Project 1: Biomarkers of Benzene Exposure and Leukemia Risk. Benzene is an important industrial chemical, a component of gasoline, and a prominent contaminant at Superfund sites. Although benzene is an undisputed cause of human leukemia, many important scientific and regulatory questions remain regarding the exposure-response relationship and mechanism of action. In particular, we plan to confirm our eariier finding that humans possess a second metabolic pathway that efficiently metabolizes benzene at low doses and determine whether enzymatic activity varies with gender and smoking status. We suspect that the enzymes CYP2F1 and CYP2A13 are responsible for the low dose metabolism of benzene. We will test this hypothesis and determine the effect of genetic variation in these enzymes on benzene metabolism and health effects among subjects with different levels of benzene exposure. The effect of variation in other candidate genes will also be explored using high-throughput genotyping, fine mapping and resequencing allowing us the better predict risks of leukemia require at low levels of benzene exposure in genetically susceptible populations. We will also develop biomarkers of early effect and historical exposure. We previously used microarrays to show that the blood mRNA transcriptome is exquisitely sensitive to low level occupational benzene exposure. Here we propose to develop a simple biomarker of -10 genes, altered in expression by benzene, which may serve as a biomarker of eariy effect for low level benzene exposure that could readily be used in a field setting such as a Superfund site. We will also measure changes in global and gene-specific DNA methylation and microRNA expression induced by benzene exposure in the blood cells of exposed workers. The goal is to determine if benzene can produce epigenetic changes of the type observed in leukemia, in addition to inducing chromosomal damage, thereby providing imporfant mechanistic insight. Furfher, we will compare the effects of benzene on gene-specific DNA methylation and microRNA expression with previously determined changes in gene expression. Finally, we will compare the DNA methylation profiles of blood cells from workers with current exposure to benzene with those with a past history of benzene exposure but with no current exposure and with control workers never exposed occupationally to benzene. This will allow us to search for epigenetic marks that might serve as a biomarker of historical exposure to benzene. The overall goal is to use biomarkers to improve the risk assessment of benzene at Superfund sites.
Benzene, an economically imporfant chemical to which we are all exposed is commonly found at Superfund sites and is an established cause of leukemia. We plan to gain furfher understanding ofthe mechanism of benzene-induced leukemia, the risks it poses at low levels and develop tests which can measure past exposure and sensitive effects on the blood. Results obtained frorri these studies should be of great use to public health regulatory agencies evaluating the risk posed by exposure to benzene.
|Counihan, Jessica L; Ford, Breanna; Nomura, Daniel K (2016) Mapping proteome-wide interactions of reactive chemicals using chemoproteomic platforms. Curr Opin Chem Biol 30:68-76|
|Shen, Hua; McHale, Cliona M; Haider, Syed I et al. (2016) Identification of Genes That Modulate Susceptibility to Formaldehyde and Imatinib by Functional Genomic Screening in Human Haploid KBM7 Cells. Toxicol Sci 154:194|
|Smith, Martyn T; Guyton, Kathryn Z; Gibbons, Catherine F et al. (2016) Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis. Environ Health Perspect 124:713-21|
|Hsu, Ling-I; Briggs, Farren; Shao, Xiaorong et al. (2016) Pathway Analysis of Genome-wide Association Study in Childhood Leukemia among Hispanics. Cancer Epidemiol Biomarkers Prev 25:815-22|
|Carlos-Wallace, Frolayne M; Zhang, Luoping; Smith, Martyn T et al. (2016) Parental, In Utero, and Early-Life Exposure to Benzene and the Risk of Childhood Leukemia: A Meta-Analysis. Am J Epidemiol 183:1-14|
|Liu, Haizhou; Bruton, Thomas A; Li, Wei et al. (2016) Oxidation of Benzene by Persulfate in the Presence of Fe(III)- and Mn(IV)-Containing Oxides: Stoichiometric Efficiency and Transformation Products. Environ Sci Technol 50:890-8|
|Barazesh, James M; Prasse, Carsten; Sedlak, David L (2016) Electrochemical Transformation of Trace Organic Contaminants in the Presence of Halide and Carbonate Ions. Environ Sci Technol 50:10143-52|
|Shen, Hua; McHale, Cliona M; Haider, Syed I et al. (2016) Identification of Genes That Modulate Susceptibility to Formaldehyde and Imatinib by Functional Genomic Screening in Human Haploid KBM7 Cells. Toxicol Sci 151:10-22|
|Hu, Xindi C; Andrews, David Q; Lindstrom, Andrew B et al. (2016) Detection of Poly- and Perfluoroalkyl Substances (PFASs) in U.S. Drinking Water Linked to Industrial Sites, Military Fire Training Areas, and Wastewater Treatment Plants. Environ Sci Technol Lett 3:344-350|
|Bailey, Kathryn A; Smith, Allan H; Tokar, Erik J et al. (2016) Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps. Environ Health Perspect 124:170-5|
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