TY - JOUR
T1 - Systems biology of human benzene exposure
AU - Zhang, Luoping
AU - McHale, Cliona M.
AU - Rothman, Nathaniel
AU - Li, Guilan
AU - Ji, Zhiying
AU - Vermeulen, Roel
AU - Hubbard, Alan E.
AU - Ren, Xuefeng
AU - Shen, Min
AU - Rappaport, Stephen M.
AU - North, Matthew
AU - Skibola, Christine F.
AU - Yin, Songnian
AU - Vulpe, Christopher
AU - Chanock, Stephen J.
AU - Smith, Martyn T.
AU - Lan, Qing
N1 - Funding Information:
We thank the participants for taking part in this study. We are extremely grateful to Heather Lustig and Kshama Mehta at Agilent Technologies, for facilitating the miRNA pilot study. We thank Ms. Suzanne May for her technical assistance with the DNA methylation analysis. We are grateful to Ms. Anh Duong for her tireless contribution and editorial assistance to this manuscript, and to Mr. Patrick Chang for his technical talent to illustrate the Systems Biology figure. This work was supported by NIH grants RO1ES06721 and P42ES04705 (MTS), P42ES05948 and P30ES10126 (SMR).
PY - 2010/3
Y1 - 2010/3
N2 - 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.
AB - 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.
KW - Benzene
KW - Epigenetics
KW - Hematotoxicity
KW - Human
KW - Systems biology
KW - Toxicogenomics
UR - http://www.scopus.com/inward/record.url?scp=77950627558&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77950627558&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2009.12.011
DO - 10.1016/j.cbi.2009.12.011
M3 - Review article
C2 - 20026094
AN - SCOPUS:77950627558
SN - 0009-2797
VL - 184
SP - 86
EP - 93
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
IS - 1-2
ER -