494. GENOMIC BIOMARKERS OF PULMONARY EXPOSURE TO TOBACCO SMOKE COMPONENTS.

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Sexton, K., Balharry, D., and BéruBé, K.A. Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, UK. Pharmacogenetics and Genomics, 18, 853-860, (2008).

Summary:
This study by researchers at the Cardiff University School of Biosciences demonstrated that MatTek's EpiAirway in vitro human tracheal/bronchial tissue equivalent can be used to accurately model the genetic effects of tobacco smoke component exposure on human respiratory epithelium.

Background:
Associations between smoking and the development of tobacco-related diseases in humans have historically been assessed by epidemiological studies. These studies are further complicated by the number of chemicals used in tobacco and individual smoking habits.

An alternative approach is required to assess the biological responses.

Objective:
Toxicogenomics was carried out to identify early molecular markers for events in pulmonary injury resulting from tobacco smoke components (TSC) exposure.

Materials and methods:
EpiAirway-100 cells were exposed at the air/liquid interface to representative particle (nicotine; cadmium) and vapour phase [formaldehyde (FA) and ethyl carbamate] components of cigarette smoke. Microarray technology was used to compare expression profiles of human genes associated with toxicity and drug resistance, from control and tobacco smoke component-treated respiratory epithelium (n= 5/dose).

Results:
Using the GEArray toxicology and drug resistance microarray followed by significance analysis of microarray analysis, 42 mRNA transcripts were found to be significantly altered by the TSC exposure. The vapour [ethyl carbamate, FA and particle (nicotine, cadmium)] phase tobacco smoke components exhibited differential transcriptional responses that could not be attributed to their chemical phase. The transcriptional changes could be classified according to a functional family, where ethyl carbamate, FA and cadmium classified as carcinogens, demonstrated the highest gene homology when compared with the noncarcinogen nicotine.

Discussion:
Analysis of the microarray data and further confirmation (reverse transcriptase-PCR) identified three potential biomarkers for tobacco smoke component-induced injury. These three genes (CYP7A1, HMOX1 and PTGS1) are highly upregulated and have been linked with mechanistic pathways of disease.

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Applications: Airway research, Apoptosis, Biomarker research, Genomics, Metabolism - drug, Microarray analysis, Smoking/Tobacco research, Toxicogenomics

Keywords: Apoptosis, Biomarker, Biomarkers, CTP synthase, Caspase 10, Cell cycle, Colony stimulating factor 2 (granulocyte-macrophage), Crystallin, Cyclin D1, Cytochrome P450, Differential gene expression, Drug metabolism, Epi-Airway-100, EpiAirway, Epidermal growth factor receptor, Gene expression, Heme oxygenase, Hypoxia-inducible factor 1, Microarray profiles, Nicotinamide N-methyltransferase, Perioxisome proliferative activated receptor ƒÔ, Prostaglandin-endoperoxide synthase, Stress response, Sulfotransferase family, Sulfotransferases, Thiopurine S-methyltransferase, Tobacco smoke, Tobacco smoke component, Topoisomerase (DNA I, Transcription factors, Transporters, Xanthine dehydrogenase

Materials Tested: Cadmium, Ethyl carbamate, Formaldehyde, Nicotine

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