title: Classification of polycyclic aromatic hydrocarbons based on mutagenicity in lung tissue through DNA microarray.
abstract: Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants produced in the combustion of organic matter. Exposure to PAHs raises the risk of lung cancer and inflammatory and allergic disorders such as asthma. DNA microarray technologies have been applied to research on toxicogenomics in the recent years. To evaluate the mutagenicity of PAHs and constituents of environmental pollutants in lung tissue, including metabolic activation, human alveolar epithelial type II cells (A549) were treated with nonmutagenic PAH pyrene and with the mutagenic PAHs benzo-[a]-pyrene, 1-nitropyrene, or 1,8-dinitropyrene. Comparison of genome-wide microarray expression profiles between a nonmutagenic and a mutagenic PAH-treated group revealed that xenobiotic response genes such as CYP1B1 were commonly upregulated in two groups and that DNA damage induced genes, especially p53-downstream genes such as p21 (CDKN1A) were upregulated only in the mutagenic PAH-treated group. Pretreatment with cytochrome P450 inhibitor α-naphthoflavone or p53 inhibitor pifithrin-α inhibited the benzo-[a]-pyrene-induced p21 expression. These data suggest that when PAHs enter the cells, lung epithelium induces PAH metabolic activating enzymes, and then the DNA damages-recognition signal is converged with p53 downstream genes. This metabolic activation and DNA damage is induced in lung epithelium, and the mutagenicity of PAHs can be classified by DNA microarray expression profiles.
authors: Toyota Central R&D Labs., Inc., Nagakute, Aichi 480-1192, Japan.
authors: Minoru
authors: M
authors: Hirano
authors: Shiho
authors: S
authors: Tanaka
authors: Osamu
authors: O
authors: Asami
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics; D001571:Benzoflavones / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D002460:Cell Line; D004249:DNA Damage; D004785:Environmental Pollutants / Q000145:classification / Q000633:toxicity*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D016158:Genes, p53; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009152:Mutagenicity Tests; D020411:Oligonucleotide Array Sequence Analysis; D011084:Polycyclic Aromatic Hydrocarbons / Q000145:classification / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001571:Benzoflavones; D052160:Benzothiazoles; D004785:Environmental Pollutants; D011084:Polycyclic Aromatic Hydrocarbons; D014050:Toluene; C011512:alpha-naphthoflavone; C121565:pifithrin; D001189:Aryl Hydrocarbon Hydroxylases