Project description:Exposure to ambient particulate matter (PM) significantly increases cardiovascular morbidity and mortality in the general population. We hypothesized that some components of PM can affect the gene expression patterns in the hearts of rats exposed for 3 months to filtered air (FA), coarse (CP; 2.5 < dp < 10 μm), fine (FP; dp ≤ 2.5 μm) or ultrafine (UFP; dp ≤ 0.18 μm) components of PM. The median diameters of CP, FP, and UFP were 3 μm, 0.7 μm and 0.07 μm, respectively. Exposures (n = 8 per group) were performed using a particle concentrator system in Riverside, California, an area with high ambient levels of photochemically derived gaseous and particulate pollutants. At the end of the exposure, hearts were subjected to gene expression profiling by using Illumina RatRef-12 bead chips and levels of malonaldehyde (MDA), a biomarker of oxidative stress, were measured. Applying fold ratio >1.5 (for both up- and downregulated genes), we found three genes in the CP and nine genes in the UFP groups with significantly changed expression, compared with FA. No significant changes in gene expression patterns were observed in the FP group. In the UFP group, thioredoxin-interacting protein (Txnip), a negative regulator of an antioxidant enzyme thioredoxin, and cytochrome P450 (Cyp2e1), an enzyme involved in the metabolism of foreign substances, demonstrated significant up-regulation (fold ratios 1.79 and 1.57, respectively, with false discovery rate, FDR < 0.05). In the CP group, there was also a trend towards increased Txnip expression (fold ratio 1.43, FDR > 0.05) and significant increase in the Cyp2e1 expression (fold ratio 1.79, FDR < 0.05). Changes in the Txnip and Cyp2e1 expression showed statistically significant positive correlation to each other (p < 0.0009) and were confirmed by real-time PCR. In addition, Txnip and Cyp2e1 expression demonstrated statistically significant moderate correlation with the levels of MDA in the heart. Up-regulation of both Cyp2e1 and Txnip are observed in hearts of patients with certain cardiac diseases. Therefore, chronic exposure to CP and UFP directly affects expression of disease-relevant genes in the myocardium.

Project description:Exposure to ambient particulate matter (PM) significantly increases cardiovascular morbidity and mortality in the general population. We hypothesized that some components of PM can affect the gene expression patterns in the hearts of rats exposed for 3 months to filtered air (FA), coarse (CP; 2.5 < dp < 10 μm), fine (FP; dp ≤ 2.5 μm) or ultrafine (UFP; dp ≤ 0.18 μm) components of PM. The median diameters of CP, FP, and UFP were 3 μm, 0.7 μm and 0.07 μm, respectively. Exposures (n = 8 per group) were performed using a particle concentrator system in Riverside, California, an area with high ambient levels of photochemically derived gaseous and particulate pollutants. At the end of the exposure, hearts were subjected to gene expression profiling by using Illumina RatRef-12 bead chips and levels of malonaldehyde (MDA), a biomarker of oxidative stress, were measured. Applying fold ratio >1.5 (for both up- and downregulated genes), we found three genes in the CP and nine genes in the UFP groups with significantly changed expression, compared with FA. No significant changes in gene expression patterns were observed in the FP group. In the UFP group, thioredoxin-interacting protein (Txnip), a negative regulator of an antioxidant enzyme thioredoxin, and cytochrome P450 (Cyp2e1), an enzyme involved in the metabolism of foreign substances, demonstrated significant up-regulation (fold ratios 1.79 and 1.57, respectively, with false discovery rate, FDR < 0.05). In the CP group, there was also a trend towards increased Txnip expression (fold ratio 1.43, FDR > 0.05) and significant increase in the Cyp2e1 expression (fold ratio 1.79, FDR < 0.05). Changes in the Txnip and Cyp2e1 expression showed statistically significant positive correlation to each other (p < 0.0009) and were confirmed by real-time PCR. In addition, Txnip and Cyp2e1 expression demonstrated statistically significant moderate correlation with the levels of MDA in the heart. Up-regulation of both Cyp2e1 and Txnip are observed in hearts of patients with certain cardiac diseases. Therefore, chronic exposure to CP and UFP directly affects expression of disease-relevant genes in the myocardium. Analysis was performed on 32 microarrays (eight microarrays in each group). After five chips with poor hybridization signals were removed, the final analysis included 27 microarrays (seven miocroarrays in the FA group, six microarrays in the CP group, six microarrays in the FP group and eight microarrays in the UFP group). The Bioconductor Lumi package was used to preprocess gene chip data with default settings (Du et al. 2007; Lin et al. 2008). Probes with all samples “Absent” (lower or around background levels) were removed from further analysis. After filtering the signals, 11,657 probes on the microarray (from a total of 22,226 probes) were kept for further analysis. To identify differentially expressed genes, we applied routines implemented in the Limma package (Linear model for microarray data) to fit linear models to normalized expression values. The variance used in the t-score calculation was corrected by an empirical Bayesian method (Smyth 2004). Genes with significantly changed expression (fold ratio >1.5 for both up- and downregulated genes) were selected. The gene list was further filtered by FDR (false discovery rate) of <0.05 and <0.25, which indicate that no more than 5% and 25% of all listed genes are false positives (an assumption that is not offered by a traditional p value-based analysis).

Project description:It is generally accepted that exposure to particulate matter (PM) increases the risk of cardiovascular-related morbidity and mortality, though the exact mechanism behind this has yet to be elucidated. Oxidative stress plays a potentially important role in the mechanism of toxicity, with Nrf2 serving as a major antioxidant gene. In the current study, a Nrf2 knockout mouse model was used in combination with an individual ventilated cage (IVC)-based real-ambient PM exposure system to assess the potential cardiotoxicity induced by real-ambient PM exposure and the potential role of Nrf2 and related signaling in this endpoint. After 6- or 11-weeks exposure to PM, ICP-mass spectrometry was used to assess the metal depositions in the heart tissue following PM exposure. Functional and morphological changes in the hearts were investigated with echocardiography and histopathology, and oxidative stress levels were assessed with a serum malondialdehyde content assay. In the further mechanistic study, an RNA-seq technique was utilized to assess the gene transcription status in the hearts of C57/B6 mice exposed to PM with or without Nrf2 knockout. The expression levels of genes of interest were then further investigated with quantitative real-time PCR and western blotting. The results indicated that PM exposure resulted in significant elevation of sodium, potassium, selenium, and ferrum levels in mouse heart tissue. Meanwhile, significantly altered heart function and morphology were observed. Interestingly, Nrf2 knockout led to abolishment of PM-induced effects in several functional parameters but not the morphological changes. Meanwhile, elevated malondialdehyde content was observed in Nrf2 knockout animals. RNA-seq results revealed thousands of genes altered by PM exposure and/or Nrf2 knockout, and this affected several pathways, such as MAPK, phagosome, calcium signaling, and JAK-STAT. In subsequent molecular studies, enhanced nuclear translocation of Nrf2 was also observed following PM exposure, while the MAPK signaling pathway along with related JAK-STAT and TGF-?1 pathway genes, such as p38MAPK, AKT, TAK1, JAK1, STAT3, GRB2, TGFb1, and SMAD2, were confirmed to be affected by PM exposure and/or Nrf2 knockout. The data suggested that PM may induce cardiotoxicity in C57/B6 mice in which Nrf2 plays both protective and detrimental roles involving cardiac-related pathways, such as MAPK, JAK-STAT, and TGF-?1.

Project description:Murine Pulmonary Responses to Ambient Baltimore Particulate Matter: Genomic Analysis and Contribution to Airway Hyperresponsiveness Asthma is a complex disease characterized by airway hyperresponsiveness (AHR) and chronic airway inflammation. Environmental factors such as ambient particulate matter (PM), a major air pollutant, has been demonstrated in epidemiological studies to contribute to asthma exacerbation and increased asthma prevalence. OBJECTIVE: We investigated the genomic and pathophysiological effects of Baltimore PM (median diameter 1.78 µm) in a murine model of asthma to identify potential biomarkers. METHODS: A/J mice with ovalbumin (OVA) –induced AHR were exposed to PM (20 mg/kg, intratracheal), and both AHR and bronchoalveolar lavage (BAL) were assayed on days 1, 4, and 7 post exposure. Lung gene expression profiling (Affymetrix Mouse430_ 2.0) by PM (20 mg/kg, intratracheal) were assayed on OVA- and / or PM--challenged mice. RESULTS: Significant increases of airway responsiveness in OVA-treated mice were observed, indicating an asthmatic phenotype. Ambient PM exposure induced significant changes in AHR in both naive mice and OVA-induced asthmatic mice. In both naive and OVA challenged asthmatic mice, PM induced eosinophil and neutrophil infiltration into airways, elevated BAL protein content, and stimulated secretion of TH1 cytokines (IFN-g, IL-6, and TNF-a) and TH2 cytokines (IL-4, IL-5, and eotaxin) into BAL. Consistent with these results, PM induced expression of genes of innate immune response, chemotaxis and complementary system. CONCLUSION: These studies, consistent with epidemiological data, indicate that PM increases AHR and lung inflammation in naïve mice and exacerbates the asthma phenotype of increased AHR and gene expression pattern changes correlated with acute lung inflammation and airway damage. We used microarrays to detail the global programme of gene expression induced by rhPBEF treatment and VALI. Keywords: gene expression

Project description:BackgroundFetal growth restriction (FGR) is not only a major determinant of perinatal morbidity and mortality but also leads to adverse health effects in later life. Over the past decade, numerous studies have indicated that maternal exposure to ambient air pollution has been a risk factor for abnormal fetal growth in developed countries where PM2.5 levels are relatively low. However, studies in highly polluted regions, such as China, and studies that rely on assessments in utero are scarce.MethodsA total of 7965 women were selected from 11,441 women from the Shanghai Maternity and Infant Living Environment (SMILE) cohort who were pregnant between January 1, 2014, and April 30, 2015. From January 1, 2014, to April 30, 2015, weekly average PM2.5 values from 53 monitors were calculated and the inverse distance weighted (IDW) method was used to create a Shanghai pollution surface map according to the participants residential addresses. Individual exposure was the average PM2.5 value of every gestational week between the first gestational week and one week before the ultrasound measurement date (the range of measurements per participant was 1 to 10). Repeated fetal ultrasound measurements during gestational weeks 14~40 were selected. The estimated fetal weight (EFW) was calculated by biparietal diameter (BPD), abdominal circumference (AC), and femur length (FL) formulas. In total, 29,926 ultrasound measurements were analysed. Demographic variables, other pollutants (SO2, NO2, PM10 and O3) and relative humidity and temperature were controlled for potential confounding through generalized estimating equations (GEE).ResultsThe full model showed that with each 10 μg/m3 increase in PM2.5 exposure, the means (mm) of AC, BPD, FL decreased by 5.48 (- 9.06, - 1.91), 5.57 (- 6.66, - 4.47), and 5.47 (- 6.39, - 4.55), respectively; the mean EFW decreased by 14.49 (- 16.05, - 13.49) grams by Hadlock's third formula and 13.56 (- 14.71, - 12.50) grams by Shepard's formula with each 10 μg/m3 increase in PM2.5 exposure.ConclusionsA negative correlation existed between maternal PM2.5 exposure during pregnancy and fetal growth indicators, which may increase the risk of fetal growth restriction.

Dataset Information

Combined effects of ambient particulate matter exposure and a high-fat diet on oxidative stress and steatohepatitis in mice.

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Combined effects of ambient particulate matter exposure and a high-fat diet on oxidative stress and steatohepatitis in mice.

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