Variation in the <i>GST mu</i> Locus and Tobacco Smoke Exposure as Determinants of Childhood Lung Function

Breton, Carrie V.; Vora, Hita; Salam, Muhammad T.; Islam, Talat; Wenten, Madé; Gauderman, W. James; Berg, David Van Den; Berhane, Kiros; Peters, John; Gilliland, Frank D.

doi:10.1164/rccm.200809-1384oc

Cited by 34 publications

(45 citation statements)

References 44 publications

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“…Glutathione S-transferase M3 (Gtsm3) is a detoxifying enzyme that metabolizes oxidative compounds from exposure to environmental toxins. Studies have shown that genetic variations of this gene are associated with poor lung growth and function in relation to environmental toxin exposure (34), and correlated with severity of lung diseases, such as cystic fibrosis (35). Betacellulin is an epidermal growth factor, the overexpression of which in mice resulted in severe pulmonary pathology, including thickening of alveolar septa, intra-alveolar accumulation of hemosiderin-containing macrophages, and nodular pulmonary remodeling-features commonly seen in BPD (36).…”

Section: Discussionmentioning

confidence: 99%

Alterations in Gene Expression and DNA Methylation during Murine and Human Lung Alveolar Septation

Cuna

Halloran

Faye-Petersen

et al. 2015

Am J Respir Cell Mol Biol

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DNA methylation, a major epigenetic mechanism, may regulate coordinated expression of multiple genes at specific time points during alveolar septation in lung development. The objective of this study was to identify genes regulated by methylation during normal septation in mice and during disordered septation in bronchopulmonary dysplasia. In mice, newborn lungs (preseptation) and adult lungs (postseptation) were evaluated by microarray analysis of gene expression and immunoprecipitation of methylated DNA followed by sequencing (MeDIP-Seq). In humans, microarray gene expression data were integrated with genome-wide DNA methylation data from bronchopulmonary dysplasia versus preterm and term lung. Genes with reciprocal changes in expression and methylation, suggesting regulation by DNA methylation, were identified. In mice, 95 genes with inverse correlation between expression and methylation during normal septation were identified. In addition to genes known to be important in lung development (Wnt signaling, Angpt2, Sox9, etc.) and its extracellular matrix (Tnc, Eln, etc.), genes involved with immune and antioxidant defense (Stat4, Sod3, Prdx6, etc.) were also observed. In humans, 23 genes were differentially methylated with reciprocal changes in expression in bronchopulmonary dysplasia compared with preterm or term lung. Genes of interest included those involved with detoxifying enzymes (Gstm3) and transforming growth factor-b signaling (bone morphogenetic protein 7 [Bmp7]). In terms of overlap, 20 genes and three pathways methylated during mouse lung development also demonstrated changes in methylation between preterm and term human lung. Changes in methylation correspond to altered expression of a number of genes associated with lung development, suggesting that DNA methylation of these genes may regulate normal and abnormal alveolar septation.Keywords: lung development; premature infant; epigenetics; bronchopulmonary dysplasia Clinical RelevanceDNA methylation is an important regulator of gene expression. Coordinated expression of multiple genes occurs at specific time points during alveolar septation in lung development. In this study, we identified multiple genes that are potentially regulated by DNA methylation during normal alveolar septation in the mouse and human lung, and in bronchopulmonary dysplasia compared to preterm or term lung.

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Section: Discussionmentioning

confidence: 99%

Alterations in Gene Expression and DNA Methylation during Murine and Human Lung Alveolar Septation

Cuna

Halloran

Faye-Petersen

et al. 2015

Am J Respir Cell Mol Biol

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“…However, some inhibition of bacterial effects was evident with 5% CSE in our experiments, even with increased cellular glutathione concentrations, suggesting that the effects of cigarette smoke may not be completely attributable to reactive oxygen species. Furthermore, polymorphisms in genes that control the glutathione and other antioxidant systems, as well as environmental factors, influence the capacity to detoxify cigarette smoke (51). Thus, significant individual variability likely occurs in the effects of cigarette smoke.…”

Section: Discussionmentioning

confidence: 99%

Inhibition by Cigarette Smoke of Nuclear Factor-κB–Dependent Response to Bacteria in the Airway

Manzel¹,

Shi²,

O’Shaughnessy³

et al. 2011

Am J Respir Cell Mol Biol

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Although individuals exposed to cigarette smoke are more susceptible to respiratory infection, the effects of cigarette smoke on pulmonary defense are incompletely understood. Based on the observation that interactions between bacteria and host cells result in the expression of critical defense genes regulated by NF-kB, we hypothesized that cigarette smoke alters NF-kB function. In this study, primary human tracheobronchial epithelial cells were treated with cigarette smoke extract (CSE) and exposed to Haemophilus influenzae, and the effects of CSE on bacteria-induced signaling and gene expression were assessed. CSE inhibited high concentrations of induced NF-kB activation and the consequent expression of defense genes that occurred in airway epithelial cells in response to H. influenzae. This decreased activation of NF-kB was not attributable to cell loss or cytotoxicity. Glutathione augmentation of epithelial cells decreased the effects of CSE on NF-kB-dependent responses, as well as the effects on the inhibitor of kB and the inhibitor of kB kinase, which are upstream NF-kB regulators, suggesting the involvement of reactive oxygen species. The relevance of these findings for lung infection was confirmed using a mouse model of H. influenzae airway infection, in which decreased NF-kB pathway activation, keratinocyte chemoattractant (KC) chemokine expression, and neutrophil recruitment occurred in animals exposed to cigarette smoke. The results indicate that although cigarette smoke can cause inflammation in the lung, exposure to smoke inhibits the robust pulmonary defense response to H. influenzae, thereby providing one explanation for the increased susceptibility to respiratory bacterial infection in individuals exposed to cigarette smoke.

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“…Notably, several common polymorphisms are linked in terms of sensitivity of offspring to maternal smoking. In particular, common deletions or structural polymorphisms in the glutathione transferase genes, which play a key role in antioxidant defenses, increase both the risk of asthma and sensitivity of the fetus to maternal smoking (45,46). Similarly, the common structural polymorphism of the a 5 nicotinic receptor, in which residue 398 is mutated from an Asp to an Asn (rs16969968), increases nicotine addiction, makes quitting more difficult, and increases the risk of lung cancer and chronic obstructive pulmonary disease (26,47).…”

Section: Genetic Influences On Likelihood Of Smoking During Pregnancymentioning

confidence: 99%

The Role of Nicotine in the Effects of Maternal Smoking during Pregnancy on Lung Development and Childhood Respiratory Disease. Implications for Dangers of E-Cigarettes

Spindel

McEvoy

2016

Am J Respir Crit Care Med

134

107

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Use of e-cigarettes, especially among the young, is increasing at nearexponential rates. This is coupled with a perception that e-cigarettes are safe and with unlimited advertising geared toward vulnerable populations, the groups most likely to smoke or vape during pregnancy. There is now wide appreciation of the dangers of maternal smoking during pregnancy and the lifelong consequences this has on offspring lung function, including the increased risk of childhood wheezing and subsequent asthma. Recent evidence strongly supports that much of the effect of smoking during pregnancy on offspring lung function is mediated by nicotine, making it highly likely that e-cigarette use during pregnancy will have the same harmful effects on offspring lung function and health as do conventional cigarettes. In fact, the evidence for nicotine being the mediator of harm of conventional cigarettes may be most compelling for its effects on lung development. This raises concerns about both the combined use of e-cigarettes plus conventional cigarettes by smokers during pregnancy as well as the use of e-cigarettes by e-cigarette-only users who think them safe or by those sufficiently addicted to nicotine to not be able to quit e-cigarette usage during pregnancy. Thus, it is important for health professionals to be aware of the risks of e-cigarette usage during pregnancy, particularly as it pertains to offspring respiratory health.

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Variation in the GST mu Locus and Tobacco Smoke Exposure as Determinants of Childhood Lung Function

Cited by 34 publications

References 44 publications

Alterations in Gene Expression and DNA Methylation during Murine and Human Lung Alveolar Septation

Alterations in Gene Expression and DNA Methylation during Murine and Human Lung Alveolar Septation

Inhibition by Cigarette Smoke of Nuclear Factor-κB–Dependent Response to Bacteria in the Airway

The Role of Nicotine in the Effects of Maternal Smoking during Pregnancy on Lung Development and Childhood Respiratory Disease. Implications for Dangers of E-Cigarettes

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