Laser-based flow cytometric analysis of genotoxicity of humans exposed to ionizing radiation during the Chernobyl accident

Jensen, Ronald H.; Bigbee, William L.; Langlois, Richard G.; Grant, Stephen G.; Pleshanov, Pavel; Chirkov, A.A.; Pilinskaya, M.

doi:10.1117/12.57307

Cited by 8 publications

(6 citation statements)

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“…Elevated frequencies at the GPA locus have been found in subjects exposed to ionizing radiation (31)(32)(33), in patients receiving anti-neoplastic drugs (34)(35)(36), and in people with cancer-prone syndromes (37)(38)(39)). An excess of both N0 and NN variants was found in patients with Bloom syndrome (with NN variants higher than N0) (37) and Fanconi anemia (39).…”

Section: Discussionmentioning

confidence: 99%

Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans.

Rothman

Haas

Hayes

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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Occupational exposure to benzene is known to cause leukemia, but the mechanism remains unclear. Unlike most other carcinogens, benzene and its metabolites are weakly or nonmutagenic in most simple gene mutation assays. Benzene and its metabolites do, however, produce chromosomal damage in a variety of systems. Here, we have used the glycophorin A (GPA) gene loss mutation assay to evaluate the nature of DNA damage produced by benzene in 24 workers heavily exposed to benzene and 23 matched control individuals in Shanghai, China. The GPA assay identifies stem cell or precursor erythroid cell mutations expressed in peripheral erythrocytes of MN-heterozygous subjects, distinguishing the NN and N0 mutant variants. A significant increase in the NN GPA variant cell frequency (Vf) was found in benzene-exposed workers as compared with unexposed control individuals (mean ± SEM, 13.9 ± 1.7 per million cells vs. 7.4 + 1.1 per million cells in control individuals; P = 0.0002). In contrast, no significant difference existed between the two groups for the N0 Vf (9.1 + 0.9 vs. 8.8 + 1.8 per million cells; P = 0.21). Further, lifetime cumulative occupational exposure to benzene was associated with the NN Vf (P = 0.005) but not with the N0 Vf (P = 0.31), suggesting that NN mutations occur in longer-lived bone marrow stem cells. NN variants result from loss of the GPA M allele and duplication of the N allele, presumably through recombination mechanisms, whereas N0 variants arise from gene inactivation, presumably due to point mutations and deletions. Thus, these results suggest that benzene produces gene-duplicating mutations but does not produce gene-inactivating mutations at the GPA locus in bone marrow cells of humans exposed to high benzene levels. This finding is consistent with data on the genetic toxicology of benzene and its metabolites and adds further weight to the hypothesis that chromosome damage and mitotic recombination are important in benzene-induced leukemia.

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Section: Discussionmentioning

confidence: 99%

Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans.

Rothman

Haas

Hayes

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the increased frequency of hprt mutants also demonstrates the long life of some mutant T-cells in vivo. An increase in the frequency of Hb, gpa, and hprt variants has been reported in individuals exposed to radiation as a result of accidental environmental contamination (6,24,(48)(49)(50).…”

Section: Induced Variant/mutant Frequenciesmentioning

confidence: 99%

“…Hprt and HLA mutations arising in vivo in T-lymphocytes may be analyzed at the molecular level using techniques such as direct Southern blotting or genomic polymerase chain reaction (PCR) amplification to define major structural alterations and the direct PCR of cDNA and sequencing to characterize point mutations (62-64). In T (45,46) NT T (15,47) Radiation accidents t 6T (48,49) T (24,50) NT Radionuclide NT NT NT 1 (51) angiography -(52) Radon (household) NT NT NT 1 (55) Abbreviations: RBC, red blood cells; Hb, hemoglobin; GPA, glycophorin-A; HPRT, hypoxanthine-guanine phosphoribosyltransferase; NT, not tested;…”

Section: Molecular Analyses Of In Vivo Somatic Mutations In Humansmentioning

confidence: 99%

Somatic cell gene mutations in humans: biomarkers for genotoxicity.

Albertini

Nicklas

O’Neill

1993

Environ Health Perspect

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Somatic cell gene mutations arising in vivo in humans provide biomarkers for genotoxicity. Four assays, each measuring changes in a different "recorder" gene, are available for detecting mutations of the hemoglobin (Hb) and glycophorin A (gpa) genes in red blood cells and the hypoxanthine-guanine phosphoribosyltransferase (hprt) and HLA genes in T-lymphocytes. Mean adult background mutant frequencies have been established; i.e., approximately 4 x 10(-8) (Hb), 5-10 x 10(-6) (hprt), 10-20 x 10(-6) (gpa) and 30 x 10(-6) (HLA). All the assays have now been used in studies of individuals exposed to physical and/or chemical genotoxic agents, and all have shown elevated values following exposures; examples are presented. In addition to quantitation, the lymphocyte assays allow molecular analyses of in vivo mutations, the definition of background and induced mutational spectra, and the search for unique changes for characterizing specific mutagens. The HPRT system currently has the largest database in this regard. Approximately 15% of adult background hprt mutations are due to gross structural alterations (primarily deletions) having random breakpoints; 85% result from "point" changes detected only by sequencing. In contrast, a specific intragenic deletion due to DNA cleavage at specific sites characterizes fetal hprt mutations, implicating a developmental mistake in their genesis. (This kind of developmental mistake in other genes is frequently observed in lymphoid malignancies.) Mutational spectra are just beginning to be defined for induced hprt mutations, e.g., ionizing radiation produces large deletions.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…The GPA assay was proposed to provide an evaluation of the life-span cumulative exposure for humans, because it detects mutations preserved at the level of red blood stem cells during the lifetime of an individual. GPA variants were found to be at significantly increased frequency among Hiroshima A-bomb survivors; the assay was tentatively used as a biodosimeter of cumulative exposure after the fall-out in the Chernobyl nuclear power center [2,5,9,16,18,26]. The GPA assay by FCM was also used for monitoring the genotoxic load in cancer patients who underwent radio-or chemotherapy [4,12,15,22,24,27], in workers exposed to styrene [6,10] and, in association with DNA adducts, for foundry workers exposed to polycyclic aromatic hydrocarbons [25].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Erythrocyte Glycophorin‐A Variants by Flow Cytometry in Lung Disease Patients Detects the Effect of Tobacco Smoke

Neri

Geido²,

Filiberti

et al. 2000

Analytical Cellular Pathology

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The glycophoryn A (GPA) assay evaluates somatic in vivo mutations. It is considered a cumulative biodosimeter for genotoxic exposures and is under evaluation in cancer risk assessment.GPA, a polymorphic membrane protein of the erythrocytes, determines the MN blood groups. The N0 and NN variant frequencies (VF) may be detected in MN subjects (about 50% of the population) by flow cytometry using two differently labelled antibodies.We explored if GPA N0 and NN VF might be relevant to the assessment of individual lung cancer risk and susceptibility, in a small population with a high prevalence of heavy tobacco smokers: 8 lung cancer patients and 16 subjects with non‐malignant lung diseases associated with increased risk of lung cancer.There was a wide interindividual variability and complete overlap between non‐neoplastic and neoplastic patients. A significant positive correlation was seen with smoking duration in N0 VF (p=0.04, age‐adjusted). Current smokers (n=12) displayed higher N0 values than never (n=1) or ex‐smokers (n=11), 36.3±18.2 and 21.0±13.2, respectively (p < 0:01). No association was shown with occupational exposure.The present exploratory study suggests that assessment of individual lung cancer risk and susceptibility by the GPA assay does not seem to be feasible. The assay appears to provide a biomarker of longterm exposure to tobacco smoke.

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Laser-based flow cytometric analysis of genotoxicity of humans exposed to ionizing radiation during the Chernobyl accident

Cited by 8 publications

References 0 publications

Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans.

Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans.

Somatic cell gene mutations in humans: biomarkers for genotoxicity.

Analysis of Erythrocyte Glycophorin‐A Variants by Flow Cytometry in Lung Disease Patients Detects the Effect of Tobacco Smoke

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