution with a precision of 90-100% for both haze episodes. However, poor performance was detected for the same model between two different clean days. In addition to gender and particular haze occurrence influences, correlation analysis revealed that NH4+, NO3-, acetic acid, mesylate, CO, NO2, PM2.5, and O3 played important roles in the changes in breath-borne VOC fingerprints following haze air pollution exposure. This work has demonstrated direct evidence of human health impacts of haze pollution while identifying potential breath-borne VOC biomarkers such as propanol and isoprene for haze air pollution exposure.
This chapter discusses microRNAs as biomarkers of chemical exposure and effect, including the mechanisms leading to their extracellular release and their expression in extracellular biofluids after environmental toxicant exposures in humans. In addition, examples are given of their promise for quantitative chemical risk assessment and clinical diagnostics. Finally, we explore some of the challenges that must be overcome for microRNAs to realize their full potential in environmental toxicological, clinical, and regulatory applications.
Large amounts of epidemiological evidence have confirmed the atmospheric particulate matter (PM2.5) exposure was positively correlated with the morbidity and mortality of respiratory diseases. Nevertheless, its pathogenesis remains incompletely understood, probably resulting from the activation of oxidative stress, inflammation, altered genetic and epigenetic modifications in the lung upon PM2.5 exposure. Currently, biomarker investigations have been widely used in epidemiological and toxicological studies, which may help in understanding the biologic mechanisms underlying PM2.5-elicited adverse health outcomes. Here, the emerging biomarkers to indicate PM2.5-respiratory system interactions were summarized, primarily related to oxidative stress (ROS, MDA, GSH, etc.), inflammation (Interleukins, FENO, CC16, etc.), DNA damage (8-OHdG, γH2AX, OGG1) and also epigenetic modulation (DNA methylation, histone modification, microRNAs). The identified biomarkers shed light on PM2.5-elicited inflammation, fibrogenesis and carcinogenesis, thus may favor more precise interventions in public health. It is worth noting that some inconsistent findings may possibly relate to the inter-study differentials in the airborne PM2.5 sample, exposure mode and targeted subjects, as well as methodological issues. Further research, particularly by -omics technique to identify novel, specific biomarkers, is warranted to illuminate the causal relationship between PM2.5 pollution and deleterious lung outcomes.
Assessment of the impact that air contaminants have on health is difficult as this is a complex mixture of substances that varies depending on the time and place. There are many studies on the association between air pollution and increased morbidity and mortality. Before the effect of polluted air is manifested at the level of the organs, an impact can be observed at the molecular level. These include some new biomarkers, like a shortening of the mean telomere length in DNA, dysregulation of gene expression caused by microRNA levels or a variation in the copy number of mitochondrial DNA. These changes may predispose individuals to premature development of age-related diseases and consequently to shortening of life. The common attribute, shared by changes at the molecular level and the development of diseases, is the presence of oxidative stress.
Environmental risk factors, including physicochemical agents, noise and mental stress, have a considerable impact on human health. This environmental exposure may lead to epigenetic reprogramming, including changes in non-coding RNAs (ncRNAs) signatures, which can contribute to the pathophysiology state. Oxidative stress is one of the results of this environmental disturbance by modifying cellular processes such as apoptosis, signal transduction cascades, and DNA repair mechanisms. In this review, we delineate environmental risk factors and their influence on (ncRNAs) in connection to disease. We focus on well-studied miRNAs and analyze the novel roles of long-non-coding-RNAs (lncRNAs). We discuss commonly regulated lncRNAs after exposure to different stressors, such as UV, heavy metals and pesticides among others, and the potential role of these lncRNA as exposure biomarkers, epigenetic regulators and potential therapeutic targets to diminish the deleterious secondary response to environmental agents.
Uncertainties for optimized air pollution control remain as the underlying mechanisms of city-specific ambient particulate matter (PM)-induced health effects are unknown. Here, water-soluble extracts of PMs collected from four global cities via automobile air conditioning filters were consecutively injected three times by an amount of 1, 2 and 2 mg into the blood circulation of Wistar rats after filtration by a 0.45 µm pore size membrane. Acute health effects such as immune and inflammatory responses and hemorrhage in alveoli were observed right after the PM extraction injection. Significant differences between cities in biomarker TNF-α and MCP-1 levels were detected following the second and third PM injections. Rats’ inflammation responses varied substantially with the injections of city-specific PMs. Repeated PM extract exposure rendered the rats more vulnerable to subsequent challenges; and down-regulations of certain microRNAs were observed in rats. Among the studied miRNAs, miR-125b and miR-21 were most sensitive to the PM exposure, exhibiting a negative dose-response type relationship with source-specific PM (oxidative potential) toxicity (r2=0.63 and 0.57; p-values<0.05). The results indicated that city-specific PMs could induce different health effects by selectively regulating different miRNAs; and certain microRNAs, e.g., miR-125b and miR-21, may be externally mediated to neutralize PM-related health damages.
Many associations were reported between air pollution and daily mortality rates for cardiopulmonary diseases. Humans are exposed to a mixture of oxidizing gases and particles, both anthropogenic and natural. Exposure to air toxics causes or exacerbates cardiovascular damages and respiratory diseases. Numerous studies have identified the induction of oxidative stress and sustained inflammatory response as among the main known underlying pathophysiological mechanisms of air pollutants. More recently, the relationship between these mechanisms of action and the secretion of extracellular vesicles (EVs) by lung cells has been revealed. EVs have been shown to be important mediators of cellular communication in the body. The purpose of this review is to first recall the main air pollutants. Then, the cardiopulmonary diseases caused by exposure to air pollution and the pathophysiological mechanisms are presented before showing, through an exhaustive review of the literature, the involvement of EVs in the toxicity of air pollutants and the initiation of cardiopulmonary diseases.
Background:
Particulate matter 2.5 (PM2.5) refers to particulate matter with aerodynamic equivalent diameter less than or equal to 2.5 µm, which is an important component of air pollution. PM2.5 aggravates allergic rhinitis (AR) and promotes AR nasal mucosa inflammation. Therefore, the influence of PM2.5 inhalation exposure on microRNA (miRNA) expression profiles and function in the nasal mucosa of AR rats was investigated.
Methods:
Female Sprague Dawley rats were distributed randomly to 2 groups: AR model PM2.5 exposure group (ARE group) and AR model PM2.5-unexposed control group (ARC group). The rats of ARE group were made to inhale PM2.5 at a concentration of 200 µg/m3, 3 h/day, for 30 days. miRNA expression profiles of the nasal mucosa from both groups were determined using an miRNA gene chip and were verified by quantitative real-time PCR (qRT-PCR). Gene function enrichment analysis was performed using bioinformatics analysis.
Results:
The ARE group revealed 20 significantly differentially expressed miRNAs, including 4 upregulated and 16 downregulated miRNAs (fold change > 1.5 or < 0.66, P < .05). Of these, 9 selected miRNAs were verified by qRT-PCR, and the results of 8 miRNAs were in accordance with the miRNA gene chip results, with highly positive correlation (r = .8583, P = .0031). Numerous target genes of differentially expressed miRNAs were functionally enriched in high-affinity immunoglobulin E receptor signaling, ErbB signaling, mucin O-glycans biosynthesis, transforming growth factor β signaling, mitogen-activated protein kinase signal transduction, phosphatidylinositol signaling, mucopolysaccharide biosynthesis, mammalian target of rapamycin signaling, T cell receptor signaling, Wnt signaling, chemokine signal transduction, and natural killer cell-mediated cytotoxicity pathways.
Conclusions:
PM2.5 causes significant changes in miRNA expression in the nasal mucosa of AR rats. miRNA plays an important role in regulating PM2.5 effects in AR rat biological behavior and mucosal inflammation. This study provides a theoretical basis for the prevention and treatment of AR from the effects of environmental pollution on the gene regulation mechanism.
Accumulating evidences support that exposure to fine particulate matter (PM2.5) could cause inflammation of the airway, but its underlying mechanisms are less known. Our study aimed to explore the potential effect of non-canonical NF-κB signaling pathway in airway inflammation, which caused by PM2.5, and the possible regulatory relationship between miR-6747–5p and NF-κB2. The histological analysis from in vivo study manifested that PM2.5 could induce the exudation and infiltration of polymorphonuclear leukocytes (PMNs). Immunohistochemistry results of lung tissues showed that PM2.5 increased ICAM-1, 6Ckine, SDF-1 and BAFF positive staining with a dose-dependent manner. In addition, PM2.5 could induce the p52 nuclear translocation to trigger non-canonical NF-κB signaling pathway in lung tissues and BEAS-2B cells. Targetscan reporter gene assay showed that there was a target regulatory relationship between miR-6747–5p and NF-κB2. Besides, the chemical mimics of miR-6747–5p weakened the activation of non-canonical NF-κB signaling pathway induced by PM2.5. In summary, exposure to PM2.5 could trigger airway inflammation by activating the non-canonical NF-κB signaling pathway, which may be related to the negative feedback regulation mechanism of miR-6747–5p. Our findings will give new ideas into the toxic effects of airway inflammation triggered by PM2.5.
MicroRNAs (miRNAs) are a class of small, non-coding RNAs with a post-transcriptional regulatory function on gene expression and cell processes, including proliferation, apoptosis and differentiation. In recent decades, miRNAs have attracted increasing interest to explore the role of epigenetics in response to air pollution. Air pollution, which always contains kinds of particulate matters, are able to reach respiratory tract and blood circulation and then causing epigenetics changes. In addition, extensive studies have illustrated that miRNAs serve as a bridge between particulate matter exposure and health-related effects, like inflammatory cytokines, blood pressure, vascular condition and lung function. The purpose of this review is to summarize the present knowledge about the expression of miRNAs in response to particulate matter exposure. Epidemiological and experimental studies were reviewed in two parts according to the size and source of particles. In this review, we also discussed various functions of the altered miRNAs and predicted potential biological mechanism participated in particulate matter-induced health effects. More rigorous studies are worth conducting to understand contribution of particulate matter on miRNAs alteration and the etiology between environmental exposure and disease development.
Exposure to particulate matter (PM) has been associated with increased risk of various diseases, possibly through its effect on inflammatory response. MicroRNAs (miRNAs), an epigenetic mechanism regulating gene expression, can affect the expression of pro-inflammatory genes. However, few epidemiological studies have examined the impact of PM on inflammation-related miRNAs and their target mRNAs, especially among vulnerable population. We recruited 160 and 113 children from areas with different PM level in Jinan, China. We measured benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts in serum and the expression of 5 candidate miRNAs involved in inflammation regulation and 7 pro-inflammatory genes predicted to be their targets in leukocytes. Generally, children in the polluted area had higher miRNAs and lower mRNAs expression than those in the control area. An interquartile increase of BPDE-Alb adducts was associated with 12.66 %, 14.13 %, and 12.76 % higher of let-7a, miR-146a-5p, and miR-155-5p, as well as 21.61 %, 20.16 %, and 12.49 % lower of IL-6, CXCL8, and TLR2 mRNAs at false discovery rate<0.05, respectively. Additionally, let-7a, miR-146a-5p, and miR-155-5p were found to mediate the associations of BPDE-Alb adducts with IL-6 and/or TLR2 expression. Our findings suggested that PM exposure might attenuate inflammatory response among children in China, which was partly mediated by miRNAs regulating pro-inflammatory genes.
Long-term exposure to fine particulate matter (PM2.5) may cause or exacerbate many diseases, including respiratory inflammation. However, the full mechanism is not yet fully understood. The newly discovered long chain non-coding RNA, though unable to encode proteins, regulates multiple life activities and participates in the development of inflammation. In this study, we set up a cell inflammation model by using normal bronchial 16HBE cells exposed to PM2.5. High-throughput sequencing, as well as real-time fluorescent quantitative PCR detection and validation, was performed on the inflamed cells to evaluate the expression level of long chain noncoding RNA that helped us to identify the LncRNA LOC101927514. Inhibiting LncRNA LOC101927514 expression by RNAi, reflected in a reduction in inflammation, is driven by PM2.5. In addition, we identify LncRNA LOC101927514 to be located within the nucleus and binds to STAT3, altering the inflammatory state of the cells and IL6 and IL8 release. This study identifies that LncRNA LOC101927514 is a new potential target for future treatment of the inflammatory response activated by PM2.5 in the respiratory system.
Environmental exposure is a growing public health burden associated with several negative health effects. An estimated 4.2 million deaths occur each year from ambient air pollution alone. Biomarkers that reflect specific exposures have the potential to measure the real integrated internal dose from all routes of complex environmental exposure. MicroRNAs, small non-coding RNAs that regulate gene expression, have been studied as biomarkers in various diseases and have also shown potential as environmental exposure biomarkers. Here we review the available human epidemiological and experimental evidence of microRNA expression changes in response to specific environmental exposures including airborne particulate matter. In doing so, we establish that miRNA exposure biomarker development remains in its infancy and future studies will need to carefully consider biological and analytical “design rules” in order to facilitate clinical translation.
Considering the unique physiochemical properties of concentrated ambient particles (CAPs), it is extremely important to be aware of their toxic effect. A number of studies have investigated the vascular toxicity of CAPs, while potential mechanisms are still not clearly defined. Differentially expressed mRNAs, miRNAs and lncRNAs were analyzed in EA.hy926 endothelial cells after incubation with 2.5 and 10 μg/cm2 urban particulate matter SRM 1648a for 24 h. As a result, the microarray profile showed that 97 mRNA, 18 miRNA, and 356 lncRNA transcripts are dysregulated in 2.5 μg/cm2 group. And the expression of 440 mRNAs, 40 miRNAs, and 1283 lncRNAs significantly changes in 10 μg/cm2 group. Through the miRNA-mRNA-transcription factor (TF) network, hsa-miR-128-3p, miR-18-5p and miR-376a-3p, miR-4306 as well, are key miRNAs in SRM 1648a-induced endothelial damage. Withal, lncRNA-mRNA-TF analysis hinted the importance of lncRNA T018951 and T200627. Subsequently, competing endogenous RNA (CeRNA) network was constructed for the comprehensive analysis of the regulation dogma between mRNAs and non-coding RNAs. It suggested that 35 GO terms and 1 KEGG pathway are significantly enriched in 2.5 μg/cm2 group. Meanwhile, 185 terms and 18 pathways are important in 10 μg/cm2 group. Pathway analysis revealed that Gap junction, Ras and MAPK signaling pathways are most significant in endothelial cell lesion. In conclusion, integrative analysis of mRNA and non-coding RNA in human endothelial cells suggests that a vast majority of non-coding RNAs regulate vascular toxicity in response to SRM 1648a. Moreover, it highlights the need for comprehensive analysis of latent mechanisms through a combination of signaling pathways with epigenetics studies.
Les particules fines atmosphériques (PF) sont capables de pénétrer dans les poumons où certains composés transportés peuvent interagir avec les cellules pulmonaires et atteindre la circulation sanguine. L'exposition aux PF affecte particulièrement les populations sensibles telles que les personnes agées. Cette thèse s'inscrit dans une démarche d'identification des effets des PF sur les lymphocytes T humains (LT) tout en visant à déterminer des biomarqueurs liés à l'exposition et à évaluer la variation de la réponse cellulaire en fonction de l'âge. Des LT ont été isolés de prélèvements sanguins de 91 volontaires appartenant à trois classes d'age (20-30, 45-55, 70-85 ans) puis exposés ex vivo pendant 72h à 45 µg/µl de PF collectées à Dunkerque. Les étapes d'isolement, purification et activation des LT ont d'abord été optimisées. Suite à la caractérisation de la population échantillonnée, une population d'étude homogène a été sélectionnée ( 10 sujets / classe d'âge). Nous avons mis en évidence une induction génique d'enzymes impliquées dans l'activation métabolique des HAP identifiés dans l'échantillon de PF. La caractérisation du profil des Lt a permis de proposer un profil mixte Th1/Th2 causé par l'exposition. L'étude transcriptomique des miARN a mis en évidence une surexpression de miR-124-3p impliqué dans la régulation de plusieurs fonctions au niveau du système immunitaire et de miR-1290 impliqué dans plusieurs types de cancer. Quant à l'influence de l'âge, une surexpression des gènes codant pour les enzymes antioxydantes (NQO1 et HMOX1), une augmentation de la concentration des cytokines (IL-4 et IL-13) ainsi qu'une modification du profil d'expression de certains miARN ont été notées chez les sujets les plus âgés.
Recently, investigators demonstrated associations between fine particulate matter (PM)-associated metals and adverse health effects. Residual oil fly ash (ROFA), a waste product of fossil fuel combustion from boilers, is rich in the transition metals Fe, Ni, and V, and when released as a fugitive particle, is an important contributor to ambient fine particulate air pollution. We hypothesized that a single-inhalation exposure to transition metal-rich PM will cause concentration-dependent cardiovascular toxicity in spontaneously hypertensive (SH) rats. Rats implanted with telemeters to monitor heart rate and electrocardiogram were exposed once by nose-only inhalation for 4 hours to 3.5 mg/m(3), 1.0 mg/m(3), or 0.45 mg/m(3) of a synthetic PM (dried salt solution), similar in composition to a well-studied ROFA sample consisting of Fe, Ni, and V. Exposure to the highest concentration of PM decreased T-wave amplitude and area, caused ST depression, reduced heart rate (HR), and increased nonconducted P-wave arrhythmias. These changes were accompanied by increased pulmonary inflammation, lung resistance, and vagal tone, as indicated by changes in markers of HR variability (increased root of the mean of squared differences of adjacent RR intervals [RMSSD], low frequency [LF], high frequency [HF], and decreased LF/HF), and attenuated myocardial micro-RNA (RNA segments that suppress translation by targeting messenger RNA) expression. The low and intermediate concentrations of PM had less effect on the inflammatory, HR variability, and micro-RNA endpoints, but still caused significant reductions in HR. In addition, the intermediate concentration caused ST depression and increased QRS area, whereas the low concentration increased the T-wave parameters. Thus, PM-induced cardiac dysfunction is mediated by multiple mechanisms that may be dependent on PM concentration and myocardial vulnerability (this abstract does not reflect the policy of the United States Environmental Protection Agency).
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.
Pro-inflammatory T cells mediate autoimmune demyelination in multiple sclerosis. However, the factors driving their development and multiple sclerosis susceptibility are incompletely understood. We investigated how micro-RNAs, newly described as post-transcriptional regulators of gene expression, contribute to pathogenic T-cell differentiation in multiple sclerosis. miR-128 and miR-27b were increased in naïve and miR-340 in memory CD4(+) T cells from patients with multiple sclerosis, inhibiting Th2 cell development and favouring pro-inflammatory Th1 responses. These effects were mediated by direct suppression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and interleukin-4 (IL4) expression, resulting in decreased GATA3 levels, and a Th2 to Th1 cytokine shift. Gain-of-function experiments with these micro-RNAs enhanced the encephalitogenic potential of myelin-specific T cells in experimental autoimmune encephalomyelitis. In addition, treatment of multiple sclerosis patient T cells with oligonucleotide micro-RNA inhibitors led to the restoration of Th2 responses. These data illustrate the biological significance and therapeutic potential of these micro-RNAs in regulating T-cell phenotypes in multiple sclerosis.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway. MicroRNAs are important regulators of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases. We recently identified miR-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of miR-146a in SLE patients. To explore why the expression of miR-146a is reduced in SLE patients, we conducted short parallel sequencing of potentially regulatory regions of miR-146a and identified a novel genetic variant (rs57095329) in the promoter region exhibiting evidence for association with SLE that was replicated independently in 7,182 Asians (P(meta) = 2.74×10(-8), odds ratio = 1.29 [1.18-1.40]). The risk-associated G allele was linked to reduced expression of miR-146a in the peripheral blood leukocytes of the controls. Combined functional assays showed that the risk-associated G allele reduced the protein-binding affinity and activity of the promoter compared with those of the promoter containing the protective A allele. Transcription factor Ets-1, encoded by the lupus-susceptibility gene ETS1, identified in recent genome-wide association studies, binds near this variant. The manipulation of Ets-1 levels strongly affected miR-146a promoter activity in vitro; and the knockdown of Ets-1, mimicking its reduced expression in SLE, directly impaired the induction of miR-146a. We also observed additive effects of the risk alleles of miR-146a and ETS1. Our data identified and confirmed an association between a functional promoter variant of miR-146a and SLE. This risk allele had decreased binding to transcription factor Ets-1, contributing to reduced levels of miR-146a in SLE patients.
Particulate air pollution has been associated with cardiovascular morbidity and mortality, but it remains unclear which time windows and pollutant sources are most critical. MicroRNA (miRNA) is thought to be involved in cardiovascular regulation. However, little is known about whether polymorphisms in genes that process microRNAs influence response to pollutant exposure. We hypothesized that averaging times longer than routinely measured one or two day moving averages are associated with higher soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) levels, and that stationary and mobile sources contribute differently to these effects. We also investigated whether single nucleotide polymorphisms (SNPs) in miRNA-processing genes modify these associations.
sICAM-1 and sVCAM-1 were measured from 1999-2008 and matched to air pollution monitoring for fine particulate matter (PM2.5) black carbon, and sulfates (SO42-). We selected 17 SNPs in five miRNA-processing genes. Mixed-effects models were used to assess effects of pollutants, SNPs, and interactions under recessive inheritance models using repeated measures.
723 participants with 1652 observations and 1-5 visits were included in our analyses for black carbon and PM2.5. Sulfate data was available for 672 participants with 1390 observations. An interquartile range change in seven day moving average of PM2.5 (4.27 μg/m3) was associated with 3.1% (95%CI: 1.6, 4.6) and 2.5% (95%CI: 0.6, 4.5) higher sICAM-1 and sVCAM-1. Interquartile range changes in sulfates (1.39 μg/m3) were associated with 1.4% higher (95%CI: 0.04, 2.7) and 1.6% (95%CI: -0.4, 3.7) higher sICAM-1 and sVCAM-1 respectively. No significant associations were observed for black carbon. In interaction models with PM2.5, both sICAM-1 and sVCAM-1 levels were lower in rs1062923 homozygous carriers. These interactions remained significant after multiple comparisons adjustment.
PM2.5 seven day moving averages are associated with higher sICAM-1 and sVCAM-1 levels. SO4-2 seven day moving averages are associated with higher sICAM-1 and a suggestive association was observed with sVCAM-1 in aging men. SNPs in miRNA-processing genes may modify associations between ambient pollution and sICAM-1 and sVCAM-1, which are correlates of atherosclerosis and cardiovascular disease.
Nuclear factor κB (NF-κB) is a transcriptional factor that regulates a battery of genes that are critical to innate and adaptive
immunity, cell proliferation, inflammation, and tumor development. MicroRNAs (miRNAs) are short RNA molecules of 20–25 nucleotides
in length that negatively regulate gene expression in animals and plants primarily by targeting 3′ untranslated regions of
mRNAs. In this work, we review the convergence of miRNAs and NF-κB signaling and dysregulation of miRNAs and NF-κB activation
in human diseases, particularly in cancer. The function of miR-146, miR-155, miR-181b, miR-21, and miR-301a in NF-κB activation
and their impact on tumorigenesis are discussed. Given that over 1000 human miRNAs have been identified, rendering miRNAs
one of the most abundant classes of regulatory molecules, deciphering their biological function and pathological contribution
in NF-κB dysregulation is essential to appreciate the complexity of immune systems and to develop therapeutics against cancer.
Receptors for advanced glycation end-products (RAGE) are cell-surface receptors expressed by alveolar type I (ATI) epithelial cells and are implicated in mechanisms of alveolar development and sustained pulmonary inflammation.
In the present study, we tested the hypothesis that diesel particulate matter (DPM) up-regulates RAGE in rat ATI-like R3/1 cells and human primary small airway epithelial cells (SAECs), leading to an inflammatory response.
Using real-time reverse transcriptase polymerase chain reaction and immunoblotting, we found that RAGE mRNA and protein are up-regulated in cells exposed to DPM for 2 hr. Use of a luciferase reporter containing nuclear factor-κB (NF-κB) response elements revealed decreased NF-κB activation in cells transfected with small interfering RNA (siRNA) for RAGE (siRAGE) before DPM exposure compared with cells transfected with scrambled control siRNA (siControl). In addition, immunostaining revealed diminished nuclear translocation of NF-κB in DPM-exposed cells transfected with siRAGE compared with cells transfected with siControl before DPM stimulation. Enzyme-linked immunosorbent assay demonstrated that in R3/1 cells DPM induced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), two cytokines induced by NF-κB and associated with leukocyte chemotaxis during an inflammatory response. Incorporating siRAGE was sufficient to significantly decrease DPM-induced MCP-1 and IL-8 secretion compared with cells transfected with siControl.
These data offer novel insights into potential mechanisms whereby RAGE influences pulmonary inflammation exacerbated by DPM exposure. Further research may demonstrate that molecules involved in RAGE signaling are potential targets in lessening the degree of particulate matter-induced exacerbations of inflammatory lung disease.
Mechanisms of cardiovascular injuries from exposure to gas and particulate air pollutants are unknown.
We sought to determine whether episodic exposure of rats to ozone or diesel exhaust particles (DEP) causes differential cardiovascular impairments that are exacerbated by ozone plus DEP.
Male Wistar Kyoto rats (10-12 weeks of age) were exposed to air, ozone (0.4 ppm), DEP (2.1 mg/m(3)), or ozone (0.38 ppm) + DEP (2.2 mg/m(3)) for 5 hr/day, 1 day/week for 16 weeks, or to air, ozone (0.51 or 1.0 ppm), or DEP (1.9 mg/m(3)) for 5 hr/day for 2 days. At the end of each exposure period, we examined pulmonary and cardiovascular biomarkers of injury. In the 16-week study, we observed mild pulmonary pathology in the ozone, DEP, and ozone + DEP exposure groups, a slight decrease in circulating lymphocytes in the ozone and DEP groups, and decreased platelets in the DEP group. After 16 weeks of exposure, mRNA biomarkers of oxidative stress (hemeoxygenase-1), thrombosis (tissue factor, plasminogen activator inhibitor-1, tissue plasminogen activator, and von Willebrand factor), vasoconstriction (endothelin-1, endothelin receptors A and B, endothelial NO synthase) and proteolysis [matrix metalloprotease (MMP)-2, MMP-3, and tissue inhibitor of matrix metalloprotease-2] were increased by DEP and/or ozone in the aorta, but not in the heart. Aortic LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) mRNA and protein increased after ozone exposure, and LOX-1 protein increased after exposure to ozone + DEP. RAGE (receptor for advanced glycation end products) mRNA increased in the ozone + DEP group. Exposure to ozone or DEP depleted cardiac mitochondrial phospholipid fatty acids (DEP > ozone). The combined effect of ozone and DEP exposure was less pronounced than exposure to either pollutant alone. Exposure to ozone or DEP for 2 days (acute) caused mild changes in the aorta.
In animals exposed to ozone or DEP alone for 16 weeks, we observed elevated biomarkers of vascular impairments in the aorta, with the loss of phospholipid fatty acids in myocardial mitochondria. We conclude that there is a possible role of oxidized lipids and protein through LOX-1 and/or RAGE signaling.
Black carbon (BC) is a marker of traffic pollution that has been associated with blood pressure (BP), but findings have been inconsistent. MicroRNAs (miRNAs) are emerging as key regulators of gene expression, but whether polymorphisms in genes involved in processing of miRNAs to maturity influence susceptibility to BC has not been elucidated.
We investigated the association between BC and BP, as well as potential effect modification by single nucleotide polymorphisms (SNPs) in miRNA processing genes.
Repeated measures analyses were performed using data from the VA Normative Aging Study. Complete covariate data were available for 789 participants with one to six study visits between 1995 and 2008. In models of systolic and diastolic BP, we examined SNP-by-BC interactions with 19 miRNA-related variants under recessive models of inheritance. Mixed-effects models were adjusted for potential confounders including clinical characteristics, lifestyle, and meteorologic factors.
A 1-SD increase in BC (0.415 microg/m(3)) was associated with 3.04 mmHg higher systolic (95% confidence interval (CI), 2.29-3.79) and 2.28 mmHg higher diastolic BP (95% CI, 1.88-2.67). Interactions modifying BC associations were observed with SNPs in the DICER, GEMIN4, and DiGeorge critical region-8 (DGCR8) genes, and in GEMIN3 and GEMIN4, predicting diastolic and systolic BP, respectively.
We observed evidence of effect modification of the association between BP and 7-day BC moving averages by SNPs associated with miRNA processing. Although the mechanisms underlying these associations are not well understood, they suggest a role for miRNA genesis and processing in influencing BC effects.
Hypoxia occurs in a number of pathological states, such as pulmonary, hematological, and cardiovascular disorders. In this study, we examined the molecular mechanism by which hypoxia contributes to increased leukotriene formation. Our studies showed hypoxia augmented the expression of 5-lipoxygenase activating protein (FLAP), a key enzyme in leukotriene formation, in both human pulmonary microvascular endothelial cells and a transformed human brain endothelial cell line. Hypoxia-induced FLAP mRNA expression involved activation of NADPH-oxidase, PI-3 kinase, mitogen-activated protein kinase, NF-kappaB, and hypoxia-inducible factor (HIF)-1alpha. Hypoxia-induced FLAP promoter activity was attenuated on mutation of hypoxia-response elements (HREs) and NF-kappaB binding motif in the FLAP promoter. Hypoxia also augmented binding of HIF-1alpha to HREs in FLAP promoter as demonstrated by EMSA with nuclear extracts. Furthermore, chromain immunoprecipitation analysis showed HIF-1alpha bound to HREs in native chromatin obtained from hypoxia-treated cells. Next, we examined the role of HIF-1alpha regulated microRNAs on FLAP expression. Our studies showed decreased expression of miR-135a and miR-199a-5p in response to hypoxia. However, overexpression of anti-miR-135a and anti-miR-199a-5p oligonucleotides led to a several fold increased FLAP mRNA and protein expression. These studies demonstrate for the first time that hypoxia-mediated FLAP expression is regulated by HREs and NF-kappaB site in its promoter, and negatively regulated by miR-135a and miR-199a-5p, which target the 3'-UTR of FLAP mRNA. An understanding of these regulatory pathways provides new avenues to ameliorate leukotriene formation and hence reactive airway disease, and inflammation in individuals who have sickle cell disease.
MicroRNAs (miRNAs) are a class of small RNAs of 19-23 nucleotides that regulate gene expression through target mRNA degradation or translational gene silencing. The miRNAs are reported to be involved in many biological processes, and the discovery of miRNAs has been provided great impacts on computational biology as well as traditional biology. Most miRNA-associated computational methods comprise the prediction of miRNA genes and their targets, and increasing numbers of computational algorithms and web-based resources are being developed to fulfill the need of scientists performing miRNA research. Here we summarize the rules to predict miRNA targets and introduce some computational algorithms that have been developed for miRNA target prediction and the application of the methods. In addition, the issue of target gene validation in an experimental way will be discussed.
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. MicroRNAs (miRNAs) are highly conserved, noncoding small RNAs that regulate the expression of broad gene networks at the posttranscriptional level.
We evaluated the effects of exposure to PM and PM metal components on candidate miRNAs (miR-222, miR-21, and miR-146a) related with oxidative stress and inflammatory processes in 63 workers at an electric-furnace steel plant.
We measured miR-222, miR-21, and miR-146a expression in blood leukocyte RNA on the first day of a workweek (baseline) and after 3 days of work (postexposure). Relative expression of miRNAs was measured by real-time polymerase chain reaction. We measured blood oxidative stress (8-hydroxyguanine) and estimated individual exposures to PM1 (< 1 microm in aerodynamic diameter), PM10 (< 10 microm in aerodynamic diameter), coarse PM (PM10 minus PM1), and PM metal components (chromium, lead, cadmium, arsenic, nickel, manganese) between the baseline and postexposure measurements.
Expression of miR-222 and miR-21 (using the 2-DeltaDeltaCT method) was significantly increased in postexposure samples (miR-222: baseline = 0.68 +/- 3.41, postexposure = 2.16 +/- 2.25, p = 0.002; miR-21: baseline = 4.10 +/- 3.04, postexposure = 4.66 +/- 2.63, p = 0.05). In postexposure samples, miR-222 expression was positively correlated with lead exposure (beta = 0.41, p = 0.02), whereas miR-21 expression was associated with blood 8-hydroxyguanine (beta = 0.11, p = 0.03) but not with individual PM size fractions or metal components. Postexposure expression of miR-146a was not significantly different from baseline (baseline = 0.61 +/- 2.42, postexposure = 1.90 +/- 3.94, p = 0.19) but was negatively correlated with exposure to lead (beta = -0.51, p = 0.011) and cadmium (beta = -0.42, p = 0.04).
Changes in miRNA expression may represent a novel mechanism mediating responses to PM and its metal components.
Particulate matter (PM) is associated with adverse airway health effects; however, the underlying mechanism in disease initiation is still largely unknown. Recently, microRNAs (miRNAs; small noncoding RNAs) have been suggested to be important in maintaining the lung in a disease-free state through regulation of gene expression. Although many studies have shown aberrant miRNA expression patterns in diseased versus healthy tissue, little is known regarding whether environmental agents can induce such changes.
We used diesel exhaust particles (DEP), the largest source of emitted airborne PM, to investigate pollutant-induced changes in miRNA expression in airway epithelial cells. We hypothesized that DEP exposure can lead to disruption of normal miRNA expression patterns, representing a plausible novel mechanism through which DEP can mediate disease initiation.
Human bronchial epithelial cells were grown at air-liquid interface until they reached mucociliary differentiation. After treating the cells with 10 microg/cm(2) DEP for 24 hr, we analyzed total RNA for miRNA expression using microarray profile analysis and quantitative real-time polymerase chain reaction.
DEP exposure changed the miRNA expression profile in human airway epithelial cells. Specifically, 197 of 313 detectable miRNAs (62.9%) were either up-regulated or down-regulated by 1.5-fold. Molecular network analysis of putative targets of the 12 most altered miRNAs indicated that DEP exposure is associated with inflammatory responses pathways and a strong tumorigenic disease signature.
Alteration of miRNA expression profiles by environmental pollutants such as DEP can modify cellular processes by regulation of gene expression, which may lead to disease pathogenesis.
Although many studies have examined the effects of air pollution on mortality, data limitations have resulted in fewer studies of both particulate matter with an aerodynamic diameter of <or= 2.5 microm (PM(2.5); fine particles) and of coarse particles (particles with an aerodynamic diameter > 2.5 and < 10 microm; PM coarse). We conducted a national, multicity time-series study of the acute effect of PM(2.5) and PM coarse on the increased risk of death for all causes, cardiovascular disease (CVD), myocardial infarction (MI), stroke, and respiratory mortality for the years 1999-2005.
We applied a city- and season-specific Poisson regression in 112 U.S. cities to examine the association of mean (day of death and previous day) PM(2.5) and PM coarse with daily deaths. We combined the city-specific estimates using a random effects approach, in total, by season and by region.
We found a 0.98% increase [95% confidence interval (CI), 0.75-1.22] in total mortality, a 0.85% increase (95% CI, 0.46-1.24) in CVD, a 1.18% increase (95% CI, 0.48-1.89) in MI, a 1.78% increase (95% CI, 0.96-2.62) in stroke, and a 1.68% increase (95% CI, 1.04-2.33) in respiratory deaths for a 10-microg/m(3) increase in 2-day averaged PM(2.5). The effects were higher in spring. For PM coarse, we found significant but smaller increases for all causes analyzed.
We conclude that our analysis showed an increased risk of mortality for all and specific causes associated with PM(2.5), and the risks are higher than what was previously observed for PM(10). In addition, coarse particles are also associated with more deaths.
MicroRNAs are important regulators of gene expression that control both physiological and pathological processes such as development and cancer. Although their mode of action has attracted great attention, the principles governing their expression and activity are only beginning to emerge. Recent studies have introduced a paradigm shift in our understanding of the microRNA biogenesis pathway, which was previously believed to be universal to all microRNAs. Maturation steps specific to individual microRNAs have been uncovered, and these offer a plethora of regulatory options after transcription with multiple proteins affecting microRNA processing efficiency. Here we review the recent advances in knowledge of the microRNA biosynthesis pathways and discuss their impact on post-transcriptional microRNA regulation during tumour development.
We have shown that smoking impacts bronchial airway gene expression and that heterogeneity in this response associates with smoking-related disease risk. In this study, we sought to determine whether microRNAs (miRNAs) play a role in regulating the airway gene expression response to smoking. We examined whole-genome miRNA and mRNA expression in bronchial airway epithelium from current and never smokers (n = 20) and found 28 miRNAs to be differentially expressed (P < 0.05) with the majority being down-regulated in smokers. We further identified a number of mRNAs whose expression level is highly inversely correlated with miRNA expression in vivo. Many of these mRNAs contain potential binding sites for the differentially expressed miRNAs in their 3'-untranslated region (UTR) and are themselves affected by smoking. We found that either increasing or decreasing the levels of mir-218 (a miRNA that is strongly affected by smoking) in both primary bronchial epithelial cells and H1299 cells was sufficient to cause a corresponding decrease or increase in the expression of predicted mir-218 mRNA targets, respectively. Further, mir-218 expression is reduced in primary bronchial epithelium exposed to cigarette smoke condensate (CSC), and alteration of mir-218 levels in these cells diminishes the induction of the predicted mir-218 target MAFG in response to CSC. These data indicate that mir-218 levels modulate the airway epithelial gene expression response to cigarette smoke and support a role for miRNAs in regulating host response to environmental toxins.
Exposure to particulate air pollution has been related to increased hospitalization and death, particularly from cardiovascular disease. Lower blood DNA methylation content is found in processes related to cardiovascular outcomes, such as oxidative stress, aging, and atherosclerosis.
We evaluated whether particulate pollution modifies DNA methylation in heavily methylated sequences with high representation throughout the human genome.
We measured DNA methylation of long interspersed nucleotide element (LINE)-1 and Alu repetitive elements by quantitative polymerase chain reaction-pyrosequencing of 1,097 blood samples from 718 elderly participants in the Boston area Normative Aging Study. We used covariate-adjusted mixed models to account for within-subject correlation in repeated measures. We estimated the effects on DNA methylation of ambient particulate pollutants (black carbon, particulate matter with aerodynamic diameter < or = 2.5 microm [PM2.5], or sulfate) in multiple time windows (4 h to 7 d) before the examination. We estimated standardized regression coefficients (beta) expressing the fraction of a standard deviation change in DNA methylation associated with a standard deviation increase in exposure.
Repetitive element DNA methylation varied in association with time-related variables, such as day of the week and season. LINE-1 methylation decreased after recent exposure to higher black carbon (beta = -0.11; 95% confidence interval [CI], -0.18 to -0.04; P = 0.002) and PM2.5 (beta = -0.13; 95% CI, -0.19 to -0.06; P < 0.001 for the 7-d moving average). In two-pollutant models, only black carbon, a tracer of traffic particles, was significantly associated with LINE-1 methylation (beta = -0.09; 95% CI, -0.17 to -0.01; P = 0.03). No association was found with Alu methylation (P > 0.12).
We found decreased repeated-element methylation after exposure to traffic particles. Whether decreased methylation mediates exposure-related health effects remains to be determined.
Although microRNAs have been investigated extensively in cancer research, little is known regarding their response to noxious agents in apparently healthy tissues. We analyzed the expression of 484 miRNAs in the lungs of rats exposed to environmental cigarette smoke (ECS) for 28 days. ECS down-regulated 126 miRNAs (26.0%) at least 2-fold and 24 miRNAs more than 3-fold. We previously demonstrated that 107 of 4858 genes (2.9%) and 50 of 518 proteins (9.7%) were up-regulated by ECS in the same tissue, which is consistent with the role of microRNAs as negative regulators of gene expression. The most remarkably down-regulated microRNAs belonged to the families of let-7, miR-10, miR-26, miR-30, miR-34, miR-99, miR-122, miR-123, miR-124, miR-125, miR-140, miR-145, miR-146, miR-191, miR-192, miR-219, miR-222, and miR-223, which regulate stress response, apoptosis, proliferation, angiogenesis, and expression of genes. In contrast, miR-294, an inhibitor of transcriptional repressor genes, was up-regulated by ECS. There was a strong parallelism in dysregulation of rodent microRNAs and their human homologues, which are often transcribed from genes localized in fragile sites deleted in lung cancer. Five ECS-down-regulated microRNAs are known to be affected by single nucleotide polymorphisms. Thus, changes in microRNA expression are an early event following exposure to cigarette smoke.
Misclassification of exposure is a well-recognized inherent limitation of epidemiologic studies of disease and the environment. For many agents of interest, exposures take place over time and in multiple locations; accurately estimating the relevant exposures for an individual participant in epidemiologic studies is often daunting, particularly within the limits set by feasibility, participant burden, and cost. Researchers have taken steps to deal with the consequences of measurement error by limiting the degree of error through a study's design, estimating the degree of error using a nested validation study, and by adjusting for measurement error in statistical analyses. In this paper, we address measurement error in observational studies of air pollution and health. Because measurement error may have substantial implications for interpreting epidemiologic studies on air pollution, particularly the time-series analyses, we developed a systematic conceptual formulation of the problem of measurement error in epidemiologic studies of air pollution and then considered the consequences within this formulation. When possible, we used available relevant data to make simple estimates of measurement error effects. This paper provides an overview of measurement errors in linear regression, distinguishing two extremes of a continuum-Berkson from classical type errors, and the univariate from the multivariate predictor case. We then propose one conceptual framework for the evaluation of measurement errors in the log-linear regression used for time-series studies of particulate air pollution and mortality and identify three main components of error. We present new simple analyses of data on exposures of particulate matter < 10 μm in aerodynamic diameter from the Particle Total Exposure Assessment Methodology Study. Finally, we summarize open questions regarding measurement error and suggest the kind of additional data necessary to address them.
Gemin3 is a DEAD-box RNA helicase that binds to the Survival of Motor Neurons (SMN) protein and is a component of the SMN complex, which also comprises SMN, Gemin2, Gemin4, Gemin5, and Gemin6. Reduction in SMN protein results in Spinal muscular atrophy (SMA), a common neurodegenerative disease. The SMN complex has critical functions in the assembly/restructuring of diverse ribonucleoprotein (RNP) complexes. Here we report that Gemin3 and Gemin4 are also in a separate complex that contains eIF2C2, a member of the Argonaute protein family. This novel complex is a large approximately 15S RNP that contains numerous microRNAs (miRNAs). We describe 40 miRNAs, a few of which are identical to recently described human miRNAs, a class of small endogenous RNAs. The genomic sequences predict that miRNAs are likely to be derived from larger precursors that have the capacity to form stem-loop structures.
Systemic inflammation because of sepsis results in endothelial cell activation and microvascular injury. High-mobility group protein-1 (HMGB1), a novel inflammatory molecule, is a late mediator of endotoxin shock and is present in the blood of septic patients. The receptor for advanced glycation end products (RAGE) is expressed on endothelium and is a receptor for HMGB1. Here we examine the effects of HMGB1 on human endothelial cell function. Recombinant human HMGB1 (rhHMGB1) was cloned and expressed in Escherichia coli and incubated with human microvascular endothelium. rhHMGB1 caused a dose- and time-dependent increase in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and RAGE. rhHMGB1 induced the secretion of tumor necrosis factor-alpha (TNFalpha), interleukin 8 (IL-8), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) (P <.01). rhHMGB1 stimulation resulted in transient phosphorylation of mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK), and p38, and in nuclear translocation of transcription factors NF-kappaB and Sp1. These effects are partially mediated by TNFalpha autocrine stimulation, as anti-TNFalpha antibodies significantly decrease chemokine and adhesion molecule responses (P </=.002). Thus, rhHMGB1 elicits proinflammatory responses on endothelial cells and may contribute to alterations in endothelial cell function in human inflammation.
Severe sepsis and septic shock is a consequence of a generalized inflammatory systemic response because of an invasive infection that may result in acute organ dysfunction. Mortality is high despite access to modern intensive care units. The nuclear DNA binding protein high mobility group 1 (HMGB1) protein has recently been suggested to act as a late mediator of septic shock via its function as a macrophage-derived pro-inflammatory cytokine (J Exp Med 2000; 192: 565, Science1999; 285: 248). We investigated the pro-inflammatory activities of the A-box and the B-box of HMGB1 on human umbilical venular endothelial cells (HUVEC).
The HUVEC obtained from healthy donors were used for experiments. Recombinant human full-length HMGB1, A-box and B-box were cloned by polymerase chain reaction (PCR) amplification from a human brain quick-clone cDNA. The activation of HUVEC was studied regarding (i) upregulation of adhesion molecules, (ii) the release of cytokines and chemokines, (iii) the adhesion of neutrophils to HUVEC, (iv) the activation of signalling transduction pathways and (v) the involvement of the receptor for advanced glycation end-products (RAGE).
The full-length protein and the B-box of HMGB1 dose-dependently activate HUVEC to upregulate adhesion molecules such as ICAM-1, VCAM-1 and E-selectin and to release IL-8 and G-CSF. The activation of HUVEC could be inhibited to 50% by antibodies directed towards the RAGE. HMGB1-mediated HUVEC stimulation resulted in phosphorylation of the ELK-1 signal transduction protein and a nuclear translocation of p65 plus c-Rel, suggesting that HMGB1 signalling is regulated in endothelial cells through NF-kappaB.
The HMGB1 acts as a potent pro-inflammatory cytokine on HUVEC and the activity is mainly mediated through the B-box of the protein. HMGB1 may be a key factor mediating part of the pro-inflammatory response occurring in septic shock and severe inflammation.
High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types. We recently discovered that HMGB1 is secreted into the extracellular milieu and acts as a proinflammatory cytokine. Administration of HMGB1 to normal animals causes inflammatory responses, including fever, weight loss and anorexia, acute lung injury, epithelial barrier dysfunction, arthritis, and death. Anti-HMGB1 treatment, with antibodies or specific antagonists, rescues mice from lethal endotoxemia or sepsis and ameliorates the severity of collagen-induced arthritis and endotoxin-induced lung injury. Here, we give an abridged review of the cytokine activity of HMGB1, its secretion and release into the extracellular milieu, the putative signal transduction pathways, including interaction with cell-surface receptors and intracellular signaling, and its role in several inflammatory diseases. Finally, the therapeutic potential of blocking HMGB1 in the treatment of inflammatory diseases is discussed.
Many studies have shown that ambient particulate air pollution (PM) is associated with increased risk of hospital admissions and deaths for cardiovascular or respiratory causes around the world. In general these have been analysed in association with PM(10) and ozone, whereas PM(2.5) is now the particle measure of greatest health and regulatory concern. And little has been published on associations of hospital admissions and PM components.
This study analysed hospital admissions for myocardial infarction (15 578 patients), and pneumonia (24 857 patients) in associations with fine particulate air pollution, black carbon (BC), ozone, nitrogen dioxide (NO(2)), PM not from traffic, and carbon monoxide (CO) in the greater Boston area for the years 1995-1999 using a case-crossover analysis, with control days matched on temperature.
A significant association was found between NO(2) (12.7% change (95% CI: 5.8, 18)), PM(2.5) (8.6% increase (95% CI: 1.2, 15.4)), and BC (8.3% increase (95% CI: 0.2, 15.8)) and the risk of emergency myocardial infarction hospitalisation; and between BC (11.7% increase (95% CI: 4.8, 17.4)), PM(2.5) (6.5% increase (95% CI: 1.1, 11.4)), and CO (5.5% increase (95% CI: 1.1, 9.5)) and the risk of pneumonia hospitalisation.
The pattern of associations seen for myocardial infarction and pneumonia (strongest associations with NO(2), CO, and BC) suggests that traffic exposure is primarily responsible for the association with heart attacks.
Defect in apoptotic signaling and up-regulation of drug transporters in cancer cells significantly limits the effectiveness of cancer chemotherapy. We propose that an agent inducing non-apoptotic cell death may overcome cancer drug resistance and showed that shikonin, a naturally occurring naphthoquinone, induced a cell death in MCF-7 and HEK293 distinct from apoptosis and characterized with (a) a morphology of necrotic cell death; (b) loss of plasma membrane integrity; (c) loss of mitochondrial membrane potentials; (d) activation of autophagy as a downstream consequence of cell death, but not a contributing factor; (e) elevation of reactive oxygen species with no critical roles contributing to cell death; and (f) that the cell death was prevented by a small molecule, necrostatin-1, that specifically prevents cells from necroptosis. The characteristics fully comply with those of necroptosis, a basic cell-death pathway recently identified by Degterev et al. with potential relevance to human pathology. Furthermore, we proved that shikonin showed a similar potency toward drug-sensitive cancer cell lines (MCF-7 and HEK293) and their drug-resistant lines overexpressing P-glycoprotein, Bcl-2, or Bcl-x(L), which account for most of the clinical cancer drug resistance. To our best knowledge, this is the first report to document the induction of necroptosis by a small molecular compound to circumvent cancer drug resistance.
Nature Reviews Genetics 5, 522–531 (2004)In figure 2, the orientation of some RNA structures was incorrect. The corrected version is shown below.
Air pollution contributes to acute exacerbations of asthma and the development of asthma in children and adults. Airway epithelial cells interface innate and adaptive immune responses, and have been proposed to regulate much of the response to pollutants. Thymic stromal lymphopoietin (TSLP) is a pivotal cytokine linking innate and Th2 adaptive immune disorders, and is upregulated by environmental pollutants, including ambient particulate matter (PM) and diesel exhaust particles (DEP). We show that DEP and ambient fine PM upregulate TSLP mRNA and human microRNA (hsa-miR)-375 in primary human bronchial epithelial cells (pHBEC). Moreover, transfection of pHBEC with anti-hsa-miR-375 reduced TSLP mRNA in DEP but not TNF-α-treated cells. In silico pathway evaluation suggested the aryl hydrocarbon receptor (AhR) as one possible target of miR-375. DEP and ambient fine PM (3 μg/cm2) downregulated AhR mRNA. Transfection of mimic-hsa-miR-375 resulted in a small downregulation of AhR mRNA compared with resting AhR mRNA. AhR mRNA was increased in pHBEC treated with DEP after transfection with anti-hsa-miR-375. Our data show that two pollutants, DEP and ambient PM, upregulate TSLP in human bronchial epithelial cells by a mechanism that includes hsa-miR-375 with complex regulatory effects on AhR mRNA. The absence of this pathway in TNF-α-treated cells suggests multiple regulatory pathways for TSLP expression in these cells.
Cell-cell interaction through binding of intercellular adhesion molecule (ICAM), B7.1, B7.2 and CD40 on monocytes to their ligands on T-cells plays a number of roles in cytokine . High mobility group box 1 (HMGB1), an abundant and conserved nuclproduction and lymphocyte proliferationear protein, acts in the extracellular environment as a primary pro-inflammatory signal. The receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-2 and TLR-4 are receptors for HMGB1. HMGB1 induces pro-inflammatory cytokine production in monocytes and T-cells. This study was designed to study the cellular mechanism of cytokine production. HMGB1 concentration-dependently induced ICAM-1, B7.1, B7.2 and CD40 expression on monocytes, and interferon (IFN)-γ and tumor necrosis factor (TNF)-α production and lymphocyte proliferation in human peripheral blood mononuclear cells (PBMCs). These HMGB1 activities depended on the stimulation of RAGE on monocytes. HMGB1 also up-regulated RAGE, but not TLR-2 or TLR-4, expression on monocytes, which was inhibited by antibodies (Abs) against ICAM-1, B7.1, B7.2 and CD40. These results together indicated that HMGB1 could induce an intimate cellular interplay between monocytes and T-cells in PBMCs through the stimulation and up-regulation of RAGE and other adhesive molecules on monocytes.
MicroRNAs (miRNA) are important noncoding regulatory molecules that bind target messenger RNA (mRNA), primarily affecting their translation into protein. Because miRNAs can simultaneously target hundreds of mRNAs, subtle changes in their expression can elicit important cellular effects. Little is known about the role of miRNAs in pulmonary responses to inhaled particulate matter. We studied pulmonary global miRNA responses to Printex 90 carbon black nanoparticles in (1) nonpregnant C57BL/6 female mice instilled with vehicle or a single dose of 0.162 mg and euthanized 1, 3, and 28 days post-exposure, and (2) C57BL/6Bom Tac dams instilled with vehicle or a cumulative dose of 0.268 mg (four separate instillations of vehicle or 0.067 mg Printex 90 during pregnancy) and euthanized at weaning (26-27 days postexposure). We measured similar expression profiles in both exposure scenarios, with marked increases in miR-135b and subtle changes in miR-21 and miR-146b. All three miRNAs were confirmed in nonpregnant females by RT-PCR, whereas only miR-135b was confirmed in the dams. Target analysis revealed no concomitant changes in established and predicted targets of miR-135b, miR-21, or miR-146b. Analysis of potentially perturbed pathways did not reveal changes that would suggest down-stream miRNA effects. The reasons for the lack of association between miRNA and transcript profiles may be related to the complexity of miRNA function and fate, or to the possibility that targets may differ from those already established or predicted in silico. We hypothesize that changes in the expression of these miRNAs may be associated with resolution of pulmonary inflammation, but future work will be necessary to precisely identify specific targets of these miRNAs in lungs.
Heme oxygenase-1 (HMOX1) is a cytoprotective enzyme degrading heme to biliverdin, iron ions, and carbon monoxide, whose expression is induced in response to oxidative stress. Its overexpression has been suggested as a strategy improving survival of transplanted muscle precursors.
Here we demonstrated that HMOX1 inhibits differentiation of myoblasts and modulates miRNA processing: downregulates Lin28 and DGCR8, lowers the total pool of cellular miRNAs, and specifically blocks induction of myomirs. Genetic or pharmacological activation of HMOX1 in C2C12 cells reduces the abundance of miR-1, miR-133a, miR-133b, and miR-206, which is accompanied by augmented production of SDF-1 and miR-146a, decreased expression of MyoD, myogenin, and myosin, and disturbed formation of myotubes. Similar relationships between HMOX1 and myomirs were demonstrated in murine primary satellite cells isolated from skeletal muscles of HMOX1(+/+), HMOX1(+/-), and HMOX1(-/-) mice or in human rhabdomyosarcoma cell lines. Inhibition of myogenic development is independent of antioxidative properties of HMOX1. Instead it is mediated by CO-dependent inhibition of c/EBPδ binding to myoD promoter, can be imitated by SDF-1, and partially reversed by enforced expression of miR-133b and miR-206. Control C2C12 myoblasts injected to gastrocnemius muscles of NOD-SCID mice contribute to formation of muscle fibers. In contrast, HMOX1 overexpressing C2C12 myoblasts form fast growing, hyperplastic tumors, infiltrating the surrounding tissues, and disseminating to the lungs.
We evidenced for the first time that HMOX1 inhibits differentiation of myoblasts, affects the miRNA processing enzymes, and modulates the miRNA transcriptome.
HMOX1 improves the survival of myoblasts, but concurrently through regulation of myomirs, may act similarly to oncogenes, increasing the risk of hyperplastic growth of myogenic precursors.
MicroRNAs (miRNAs) are a novel class of small, non-coding RNAs that play a significant role in both inflammatory and cardiovascular diseases. Immune cells, especially T helper (Th) cells, are critical in the development of atherosclerosis and the onset of acute coronary syndrome (ACS). To assess whether inflammation-related miRNAs (such as miR-155, 146a, 21, 125a-5p, 125b, 31) are involved in the imbalance of Th cell subsets in patients with ACS, we measured the expression of related miRNAs in patients with acute myocardial infarction (AMI), unstable angina (UA), stable angina (SA) and chest pain syndrome (CPS); analyzed the relationship between miRNA expression and the frequency of Th cell subsets; and observed the co-expression of miR-155 and IL-17A in peripheral blood mononuclear cells (PBMCs) of patients with ACS. The results showed that the expression of miR-155 in the PBMCs of patients with ACS was decreased by approximately 60%, while the expression of both miR-21 and miR-146a was increased by approximately twofold. The expression patterns of miRNAs in plasma correlated with those in PBMCs, except for miR-21, which was increased by approximately sixfold in the AMI group and showed no significant difference between the UA group and the CPS group. We also found that the expression of miR-155 inversely correlated with the frequency of Th17 cells (r=-0.896, P<0.01) and that miR-155 was co-expressed with IL-17A in patients with ACS. In conclusion, our study revealed the expression patterns of inflammation-related miRNAs in patients with ACS and found that miR-155 may be associated with Th17 cell differentiation.
MicroRNAs (miRNAs) are short single-stranded non-coding molecules that function as negative regulators to silence or suppress gene expression. Aberrant miRNA expression has been implicated in a several cellular processes and pathogenic pathways of a number of diseases. Evidence is rapidly growing that miRNA regulation of gene expression may be affected by environmental chemicals. These environmental exposures include those that have frequently been associated with chronic diseases, such as heavy metals, air pollution, bisphenol A, and cigarette smoking. In this article, we review the published data on miRNAs in relation to the exposure to several environmental chemicals, and discuss the potential mechanisms that may link environmental chemicals to miRNA alterations. We further discuss the challenges in environmental-miRNA research and possible future directions. The accumulating evidence linking miRNAs to environmental chemicals, coupled with the unique regulatory role of miRNAs in gene expression, makes miRNAs potential biomarkers for better understanding the mechanisms of environmental diseases.
The purpose of this review is to provide an update of the current understanding on the role of microRNAs in mediating genetic responses to air pollutants and to contemplate on how these responses ultimately control susceptibility to ambient air pollution. Morbidity and mortality attributable to air pollution continues to be a growing public health concern worldwide. Despite several studies on the health effects of ambient air pollution, underlying molecular mechanisms of susceptibility and disease remain elusive. In the last several years, special attention has been given to the role of epigenetics in mediating, not only genetic and physiological responses to certain environmental insults, but also in regulating underlying susceptibility to environmental stressors. Epigenetic mechanisms control the expression of gene products, both basally and as a response to a perturbation, without affecting the sequence of DNA itself. These mechanisms include structural regulation of the chromatin structure, such as DNA methylation and histone modifications, and post-transcriptional gene regulation, such as microRNA mediated repression of gene expression. microRNAs are small noncoding RNAs that have been quickly established as key regulators of gene expression. As such, miRNAs have been found to control several cellular processes including apoptosis, proliferation and differentiation. More recently, research has emerged suggesting that changes in the expression of some miRNAs may be critical for mediating biological, and ultimately physiological, responses to air pollutants. Although the study of microRNAs, and epigenetics as a whole, has come quite far in the field of cancer, the understanding of how these mechanisms regulate gene-environment interactions to environmental exposures in everyday life is unclear. This article does not necessarily reflect the views and policies of the US EPA.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate basic biological processes by posttranscriptional suppression of their target genes. Altered miRNA expression may lead to widespread gene expression changes and has been implicated in pathophysiological processes such as cancer and inflammation. In this review, we summarize the present knowledge about the role of miRNAs in inflammation and in the response to environmental agents and pollutants, such as cigarette smoke, ethanol, carcinogenic chemicals such as benzo(a)pyrene (BaP) and dioxin, and UV radiation.
Establishment of a functional vasculature requires the interconnection and remodeling of nascent blood vessels. Precise regulation of factors that influence endothelial cell migration and function is essential for these stereotypical vascular patterning events. The secreted Slit ligands and their Robo receptors constitute a critical signaling pathway controlling the directed migration of both neurons and vascular endothelial cells during embryonic development, but the mechanisms of their regulation are incompletely understood.
To identify microRNAs regulating aspects of the Slit-Robo pathway and vascular patterning.
Here, we provide evidence that microRNA (miR)-218, which is encoded by an intron of the Slit genes, inhibits the expression of Robo1 and Robo2 and multiple components of the heparan sulfate biosynthetic pathway. Using in vitro and in vivo approaches, we demonstrate that miR-218 directly represses the expression of Robo1, Robo2, and glucuronyl C5-epimerase (GLCE), and that an intact miR-218-Slit-Robo regulatory network is essential for normal vascularization of the retina. Knockdown of miR-218 results in aberrant regulation of this signaling axis, abnormal endothelial cell migration, and reduced complexity of the retinal vasculature.
Our findings link Slit gene expression to the posttranscriptional regulation of Robo receptors and heparan sulfate biosynthetic enzymes, allowing for precise control over vascular guidance cues influencing the organization of blood vessels during development.
Small, noncoding, microRNAs (miRNAs) have emerged as key mediators of posttranscriptional gene silencing in both pathogenic and pathological aspects of ischemic stroke biology. In stroke etiology, miRNA have distinct expression patterns that modulate pathogenic processes including atherosclerosis (miR-21, miR-126), hyperlipidemia (miR-33, miR-125a-5p), hypertension (miR-155), and plaque rupture (miR-222, miR-210). Following focal cerebral ischemia, significant changes in the miRNA transcriptome, independent of an effect on expression of miRNA machinery, implicate miRNA in the pathological cascade of events that include blood brain barrier disruption (miR-15a) and caspase mediated cell death signaling (miR-497). Early activation of miR-200 family members improves neural cell survival via prolyl hydroxylase mRNA silencing and subsequent HIF-1α stabilization. Pro- (miR-125b) and anti-inflammatory (miR-26a, -34a, -145, and let-7b) miRNA may also be manipulated to positively influence stroke outcomes. Recent examples of successfully implemented miRNA-therapeutics direct the future of gene therapy and offer new therapeutic strategies by regulating large sets of genes in related pathways of the ischemic stroke cascade.
In 2004, the first American Heart Association scientific statement on "Air Pollution and Cardiovascular Disease" concluded that exposure to particulate matter (PM) air pollution contributes to cardiovascular morbidity and mortality. In the interim, numerous studies have expanded our understanding of this association and further elucidated the physiological and molecular mechanisms involved. The main objective of this updated American Heart Association scientific statement is to provide a comprehensive review of the new evidence linking PM exposure with cardiovascular disease, with a specific focus on highlighting the clinical implications for researchers and healthcare providers. The writing group also sought to provide expert consensus opinions on many aspects of the current state of science and updated suggestions for areas of future research. On the basis of the findings of this review, several new conclusions were reached, including the following: Exposure to PM <2.5 microm in diameter (PM(2.5)) over a few hours to weeks can trigger cardiovascular disease-related mortality and nonfatal events; longer-term exposure (eg, a few years) increases the risk for cardiovascular mortality to an even greater extent than exposures over a few days and reduces life expectancy within more highly exposed segments of the population by several months to a few years; reductions in PM levels are associated with decreases in cardiovascular mortality within a time frame as short as a few years; and many credible pathological mechanisms have been elucidated that lend biological plausibility to these findings. It is the opinion of the writing group that the overall evidence is consistent with a causal relationship between PM(2.5) exposure and cardiovascular morbidity and mortality. This body of evidence has grown and been strengthened substantially since the first American Heart Association scientific statement was published. Finally, PM(2.5) exposure is deemed a modifiable factor that contributes to cardiovascular morbidity and mortality.
The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation, whereas apoptotic cell death provides an important signal for tolerance induction. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders. HMGB1 can associate with other molecules, including TLR ligands and cytokines, and activates cells through the differential engagement of multiple surface receptors including TLR2, TLR4, and RAGE. RAGE is a multiligand receptor that binds structurally diverse molecules, including not only HMGB1, but also S100 family members and amyloid-beta. RAGE activation has been implicated in sterile inflammation as well as in cancer, diabetes, and Alzheimer's disease. While HMGB1 through interactions with TLRs may also be important, this review focuses on the role of the HMGB1-RAGE axis in inflammation and cancer.
MicroRNA (miRNA) are a class of post-transcriptional regulators of gene expression targeting mRNA for translational repression and/or degradation. We analyzed the expression of 365 miRNA in lymphocytes in relapsing-remitting MS patients, and show the first evidence for distinct miRNA expression profiles in CD4(+), CD8(+) and B cells in MS when compared with those in healthy volunteers. MiR-17-5p, which is involved in autoimmunity, was up-regulated in CD4(+) cells from MS patients. This was correlated with alterations in the expression of potential target genes of miR-17-5p, i.e. phosphatase and tensin homology and phosphatidyl-inositol-3-kinase regulatory subunit 1, which were down-regulated upon stimulation of CD4(+) cells with anti-CD3/CD28 in vitro. Functional experiments with a synthetic inhibitor of miR-17 supported the link between miRNA expression and the altered target gene expression. Moreover, we found distinct responses of deregulated miRNA to stimulation, i.e. miR-17-5p and miR-193a were strongly up-regulated, in contrast to the down-regulation of miR-497, miR-1 and miR-126. Other deregulated miRNA did not respond to the stimulation probably due to other, non-T-cell activation related, mechanisms in their mode of action. Our findings support the role of miRNA-dependent regulatory mechanisms in the immunopathogenesis of MS.
Inflammation is a formidable ally in the constant battle against infection, cancer and tissue injury. It is a primordial response that protects against injury and restores damaged tissue to its normal physiological functioning. In fact, our wellbeing and survival depends upon its efficiency and carefully balanced control. In general, the innate inflammatory response initiates within minutes and, if all is well, resolves within hours. In contrast, chronic inflammation persists for weeks, months or even years. Here, we are going to discuss the key endogenous checkpoints necessary for mounting an effective yet limited inflammatory response and the crucial biochemical pathways necessary to prevent its persistence. In this setting, the biochemical synthesis of key pro-resolution eicosanoids as well as their mode of action in self-limiting inflammation will be discussed.
High mobility group box 1 (HMGB1), a highly conserved, ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types, is a necessary and sufficient mediator of inflammation during sterile and infection-associated responses. Elevated levels of HMGB1 in serum and tissues occur during sterile tissue injury and during infection, and targeting HMGB1 with antibodies or specific antagonists is protective in established preclinical inflammatory disease models including lethal endotoxemia or sepsis, collagen-induced arthritis, and ischemia-reperfusion induced tissue injury. Future advances in this field will stem from understanding the biological basis for the success of targeting HMGB1 to therapeutic improvement in the treatment of inflammation, infection and ischemia-reperfusion induced injury.
Variation in platelet reactivity contributes to disorders of hemostasis and thrombosis, but the molecular mechanisms are not well understood.
To discover associations between interindividual platelet variability and the responsible platelet genes, and to begin to define the molecular mechanisms altering platelet gene expression.
Two hundred and eighty-eight healthy subjects were phenotyped for platelet responsiveness. Platelet RNA from subjects demonstrating hyperreactivity (n=18) and hyporeactivity (n=11) was used to screen the human transcriptome.
Distinctly different mRNA profiles were observed between subjects with differing platelet reactivity. Increased levels of mRNA for VAMP8/endobrevin, a critical v-SNARE involved in platelet granule secretion, were associated with platelet hyperreactivity (Q=0.0275). Validation studies of microarray results showed 4.8-fold higher mean VAMP8 mRNA levels in hyperreactive than hyporeactive platelets (P=0.0023). VAMP8 protein levels varied 13-fold among platelets from these normal subjects, and were 2.5-fold higher in hyperreactive platelets (P=0.05). Among our cohort of 288 subjects, a VAMP8 single-nucleotide polymorphism (rs1010) was associated with platelet reactivity in an age-dependent manner (P<0.003). MicroRNA-96 was predicted to bind to the 3'-untranslated regionof VAMP8 mRNA and was detected in platelets. Overexpression of microRNA-96 in VAMP8-expressing cell lines caused a dose-dependent decrease in VAMP8 protein and mRNA, suggesting a role in VAMP8 mRNA degradation.
These findings support a role for VAMP8/endobrevin in the heterogeneity of platelet reactivity, and suggest a role for microRNA-96 in the regulation of VAMP8 expression.
Toll-like receptors (TLRs) are major receptors that enable inflammatory cells to recognize invading microbial pathogens. MicroRNAs are small non-coding RNAs that play important regulatory roles in a variety of biological processes. In this study, we found that a microRNA, miR-147, was induced upon stimulation of multiple TLRs and functioned as a negative regulator of TLR-associated signaling events in murine macrophages. We first demonstrated that the NMES1 transcript was a functional primary miR-147. miR-147 was induced in LPS-stimulated mouse macrophages and under in vivo conditions in the lungs of LPS-treated mice. Expression of miR-147 was greater after cellular activation by TLR4 than after engagement of either TLR2 or TLR3, suggesting that maximal induction of miR-147 required activation of both NF-kappaB and IRF3. TLR4-induced miR-147 expression was both MyD88- and TRIF-dependent. The miR-147 promoter was responsive to TLR4 stimulation and both NF-kappaB and STAT1alpha bound to the miR-147 promoter. miR-147 mimics or induced expression of miR-147 decreased, whereas miR-147 knockdown increased inflammatory cytokine expression in macrophages stimulated with ligands to TLR2, TLR3, and TLR4. These data demonstrate a negative-feedback loop in which TLR stimulation induces miR-147 to prevent excessive inflammatory responses.
The inflammatory responses of monocytes/macrophages and the stimulation of lipid uptake into these cells by oxidized low density lipoprotein (oxLDL) are critical to the initiation and development of atherosclerosis. Increasing evidence has demonstrated that many microRNAs play important roles in the cell proliferation, apoptosis, and differentiation that accompany inflammatory responses. However, whether microRNAs are associated with monocyte/macrophage inflammatory responses or oxLDL stimulation is not yet known. The aim of the present study is to investigate microRNAs in monocytes/macrophages and their potential role in oxLDL-stimulation of lipid uptake and other atherosclerotic responses.
Microarrays were used to analyse the global expression of microRNAs in oxLDL-stimulated human primary peripheral blood monocytes. Expression profiles of the microRNAs were verified using TaqMan real-time PCR. Five microRNAs (microRNA-125a-5p, microRNA-9, microRNA-146a, microRNA-146b-5p, and microRNA-155) were aberrantly expressed after oxLDL treatment of human primary monocytes. Bioinformatics analysis suggested that microRNA-125a-5p is related to a protein similar to ORP9 (oxysterol binding protein-like 9) and this was confirmed by a luciferase reporter assay. MicroRNA-125a-5p was found to mediate lipid uptake and to decrease the secretion of some inflammatory cytokines (interleukin-2, interleukin-6, tumour necrosis factor-alpha, transforming growth factor-beta) in oxLDL-stimulated monocyte-derived macrophages.
MicroRNA-125a-5p may partly provide post-transcriptional regulation of the proinflammatory response, lipid uptake, and expression of ORP9 in oxLDL-stimulated monocyte/macrophages.
This study characterizes the personal, indoor, and outdoor PM2.5, PM10, and PM2.5-10 exposures of 18 individuals with chronic obstructive pulmonary disease (COPD) living in Boston, MA. Monitoring was performed for each participant for six consecutive days in the winters of 1996 or 1997 and for six to twelve days in the summer of 1996. On each day, 12-h personal, indoor, and outdoor samples of PM2.5 and PM10 were collected simultaneously. Home characteristic information and time-activity patterns were also obtained. Personal exposures were higher than corresponding indoor and outdoor concentrations for all particle measures and for all seasons, except for winter indoor PM2.5-10 levels, which were higher than personal and outdoor levels. Higher personal exposures may be due to the proximity of the individuals to particle sources, such as cooking and cleaning. Indoor concentrations were associated with both outdoor concentrations and personal exposures (as determined by individual least square regression analyses), with associations strongest for PM2.5. Indoor PM2.5 concentrations were significantly associated with outdoor and personal levels for 12 and 15 of the 17 individuals, respectively. Both the strength and magnitude of the associations varied by individual. Also, personal PM2.5, but not PM2.5-10, exposures were associated with outdoor levels, with 10 of the 17 subjects having significant associations. The strength of the personal-outdoor association for PM2.5 was strongly related to that for indoor and outdoor levels, suggesting that home characteristics and indoor particulate sources were key determinants of the personal-outdoor association for PM2.5. Air exchange rates were found to be important determinants of both indoor and personal levels. Again, substantial interpersonal variability in the personal-outdoor relationship was found, as personal exposures varied by as much as 200% for a given outdoor level.
HMGB1 (high mobility group box chromosomal protein 1), historically known as an abundant, nonhistone architectural chromosomal protein, is extremely conserved across species. As a nuclear protein, HMGB1 stabilizes nucleosomes and allows bending of DNA that facilitates gene transcription. Unexpectedly, recent studies identified extracellular HMGB1 as a potent macrophage-activating factor, signaling via the receptor for advanced glycation end-products to induce inflammatory responses. It is released as a late mediator during inflammation and participates in the pathogenesis of systemic inflammation after the early mediator response has resolved. HMGB1 occupies a critical role as a proinflammatory mediator passively released by necrotic but not apoptotic cells. Necrotic Hmgb1(-/-) cells mediate minimal inflammatory responses. Stimulated macrophages actively secrete HMGB1 to promote inflammation and in turn, stimulate production of multiple, proinflammatory cytokines. HMGB1 mediates endotoxin lethality, acute lung injury, arthritis induction, activation of macrophages, smooth muscle cell chemotaxis, and epithelial cell barrier dysfunction. HMGB1 is structurally composed of three different domains: two homologous DNA-binding sequences entitled box A and box B and a highly, negatively charged C terminus. The B box domain contains the proinflammatory cytokine functionality of the molecule, whereas the A box region has an antagonistic, anti-inflammatory effect with therapeutic potential. Administration of highly purified, recombinant A box protein or neutralizing antibodies against HMGB1 rescued mice from lethal sepsis, even when initial treatment was delayed for 24 h after the onset of infection, establishing a clinically relevant therapeutic window that is significantly wider than for other known cytokines.
High mobility group box chromosomal protein 1 (HMGB-1), a nuclear DNA binding protein, was recently rediscovered as a new proinflammatory cytokine. The purpose of this study was to demonstrate HMGB-1 expression in vivo and to identify the role of HMGB-1 in the pathogenesis of rheumatoid arthritis (RA).
HMGB-1 concentrations in synovial fluid (SF) and serum from RA and osteoarthritis (OA) patients were measured by immunoblot analysis. The protein's specific receptor, receptor for advanced glycation end products (RAGE), was examined in SF macrophages (SFMs). We measured levels of proinflammatory cytokines released by SFMs treated with HMGB-1 via enzyme-linked immunosorbent assay and used soluble RAGE (sRAGE) to block the release of tumor necrosis factor alpha (TNFalpha). Immunohistochemical analysis and immunofluorescence assay were employed to examine localization of HMGB-1 in RA synovium and its translocation in SFMs after TNFalpha stimulation.
HMGB-1 concentrations were significantly higher in SF of RA patients than in that of OA patients. SFMs expressed RAGE and released TNFalpha, interleukin-1beta (IL-1beta), and IL-6 upon stimulation with HMGB-1. HMGB-1 was found in CD68-positive cells of RA synovium, and TNFalpha stimulation translocated HMGB-1 from the nucleus to the cytosol in SFMs. Blockade by sRAGE inhibited the release of TNFalpha from SFMs.
HMGB-1 was more strongly expressed in SF of RA patients than in that of OA patients, inducing the release of proinflammatory cytokines from SFMs. HMGB-1 plays a pivotal role in the pathogenesis of RA and may be an original target of therapy as a novel cytokine.
MicroRNAs are a family of small, non-coding RNAs that regulate gene expression in a sequence-specific manner. The two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events. Since then, hundreds of microRNAs have been identified in almost all metazoan genomes, including worms, flies, plants and mammals. MicroRNAs have diverse expression patterns and might regulate various developmental and physiological processes. Their discovery adds a new dimension to our understanding of complex gene regulatory networks.
Expression profiling of T24 cells revealed that 17 out of 313 human miRNAs were upregulated more than 3-fold by simultaneous treatment with the chromatin-modifying drugs 5-aza-2'-deoxycytidine and 4-phenylbutyric acid. One of these, miR-127, is embedded in a CpG island and is highly induced from its own promoter after treatment. miR-127 is usually expressed as part of a miRNA cluster in normal cells but not in cancer cells, suggesting that it is subject to epigenetic silencing. In addition, the proto-oncogene BCL6, a potential target of miR-127, was translationally downregulated after treatment. These results suggest that DNA demethylation and histone deacetylase inhibition can activate expression of miRNAs that may act as tumor suppressors.