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.