Dataset Information

Relationships between pulmonary micro-RNA and proteome profiles, systemic cytogenetic damage and lung tumors in cigarette smoke-exposed mice treated with chemopreventive agents.

ABSTRACT: Assessing the correlation between molecular endpoints and cancer induction or prevention aims at validating the use of intermediate biomarkers. We previously developed murine models that are suitable to detect both the carcinogenicity of mainstream cigarette smoke (MCS) and the induction of molecular alterations. In this study, we used 931 Swiss mice in two parallel experiments and in a preliminary toxicity study. The chemopreventive agents included vorinostat, myo-inositol, bexarotene, pioglitazone and a combination of bexarotene and pioglitazone. Pulmonary micro-RNAs and proteins were evaluated by microarray analyses at 10 weeks of age in male and female mice, either unexposed or exposed to MCS since birth, and either untreated or receiving each one of the five chemopreventive regimens with the diet after weaning. At 4 months of age, the frequency of micronucleated normochromatic erythrocytes was evaluated. At 7 months, the lungs were subjected to standard histopathological analysis. The results showed that exposure to MCS significantly downregulated the expression of 79 of 694 lung micro-RNAs (11.4%) and upregulated 66 of 1164 proteins (5.7%). Administration of chemopreventive agents modulated the baseline micro-RNA and proteome profiles and reversed several MCS-induced alterations, with some intergender differences. The stronger protective effects were produced by the combination of bexarotene and pioglitazone, which also inhibited the MCS-induced clastogenic damage and the yield of malignant tumors. Pioglitazone alone increased the yield of lung adenomas. Thus, micro-RNAs, proteins, cytogenetic damage and lung tumors were closely related. The molecular biomarkers contributed to evaluate both protective and adverse effects of chemopreventive agents and highlighted the mechanisms involved.

SUBMITTER: Izzotti A

PROVIDER: S-EPMC3786376 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Relationships between pulmonary micro-RNA and proteome profiles, systemic cytogenetic damage and lung tumors in cigarette smoke-exposed mice treated with chemopreventive agents.

Izzotti Alberto A Balansky Roumen R D'Agostini Francesco F Longobardi Mariagrazia M Cartiglia Cristina C La Maestra Sebastiano S Micale Rosanna T RT Camoirano Anna A Ganchev Gancho G Iltcheva Marietta M Steele Vernon E VE De Flora Silvio S

Carcinogenesis 20130524 10

Assessing the correlation between molecular endpoints and cancer induction or prevention aims at validating the use of intermediate biomarkers. We previously developed murine models that are suitable to detect both the carcinogenicity of mainstream cigarette smoke (MCS) and the induction of molecular alterations. In this study, we used 931 Swiss mice in two parallel experiments and in a preliminary toxicity study. The chemopreventive agents included vorinostat, myo-inositol, bexarotene, pioglita ...[more]

PMID: 23708261

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Project description:In urban areas with a predominance of early to mid-20th century housing stock, islands of children possessing blood lead levels (PbB) in excess of CDC guidelines (>10?g/dL) exist. Many of these children are also exposed to environmental tobacco smoke (ETS). The current study examined the impact of Pb-exposure (PbB levels of 1-55?g/dL) with/without concurrent ETS exposure on immune system function in 318 children aged 6-84 months from the urban area of Springfield-Greene County, MO. In this population, 36.5% of children possessed PbB levels >10?g/dL, 62.9% of children came from smoking homes, 51.9% of children were under 2 years of age, and the population was WIC eligible and predominantly of white, non-Hispanic ethnicity. Multiple immune function markers including cell counts, IgE levels, sCD25 (sIL2R) and IL4 concentrations, and titers to common childhood immunizations were analyzed for correlation with Pb and/or ETS exposure. Increased IgE levels (p<0.01) were found in children with PbB levels within CDC Classes II-IV - this finding was primarily attributable to elevated IgE levels in the subpopulation of children with concurrent Pb and ETS exposure. A trend (0.05<p<0.01) of increases in % total T-cells (p=0.06) was also found in children with concurrent elevated PbB levels and ETS exposure. This trend was not found in the subset of children without ETS exposure nor was it present in the analysis of the entire population set. Conversely, alterations in median values for % lymphocytes, % granulocytes, and % activated T-cells across Pb classes were present in the subpopulation of children expose to Pb alone (without concurrent ETS exposure) though a clear trend was not evident. In the entire population set, a statistically significant correlation between ETS and PbB levels was found. This study indicates that prior reports of a correlation between elevated PbB levels and serum IgE levels may be strongly influenced by exposure to ETS. Findings from this study also indicate that Pb is an immune modulator and PbB levels may be influenced by ETS exposure.

Project description:BACKGROUND:Lung aging is characterized by a number of structural alterations including fibrosis, chronic inflammation and the alteration of inflammatory cell composition. Chronic exposure to cigarette smoke (CS) is known to induce similar alterations and may contribute to premature lung aging. Additionally, aging and CS exposure are associated with transcriptional alterations in the lung. The current work aims to explore the interaction between age- and CS- associated transcriptomic perturbations and develop a transcriptomic clock able to predict the biological age and the impact of external factors on lung aging. RESULTS:Our investigations revealed a substantial overlap between transcriptomic response to CS exposure and age-related transcriptomic alterations in the murine lung. Of particular interest is the strong upregulation of immunoglobulin genes with increased age and in response to CS exposure, indicating an important implication of B-cells in lung inflammation associated with aging and smoking. Furthermore, we used a machine learning approach based on Lasso regression to build a transcriptomic age model that can accurately predict chronological age in untreated mice and the deviations associated with certain exposures. Interestingly, CS-exposed-mice were predicted to be prematurely aged in contrast to mice exposed to fresh air or to heated tobacco products (HTPs). The accelerated aging rate associated with CS was reversed upon smoking cessation or switching to HTPs. Additionally, our model was able to predict premature aging associated with thoracic irradiation from an independent public dataset. CONCLUSIONS:Aging and CS exposure share common transcriptional alteration patterns in the murine lung. The massive upregulation of B-cell restricted genes during these processes shed light on the contribution of cell composition and particularly immune cells to the measured transcriptomic signal. Through machine learning approach, we show that gene expression changes can be used to accurately monitor the biological age and the modulations associated with certain exposures. Our findings also suggest that the premature lung aging is reversible upon the reduction of harmful exposures.

Dataset Information

Relationships between pulmonary micro-RNA and proteome profiles, systemic cytogenetic damage and lung tumors in cigarette smoke-exposed mice treated with chemopreventive agents.

Publications

Relationships between pulmonary micro-RNA and proteome profiles, systemic cytogenetic damage and lung tumors in cigarette smoke-exposed mice treated with chemopreventive agents.

Similar Datasets

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