Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7356, USA.
Chem Biol Interact. 2010 Mar 19;184(1-2):86-93. doi: 10.1016/j.cbi.2009.12.011. Epub 2009 Dec 21.
Toxicogenomic studies, including genome-wide analyses of susceptibility genes (genomics), gene expression (transcriptomics), protein expression (proteomics), and epigenetic modifications (epigenomics), of human populations exposed to benzene are crucial to understanding gene-environment interactions, providing the ability to develop biomarkers of exposure, early effect and susceptibility. Comprehensive analysis of these toxicogenomic and epigenomic profiles by bioinformatics in the context of phenotypic endpoints, comprises systems biology, which has the potential to comprehensively define the mechanisms by which benzene causes leukemia. We have applied this approach to a molecular epidemiology study of workers exposed to benzene. Hematotoxicity, a significant decrease in almost all blood cell counts, was identified as a phenotypic effect of benzene that occurred even below 1 ppm benzene exposure. We found a significant decrease in the formation of progenitor colonies arising from bone marrow stem cells with increasing benzene exposure, showing that progenitor cells are more sensitive to the effects of benzene than mature blood cells, likely leading to the observed hematotoxicity. Analysis of transcriptomics by microarray in the peripheral blood mononuclear cells of exposed workers, identified genes and pathways (apoptosis, immune response, and inflammatory response) altered at high (>10 ppm) and low (<1 ppm) benzene levels. Serum proteomics by SELDI-TOF-MS revealed proteins consistently down-regulated in exposed workers. Preliminary epigenomics data showed effects of benzene on the DNA methylation of specific genes. Genomic screens for candidate genes involved in susceptibility to benzene toxicity are being undertaken in yeast, with subsequent confirmation by RNAi in human cells, to expand upon the findings from candidate gene analyses. Data on these and future biomarkers will be used to populate a large toxicogenomics database, to which we will apply bioinformatic approaches to understand the interactions among benzene toxicity, susceptibility genes, mRNA, and DNA methylation through a systems biology approach.
毒理基因组学研究，包括对暴露于苯的人类群体的易感基因（基因组学）、基因表达（转录组学）、蛋白质表达（蛋白质组学）和表观遗传修饰（表观基因组学）进行全基因组分析，对于理解基因-环境相互作用至关重要，为暴露、早期效应和易感性的生物标志物的开发提供了可能。在表型终点的背景下，通过生物信息学对这些毒理基因组学和表观基因组学图谱进行综合分析，构成了系统生物学，它有可能全面定义苯引起白血病的机制。我们已经将这种方法应用于一项对接触苯的工人进行的分子流行病学研究。血液毒性，即几乎所有血细胞计数的显著下降，被确定为苯的表型效应，即使在 1ppm 以下的苯暴露下也会发生。我们发现，随着苯暴露的增加，源自骨髓干细胞的祖细胞集落的形成显著减少，表明祖细胞对苯的作用比成熟血细胞更为敏感，可能导致了观察到的血液毒性。对暴露工人外周血单个核细胞进行的转录组学微阵列分析，确定了在高（>10ppm）和低（<1ppm）苯水平下改变的基因和途径（细胞凋亡、免疫反应和炎症反应）。SELDI-TOF-MS 血清蛋白质组学揭示了暴露工人中一致下调的蛋白质。初步的表观基因组学数据显示，苯对特定基因的 DNA 甲基化有影响。正在酵母中进行涉及苯毒性易感性的候选基因的基因组筛选，随后在人细胞中通过 RNAi 进行确认，以扩展候选基因分析的结果。这些和未来生物标志物的数据将用于填充一个大型毒理基因组学数据库，我们将应用生物信息学方法通过系统生物学方法来理解苯毒性、易感性基因、mRNA 和 DNA 甲基化之间的相互作用。
