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Leukemia-related chromosomal loss detected in hematopoietic progenitor cells of benzene-exposed workers.

Zhang L, Lan Q, Ji Z, Li G, Shen M, Vermeulen R, Guo W, Hubbard AE, McHale CM, Rappaport SM, Hayes RB, Linet MS, Yin S, Smith MT, Rothman N - Leukemia (2012)

Bottom Line: We measured loss and gain of chromosomes 7 and 8 by fluorescence in situ hybridization in interphase colony-forming unit-granulocyte-macrophage (CFU-GM) cells cultured from otherwise healthy benzene-exposed (n=28) and unexposed (n=14) workers.CFU-GM monosomy 7 and 8 levels (but not trisomy) were significantly increased in subjects exposed to benzene overall, compared with levels in the control subjects (P=0.0055 and P=0.0034, respectively).Levels of monosomy 7 and 8 were significantly increased in subjects exposed to <10 p.p.m. (20%, P=0.0419 and 28%, P=0.0056, respectively) and ≥ 10 p.p.m. (48%, P=0.0045 and 32%, 0.0354) benzene, compared with controls, and significant exposure-response trends were detected (P(trend)=0.0033 and 0.0057).

View Article: PubMed Central - PubMed

Affiliation: School of Public Health, Division of Environmental Health Sciences, University of California, Berkeley, CA, USA.

ABSTRACT
Benzene exposure causes acute myeloid leukemia and hematotoxicity, shown as suppression of mature blood and myeloid progenitor cell numbers. As the leukemia-related aneuploidies monosomy 7 and trisomy 8 previously had been detected in the mature peripheral blood cells of exposed workers, we hypothesized that benzene could cause leukemia through the induction of these aneuploidies in hematopoietic stem and progenitor cells. We measured loss and gain of chromosomes 7 and 8 by fluorescence in situ hybridization in interphase colony-forming unit-granulocyte-macrophage (CFU-GM) cells cultured from otherwise healthy benzene-exposed (n=28) and unexposed (n=14) workers. CFU-GM monosomy 7 and 8 levels (but not trisomy) were significantly increased in subjects exposed to benzene overall, compared with levels in the control subjects (P=0.0055 and P=0.0034, respectively). Levels of monosomy 7 and 8 were significantly increased in subjects exposed to <10 p.p.m. (20%, P=0.0419 and 28%, P=0.0056, respectively) and ≥ 10 p.p.m. (48%, P=0.0045 and 32%, 0.0354) benzene, compared with controls, and significant exposure-response trends were detected (P(trend)=0.0033 and 0.0057). These data show that monosomies 7 and 8 are produced in a dose-dependent manner in the blood progenitor cells of workers exposed to benzene, and may be mechanistically relevant biomarkers of early effect for benzene and other leukemogens.

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Related in: MedlinePlus

Linear vs non-linear models of monsosomy 7 and 8 versus benzene exposureObserved versus predicted monosomy 7 and 8 counts versus benzene exposure, determined using a cross-validation approach in linear and non-linear (completely unspecified smooths) models, are plotted. There is no significant difference in the relative fit of the models.
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Figure 2: Linear vs non-linear models of monsosomy 7 and 8 versus benzene exposureObserved versus predicted monosomy 7 and 8 counts versus benzene exposure, determined using a cross-validation approach in linear and non-linear (completely unspecified smooths) models, are plotted. There is no significant difference in the relative fit of the models.

Mentions: We used a cross-validation procedure (10-fold) to examine whether there was a significant departure from log-linearity in the dose-response. For each of the training samples, we estimated two models of continuous benzene exposure versus mean monosomy rate: a linear model and a completely unspecified smooth model (generalized additive model; GAM21). For each training sample, we predicted on the corresponding validation sample, so that we derived an unbiased estimate of the fit of the two approaches. The models revealed nearly identical fits, with , for monosomy 7 and , for monosomy 8 (Figure 2). Though the increase in flexibility of these models reduced the bias of a smaller model, it resulted in added variance. These data do not provide any evidence of a departure from a log-linear dose-response in monosomy 7 and 8 versus benzene exposure. Thus, increasing exposure to benzene appears to induce monosomy 7 and 8 in a linear fashion.


Leukemia-related chromosomal loss detected in hematopoietic progenitor cells of benzene-exposed workers.

Zhang L, Lan Q, Ji Z, Li G, Shen M, Vermeulen R, Guo W, Hubbard AE, McHale CM, Rappaport SM, Hayes RB, Linet MS, Yin S, Smith MT, Rothman N - Leukemia (2012)

Linear vs non-linear models of monsosomy 7 and 8 versus benzene exposureObserved versus predicted monosomy 7 and 8 counts versus benzene exposure, determined using a cross-validation approach in linear and non-linear (completely unspecified smooths) models, are plotted. There is no significant difference in the relative fit of the models.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3472034&req=5

Figure 2: Linear vs non-linear models of monsosomy 7 and 8 versus benzene exposureObserved versus predicted monosomy 7 and 8 counts versus benzene exposure, determined using a cross-validation approach in linear and non-linear (completely unspecified smooths) models, are plotted. There is no significant difference in the relative fit of the models.
Mentions: We used a cross-validation procedure (10-fold) to examine whether there was a significant departure from log-linearity in the dose-response. For each of the training samples, we estimated two models of continuous benzene exposure versus mean monosomy rate: a linear model and a completely unspecified smooth model (generalized additive model; GAM21). For each training sample, we predicted on the corresponding validation sample, so that we derived an unbiased estimate of the fit of the two approaches. The models revealed nearly identical fits, with , for monosomy 7 and , for monosomy 8 (Figure 2). Though the increase in flexibility of these models reduced the bias of a smaller model, it resulted in added variance. These data do not provide any evidence of a departure from a log-linear dose-response in monosomy 7 and 8 versus benzene exposure. Thus, increasing exposure to benzene appears to induce monosomy 7 and 8 in a linear fashion.

Bottom Line: We measured loss and gain of chromosomes 7 and 8 by fluorescence in situ hybridization in interphase colony-forming unit-granulocyte-macrophage (CFU-GM) cells cultured from otherwise healthy benzene-exposed (n=28) and unexposed (n=14) workers.CFU-GM monosomy 7 and 8 levels (but not trisomy) were significantly increased in subjects exposed to benzene overall, compared with levels in the control subjects (P=0.0055 and P=0.0034, respectively).Levels of monosomy 7 and 8 were significantly increased in subjects exposed to <10 p.p.m. (20%, P=0.0419 and 28%, P=0.0056, respectively) and ≥ 10 p.p.m. (48%, P=0.0045 and 32%, 0.0354) benzene, compared with controls, and significant exposure-response trends were detected (P(trend)=0.0033 and 0.0057).

View Article: PubMed Central - PubMed

Affiliation: School of Public Health, Division of Environmental Health Sciences, University of California, Berkeley, CA, USA.

ABSTRACT
Benzene exposure causes acute myeloid leukemia and hematotoxicity, shown as suppression of mature blood and myeloid progenitor cell numbers. As the leukemia-related aneuploidies monosomy 7 and trisomy 8 previously had been detected in the mature peripheral blood cells of exposed workers, we hypothesized that benzene could cause leukemia through the induction of these aneuploidies in hematopoietic stem and progenitor cells. We measured loss and gain of chromosomes 7 and 8 by fluorescence in situ hybridization in interphase colony-forming unit-granulocyte-macrophage (CFU-GM) cells cultured from otherwise healthy benzene-exposed (n=28) and unexposed (n=14) workers. CFU-GM monosomy 7 and 8 levels (but not trisomy) were significantly increased in subjects exposed to benzene overall, compared with levels in the control subjects (P=0.0055 and P=0.0034, respectively). Levels of monosomy 7 and 8 were significantly increased in subjects exposed to <10 p.p.m. (20%, P=0.0419 and 28%, P=0.0056, respectively) and ≥ 10 p.p.m. (48%, P=0.0045 and 32%, 0.0354) benzene, compared with controls, and significant exposure-response trends were detected (P(trend)=0.0033 and 0.0057). These data show that monosomies 7 and 8 are produced in a dose-dependent manner in the blood progenitor cells of workers exposed to benzene, and may be mechanistically relevant biomarkers of early effect for benzene and other leukemogens.

Show MeSH
Related in: MedlinePlus