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Altered Gene Expression Patterns in MCF-7 Cells Induced by the Urban Dust Particulate Complex Mixture Standard Reference Material 1649a

¹ Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon and ² Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, CDC, Morgantown, West Virginia

Requests for reprints: William M. Baird, Department of Environmental and Molecular Toxicology, Oregon State University, 1007 Agricultural and Life Sciences, Corvallis, OR. Phone: 541-737-1886; Fax: 541-737-0497; E-mail: william.baird{at}orst.edu.

Human exposures to polycyclic aromatic hydrocarbon (PAH) occur in complex mixtures. Here, gene expression patterns were investigated using standard reference material (SRM) 1649a (urban dust). MCF-7 cells were exposed to SRM 1649a alone or SRM 1649a with either benzo[a]pyrene (BP) or dibenzo[a,l]pyrene (DBP) for 24 hours. Global analyses of the gene expression data revealed alterations of 41 RNA transcripts with at least 2-fold change (signal log ratio –1 or 1) in response to SRM 1649a exposure. Increase in expression of cytochrome P450 (CYP) genes was observed in response to BP exposure (CYP1A1 and CYP1B1; signal log ratio of 4.7 and 2.5, respectively). An additive induction of CYP1A1 and CYP1B1 was observed with cotreatment of SRM 1649a and BP. On the contrary, no change in gene expression of CYP1A1 and CYP1B1 was observed when the cells were exposed to DBP. Furthermore, to study the effect of complex PAH mixtures on the metabolic activation of carcinogenic PAH to DNA-binding derivatives and to relate this with gene expression studies, PAH-DNA adduct formation was determined. SRM 1649a decreased the total level of BP-DNA adducts in comparison with BP alone. No significant difference in adduct levels was observed in response to either DBP alone or in combination with SRM 1649a. These results provide a transcriptional signature for chemical carcinogen exposure; in addition, they suggest a major factor in carcinogenic activity of PAH within complex mixtures is their ability to promote or inhibit the activation of carcinogenic PAH by the induction of CYP enzymes.

Key Words: DNA adducts • cytochrome P450 • microarrays • PAH • complex mixture

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