Transcriptomic changes in the airway due to diesel engine exhaust exposure
Drizik, Eduard Iosifovich
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INTRODUCTION: Recent epidemiological studies have shown that Diesel Engine Exhaust (DEE) exposure is associated with lung cancer. Well recognized exposures, such as smoking, have long been known to cause lung cancer, and the mechanisms by which the disease occurs have been closely investigated. However, there is very little information regarding the mechanisms by which chronic DEE exposure leads to a disease outcome. It has also been shown that transcriptomic changes in the deeper portions of the airway may be detectable in the more proximal parts. The goal of this study was to assess transcriptomic alterations in the nasal epithelium of DEE exposed factory workers to better understand the physiologic effects of DEE and how chronic exposure may lead to disease. METHODS: Nasal epithelium brushings were obtained from 41 subjects who work in a factory with DEE exposure, and 38 comparable control subjects who work in factories without DEE exposure. The median Elemental Carbon (EC) levels of exposed individuals was 60.7g/m3, with a range of 17.2-105.4 g/m3, while the median of EC levels of unexposed controls was 10.87g/m3, with a range of 9.89-12.55g/m3. RNA was isolated from nasal epithelial cells, and profiled for gene expression using Affymetrix Human Gene 1.0ST microarray chips. Linear modeling was used to detect differential expression between DEE exposure and controls. Pathway enrichment in differentially expressed genes was assessed using EnrichR. GSEA provided comparisons between the genes known to be differentially expressed due to smoking, and the genes that were found in our data to be differentially expressed due to smoking or DEE. A linear modeling approach was further used to investigate the effects of the interaction between smoking status and DEE exposure, and boxplot analysis was used to explore the interaction effect. RESULTS: We found 225 genes whose expression is associated with DEE exposure at FDR q < 0.25, after adjusting for smoking status. Within this set of genes, we observed increased expression of genes involved in the oxidative stress response, cell cycle, and protein modification, as well as genes associated with the AhR pathway and the Nrf2-mediated xenobiotic metabolism response. Additionally, decreased expression of genes involved in transmembrane transport, such as CFTR and the solute carrier family genes was also found. Furthermore, we discovered 8 genes at FDR q < 0.25 that have altered expression due to the interaction of DEE and smoking status, suggesting a synergistic relationship between the effects of these exposures on some aspects of the physiological response. For these genes, the effects of DEE were generally more dramatic in never smokers. CONCLUSIONS: The transcriptomic alterations we identified may help provide insight into the underlying mechanisms of DEE carcinogenicity. The relationship between cigarette smoke exposure and DEE exposure may provide more information about how chronic DEE exposure leads to lung cancer and other respiratory diseases.