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Global gene expression profiling of a population exposed to a range of benzene levels.

McHale CM, Zhang L, Lan Q, Vermeulen R, Li G, Hubbard AE, Porter KE, Thomas R, Portier CJ, Shen M, Rappaport SM, Yin S, Smith MT, Rothman N - Environ. Health Perspect. (2010)

Bottom Line: The goals of this study were to identify potential biomarkers of benzene exposure and/or early effects and to elucidate mechanisms relevant to risk of hematotoxicity, leukemia, and lymphoid malignancy in occupationally exposed individuals, many of whom were exposed to benzene levels < 1 ppm, the current U.S. occupational standard.Study design and analysis with a mixed-effects model minimized potential confounding and experimental variability.These findings expand our understanding of the mechanisms by which benzene may induce hematotoxicity, leukemia, and lymphoma and reveal relevant potential biomarkers associated with a range of exposures.

View Article: PubMed Central - PubMed

Affiliation: School of Public Health, University of California-Berkeley, Berkeley, California 64720, USA. cmchale@berkeley.edu

ABSTRACT

Background: Benzene, an established cause of acute myeloid leukemia (AML), may also cause one or more lymphoid malignancies in humans. Previously, we identified genes and pathways associated with exposure to high (> 10 ppm) levels of benzene through transcriptomic analyses of blood cells from a small number of occupationally exposed workers.

Objectives: The goals of this study were to identify potential biomarkers of benzene exposure and/or early effects and to elucidate mechanisms relevant to risk of hematotoxicity, leukemia, and lymphoid malignancy in occupationally exposed individuals, many of whom were exposed to benzene levels < 1 ppm, the current U.S. occupational standard.

Methods: We analyzed global gene expression in the peripheral blood mononuclear cells of 125 workers exposed to benzene levels ranging from < 1 ppm to > 10 ppm. Study design and analysis with a mixed-effects model minimized potential confounding and experimental variability.

Results: We observed highly significant widespread perturbation of gene expression at all exposure levels. The AML pathway was among the pathways most significantly associated with benzene exposure. Immune response pathways were associated with most exposure levels, potentially providing biological plausibility for an association between lymphoma and benzene exposure. We identified a 16-gene expression signature associated with all levels of benzene exposure.

Conclusions: Our findings suggest that chronic benzene exposure, even at levels below the current U.S. occupational standard, perturbs many genes, biological processes, and pathways. These findings expand our understanding of the mechanisms by which benzene may induce hematotoxicity, leukemia, and lymphoma and reveal relevant potential biomarkers associated with a range of exposures.

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Related in: MedlinePlus

Network interactions among biomarkers of benzene exposure associated with all exposure levels, illustrating a high degree of interrelatedness based on the literature, with central roles for IL1A and PTGS2. Pathway Studio software identified interactions among 10 of the 16 potential biomarkers of benzene exposure. The interactions are mainly expression, with some regulation (regulator changes the activity of the target) and one binding interaction. Red indicates up-regulation.
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f2-ehp-119-628: Network interactions among biomarkers of benzene exposure associated with all exposure levels, illustrating a high degree of interrelatedness based on the literature, with central roles for IL1A and PTGS2. Pathway Studio software identified interactions among 10 of the 16 potential biomarkers of benzene exposure. The interactions are mainly expression, with some regulation (regulator changes the activity of the target) and one binding interaction. Red indicates up-regulation.

Mentions: Twelve genes were up-regulated ≥ 1.5-fold at all four doses relative to unexposed controls, including five genes [PTX3 (pentraxin-related gene), CD44 (CD44 antigen), PTGS2 (prostaglandin-endoperoxide synthase 2), IL1A (interleukin 1, alpha), and SERPINB2 (serpin peptidase inhibitor, clade B, member 2) with FDR-adjusted p-values ≤ 0.005. An additional four genes were up-regulated > 1.5-fold at the top three doses, and > 1.3-fold at the lowest dose (Table 4). Expression of each of the 16 signature genes across the five exposure categories shows a distinct pattern, with the highest expression in the < 1-ppm (low) exposure group [see Supplemental Material, Figure 2 (doi:10.1289/ehp.1002546)]. The 16 genes are involved in immune response, inflammatory response, cell adhesion, cell–matrix adhesion, and blood coagulation (see Supplemental Material, Table 11). Ten of the 16 genes (or their products), 7 of which are involved in inflammatory response (p = 1.4E-12), form a network (Figure 2) with central roles for IL1A and PTGS2.


Global gene expression profiling of a population exposed to a range of benzene levels.

McHale CM, Zhang L, Lan Q, Vermeulen R, Li G, Hubbard AE, Porter KE, Thomas R, Portier CJ, Shen M, Rappaport SM, Yin S, Smith MT, Rothman N - Environ. Health Perspect. (2010)

Network interactions among biomarkers of benzene exposure associated with all exposure levels, illustrating a high degree of interrelatedness based on the literature, with central roles for IL1A and PTGS2. Pathway Studio software identified interactions among 10 of the 16 potential biomarkers of benzene exposure. The interactions are mainly expression, with some regulation (regulator changes the activity of the target) and one binding interaction. Red indicates up-regulation.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3094412&req=5

f2-ehp-119-628: Network interactions among biomarkers of benzene exposure associated with all exposure levels, illustrating a high degree of interrelatedness based on the literature, with central roles for IL1A and PTGS2. Pathway Studio software identified interactions among 10 of the 16 potential biomarkers of benzene exposure. The interactions are mainly expression, with some regulation (regulator changes the activity of the target) and one binding interaction. Red indicates up-regulation.
Mentions: Twelve genes were up-regulated ≥ 1.5-fold at all four doses relative to unexposed controls, including five genes [PTX3 (pentraxin-related gene), CD44 (CD44 antigen), PTGS2 (prostaglandin-endoperoxide synthase 2), IL1A (interleukin 1, alpha), and SERPINB2 (serpin peptidase inhibitor, clade B, member 2) with FDR-adjusted p-values ≤ 0.005. An additional four genes were up-regulated > 1.5-fold at the top three doses, and > 1.3-fold at the lowest dose (Table 4). Expression of each of the 16 signature genes across the five exposure categories shows a distinct pattern, with the highest expression in the < 1-ppm (low) exposure group [see Supplemental Material, Figure 2 (doi:10.1289/ehp.1002546)]. The 16 genes are involved in immune response, inflammatory response, cell adhesion, cell–matrix adhesion, and blood coagulation (see Supplemental Material, Table 11). Ten of the 16 genes (or their products), 7 of which are involved in inflammatory response (p = 1.4E-12), form a network (Figure 2) with central roles for IL1A and PTGS2.

Bottom Line: The goals of this study were to identify potential biomarkers of benzene exposure and/or early effects and to elucidate mechanisms relevant to risk of hematotoxicity, leukemia, and lymphoid malignancy in occupationally exposed individuals, many of whom were exposed to benzene levels < 1 ppm, the current U.S. occupational standard.Study design and analysis with a mixed-effects model minimized potential confounding and experimental variability.These findings expand our understanding of the mechanisms by which benzene may induce hematotoxicity, leukemia, and lymphoma and reveal relevant potential biomarkers associated with a range of exposures.

View Article: PubMed Central - PubMed

Affiliation: School of Public Health, University of California-Berkeley, Berkeley, California 64720, USA. cmchale@berkeley.edu

ABSTRACT

Background: Benzene, an established cause of acute myeloid leukemia (AML), may also cause one or more lymphoid malignancies in humans. Previously, we identified genes and pathways associated with exposure to high (> 10 ppm) levels of benzene through transcriptomic analyses of blood cells from a small number of occupationally exposed workers.

Objectives: The goals of this study were to identify potential biomarkers of benzene exposure and/or early effects and to elucidate mechanisms relevant to risk of hematotoxicity, leukemia, and lymphoid malignancy in occupationally exposed individuals, many of whom were exposed to benzene levels < 1 ppm, the current U.S. occupational standard.

Methods: We analyzed global gene expression in the peripheral blood mononuclear cells of 125 workers exposed to benzene levels ranging from < 1 ppm to > 10 ppm. Study design and analysis with a mixed-effects model minimized potential confounding and experimental variability.

Results: We observed highly significant widespread perturbation of gene expression at all exposure levels. The AML pathway was among the pathways most significantly associated with benzene exposure. Immune response pathways were associated with most exposure levels, potentially providing biological plausibility for an association between lymphoma and benzene exposure. We identified a 16-gene expression signature associated with all levels of benzene exposure.

Conclusions: Our findings suggest that chronic benzene exposure, even at levels below the current U.S. occupational standard, perturbs many genes, biological processes, and pathways. These findings expand our understanding of the mechanisms by which benzene may induce hematotoxicity, leukemia, and lymphoma and reveal relevant potential biomarkers associated with a range of exposures.

Show MeSH
Related in: MedlinePlus