Mahadevan Brinda, Keshava Channa, Musafia-Jeknic Tamara, Pecaj Arta, Weston Ainsley, Baird William M
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, USA.
Cancer Res. 2005 Feb 15;65(4):1251-8. doi: 10.1158/0008-5472.CAN-04-2357.
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.
人类接触多环芳烃（PAH）是在复杂混合物中发生的。在此，使用标准参考物质（SRM）1649a（城市灰尘）研究基因表达模式。MCF-7细胞单独暴露于SRM 1649a或与苯并[a]芘（BP）或二苯并[a,l]芘（DBP）一起的SRM 1649a中24小时。对基因表达数据的整体分析显示，响应于SRM 1649a暴露，有41个RNA转录本发生改变且变化至少2倍（信号对数比≤ -1或≥ 1）。响应于BP暴露观察到细胞色素P450（CYP）基因表达增加（CYP1A1和CYP1B1；信号对数比分别为4.7和2.5）。当SRM 1649a和BP共同处理时，观察到CYP1A1和CYP1B1的加性诱导。相反，当细胞暴露于DBP时，未观察到CYP1A1和CYP1B1基因表达的变化。此外，为了研究复杂PAH混合物对致癌PAH代谢活化为DNA结合衍生物的影响，并将此与基因表达研究相关联，测定了PAH-DNA加合物的形成。与单独的BP相比，SRM 1649a降低了BP-DNA加合物的总水平。单独使用DBP或与SRM 1649a联合使用时，在加合物水平上未观察到显著差异。这些结果提供了化学致癌物暴露的转录特征；此外，它们表明复杂混合物中PAH致癌活性的一个主要因素是其通过诱导CYP酶促进或抑制致癌PAH活化的能力。
