Belitskaya-Levy Ilana, Hajjou Mustapha, Su Wei-cheng, Yie Ting-An, Tchou-Wong Kam-Meng, Tang Moon-shong, Goldberg Judith D, Rom William N
Division of Biostatistics, Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
J Environ Pathol Toxicol Oncol. 2007;26(4):281-94. doi: 10.1615/jenvironpatholtoxicoloncol.v26.i4.50.
Asbestos and benzo(a)pyrene diol epoxide (BPDE) are pulmonary carcinogens with synergistic interaction in causing lung cancer. We used Affymetrix microarrays to study gene modulation in vitro using normal human bronchial epithelial cells exposed to chrysotile asbestos and/or BPDE for 4 or 24 h. Linear models were used to compare treated cells to controls at each time point to identify statistically significant up- or downregulation of genes. Profiles of genes regulated by chrysotile were dominated by cytokines, growth factors, and DNA damage. Profiles of genes with BPDE and chrysotile regulation were correlated with proliferation, DNA damage recognition and nucleotide-excision repair, cytokines, and apoptosis. Chemokines, growth-regulated oncogene-alpha (Gro-alpha, CXCL-1), and IL-8, were significantly increased, and these had previously been observed in bronchoalveolar lavage from asbestos workers or in animal models. Interestingly, the Hermansky-Pudlak gene, which is mutated in an autosomal recessive form of pulmonary fibrosis, was downregulated threefold by BPDE at 4 h. This is an interesting example of gene (Hermansky-Pudlak syndrome) and environment (BPDE) interaction. Transcription factors, including activating transcription factor 3 and Cbp/p300-interacting transactivator, were upregulated by chrysotile. Real Time PCR for IL-8, ATF-3, GADD45B, CXC Ligand 1, and CTGF compared to GAPDH validated microarray findings at 24 h. These in vitro findings in NHBE cells model environment-gene interaction for asbestos and BPDE, highlighting effects of inflammation, fibrosis, proliferation, and DNA damage recognition and repair.
石棉和苯并(a)芘二醇环氧化物（BPDE）是肺部致癌物，在引发肺癌方面具有协同相互作用。我们使用Affymetrix微阵列，以暴露于温石棉和/或BPDE 4小时或24小时的正常人支气管上皮细胞为研究对象，在体外研究基因调控情况。采用线性模型在每个时间点将处理过的细胞与对照细胞进行比较，以确定基因在统计学上的显著上调或下调。由温石棉调控的基因谱以细胞因子、生长因子和DNA损伤为主。受BPDE和温石棉调控的基因谱与增殖、DNA损伤识别和核苷酸切除修复、细胞因子及细胞凋亡相关。趋化因子、生长调节致癌基因-α（Gro-α，CXCL-1）和白细胞介素-8显著增加，这些在石棉工人的支气管肺泡灌洗或动物模型中曾有观察到。有趣的是，在常染色体隐性形式的肺纤维化中发生突变的Hermansky-Pudlak基因，在4小时时被BPDE下调了三倍。这是基因（Hermansky-Pudlak综合征）与环境（BPDE）相互作用的一个有趣例子。包括激活转录因子3和Cbp/p300相互作用反式激活因子在内的转录因子，被温石棉上调。与甘油醛-3-磷酸脱氢酶（GAPDH）相比，对白细胞介素-8、激活转录因子3、生长停滞和DNA损伤诱导蛋白45β（GADD45B）、CXC趋化因子配体1和结缔组织生长因子（CTGF）进行实时聚合酶链反应，验证了24小时时的微阵列结果。在正常人支气管上皮细胞中的这些体外研究结果模拟了石棉和BPDE的环境-基因相互作用，突出了炎症、纤维化、增殖以及DNA损伤识别和修复的影响。
