Chromosome Translocations and Cosmic Radiation Dose in Male U.S. Commercial Airline Pilots.

Background: Chromosome translocations are a biomarker of cumulative exposure to ionizing radiation. We examined the relation between the frequency of translocations and cosmic radiation dose in 83 male airline pilots.

Methods: Translocations were scored using fluorescence in situ hybridization chromosome painting.

Effects of low oxygen levels on G2-specific cytogenetic low-dose hyper-radiosensitivity in irradiated human cells.

Low-dose hyper-radiosensitivity (HRS) has been reported in normal human lymphoblastoid cell lines for exposures at ≤ 20 cGy, but the cytogenetic effects of oxygen (O2 ) levels in tissue culture medium on HRS have not been evaluated. We asked whether HRS was lost in G2-irradiated cells grown in atmospheres of 2.5% or 5% O2 , compared to responses by cells cultured in ambient O2 (21%).

Reflections on the development and application of FISH whole chromosome painting.

This review describes my personal reflections on the development of whole chromosome painting using fluorescence in situ hybridization and how my laboratory applied the technology in humans and in animal models. The trials and triumphs of the early years are emphasized, along with some of the scientific surprises that were encountered along the way. Scientific issues that my laboratory addressed using chromosome painting technologies are summarized and related to questions in radiation dosimetry, chemical clastogenesis, translocation persistence, and translocation frequencies in unexposed people.

Cytogenetic characterization of low-dose hyper-radiosensitivity in Cobalt-60 irradiated human lymphoblastoid cells.

The dose-effect relationships of cells exposed to ionizing radiation are frequently described by linear quadratic (LQ) models over an extended dose range. However, many mammalian cell lines, when acutely irradiated in G2 at doses ≤0.3Gy, show hyper-radiosensitivity (HRS) as measured by reduced clonogenic cell survival, thereby indicating greater cell lethality than is predicted by extrapolation from high-dose responses.

Cytogenetic low-dose hyperradiosensitivity is observed in human peripheral blood lymphocytes.

Purpose: The shape of the ionizing radiation response curve at very low doses has been the subject of considerable debate. Linear-no-threshold (LNT) models are widely used to estimate risks associated with low-dose exposures. However, the low-dose hyperradiosensitivity (HRS) phenomenon, in which cells are especially sensitive at low doses but then show increased radioresistance at higher doses, provides evidence of nonlinearity in the low-dose region.

Association of chromosome translocation rate with low dose occupational radiation exposures in U.S. radiologic technologists.

Chromosome translocations are a well-recognized biological marker of radiation exposure and cancer risk. However, there is uncertainty about the lowest dose at which excess translocations can be detected, and whether there is temporal decay of induced translocations in radiation-exposed populations. Dosimetric uncertainties can substantially alter the shape of dose-response relationships; although regression-calibration methods have been used in some datasets, these have not been applied in radio-occupational studies, where there are also complex patterns of shared and unshared errors that these methods do not account for.

Neutron exposures in human cells: bystander effect and relative biological effectiveness.

Bystander effects have been observed repeatedly in mammalian cells following photon and alpha particle irradiation. However, few studies have been performed to investigate bystander effects arising from neutron irradiation. Here we asked whether neutrons also induce a bystander effect in two normal human lymphoblastoid cell lines.

Differences in cytogenetic sensitivity to ionizing radiation in newborns and adults.

Radiation exposure causes DNA breaks leading to structural chromosome aberrations that can be carcinogenic. Lifetime cancer risks are elevated in irradiated children compared to similarly exposed adults. To determine the extent to which age influences the frequency and types of chromosome damage in response to ionizing radiation, peripheral blood samples were collected from 20 adults (aged 22-78 years) and from the umbilical cords of 10 newborns and acutely exposed to 0 (control), 1, 2, 3 or 4 Gy of cobalt-60 gamma rays.

Accurate gene expression-based biodosimetry using a minimal set of human gene transcripts.

Purpose: Rapid and reliable methods for conducting biological dosimetry are a necessity in the event of a large-scale nuclear event. Conventional biodosimetry methods lack the speed, portability, ease of use, and low cost required for triaging numerous victims. Here we address this need by showing that polymerase chain reaction (PCR) on a small number of gene transcripts can provide accurate and rapid dosimetry.

Gene expression-based dosimetry by dose and time in mice following acute radiation exposure.

Rapid and reliable methods for performing biological dosimetry are of paramount importance in the event of a large-scale nuclear event. Traditional dosimetry approaches lack the requisite rapid assessment capability, ease of use, portability and low cost, which are factors needed for triaging a large number of victims. Here we describe the results of experiments in which mice were acutely exposed to (60)Co gamma rays at doses of 0 (control) to 10 Gy.

Long-term exposure to depleted uranium in Gulf-War veterans does not induce chromosome aberrations in peripheral blood lymphocytes.

Depleted uranium (DU) is a high-density heavy metal that has been used in munitions since the 1991 Gulf War. DU is weakly radioactive and chemically toxic, and long-term exposure may cause adverse health effects. This study evaluates genotoxic effects of exposure to DU by measuring chromosome damage in peripheral blood lymphocytes with fluorescence in situ hybridization whole-chromosome painting.

Estimating the lowest detectable dose of ionizing radiation by the cytokinesis-block micronucleus assay.

The frequency of binucleated cells containing one or more micronuclei (MNBN cells) in cytokinesis-blocked peripheral blood lymphocytes can be used to determine whether a person has received an overexposure to ionizing radiation. However, the absence of a pre-exposure sample can preclude precise dosimetry. Here we use a database of MNBN cell frequencies in peripheral blood lymphocytes from 3,104 apparently healthy, unexposed, control subjects aged birth to 88 years, contributed by laboratories participating in the HUMN project.

Relationships among micronuclei, nucleoplasmic bridges and nuclear buds within individual cells in the cytokinesis-block micronucleus assay.

Micronuclei have been used extensively in studies as an easily evaluated indicator of DNA damage but little is known about their association with other types of damage such as nucleoplasmic bridges and nuclear buds. Here, radiation-induced clastogenic events were evaluated via the cytokinesis-block micronucleus assay in two normal human lymphoblastoid cell lines exposed to neutrons or γ-radiation. DNA damage induced by the chemical agents mitomycin C and phleomycin was also evaluated in two normal and two mitochondrial mutant human lymphoblastoid cell lines.

Gene expression-based detection of radiation exposure in mice after treatment with granulocyte colony-stimulating factor and lipopolysaccharide.

In a large-scale nuclear incident, many thousands of people may be exposed to a wide range of radiation doses. Rapid biological dosimetry will be required on an individualized basis to estimate the exposures and to make treatment decisions. To ameliorate the adverse effects of exposure, victims may be treated with one or more cytokine growth factors, including granulocyte colony-stimulating factor (G-CSF), which has therapeutic efficacy for treating radiation-induced bone marrow ablation by stimulating granulopoiesis.

Measures of genotoxicity in Gulf war I veterans exposed to depleted uranium.

Exposure to depleted uranium (DU), an alpha-emitting heavy metal, has prompted the inclusion of markers of genotoxicity in the long-term medical surveillance of a cohort of DU-exposed Gulf War veterans followed since 1994. Using urine U (uU) concentration as the measure of U body burden, the cohort has been stratified into low-u (<0.10 μg U/g creatinine) and high-u groups (≥ 0.

Developing point of care and high-throughput biological assays for determining absorbed radiation dose.

Background And Purpose: Systems are being developed to assess radiation exposure based on leukocyte mRNA levels obtained by finger-stick sampling. The goal is to provide accurate detection of dose exposures up to 10 Gy for up to 1 week following exposure. We previously showed that specific mRNA sequences increase expression within an hour of exposure, and some genes continue to show elevated expression for at least 24 h.

Estimating the lowest detectable dose of ionizing radiation by FISH whole-chromosome painting.

Chromosome translocations are the hallmark of exposure to ionizing radiation, but they also occur spontaneously, and their frequencies increase dramatically with age. This complicates dosimetry unless a pre-exposure sample is available for each putatively exposed individual. Here we use published values for translocations in unexposed subjects from a wide range of ages, together with data from an in vitro (137)Cs dose-response curve, to estimate the minimum dose of whole-body radiation that is detectable by translocation analyses in individuals of a given age.

Cytogenetic analysis of an exposed-referent study: perchloroethylene-exposed dry cleaners compared to unexposed laundry workers.

Background: Significant numbers of people are exposed to tetrachloroethylene (perchloroethylene, PCE) every year, including workers in the dry cleaning industry. Adverse health effects have been associated with PCE exposure. However, investigations of possible cumulative cytogenetic damage resulting from PCE exposure are lacking.

The role of mitochondria in the radiation-induced bystander effect in human lymphoblastoid cells.

Cells without intact mitochondrial DNA have been shown to lack the bystander effect, which is an energy-dependent process. We hypothesized that cells harboring mutations in mitochondrial genes responsible for ATP synthesis would show a decreased bystander effect compared to normal cells. Radiation-induced bystander effects were analyzed in two normal and four mitochondrial mutant human lymphoblastoid cells.

Expression of DNA repair and apoptosis genes in mitochondrial mutant and normal cells following exposure to ionizing radiation.

In double-strand DNA damage repair, nonhomologous end joining (NHEJ) is more error-prone than homologous recombination repair (HRR), indicating that the relative prevalence of NHEJ may lead to more incorrect repair and thus to increases in chromosome damage. If DNA damage is extensive and cells are unable to repair that damage they typically undergo apoptosis. The mechanism(s) by which cells decide to switch from DNA repair to apoptosis is unknown.

Diagnostic X-ray examinations and increased chromosome translocations: evidence from three studies.

Controversy regarding potential health risks from increased use of medical diagnostic radiologic examinations has come to public attention. We evaluated whether chromosome damage, specifically translocations, which are a potentially intermediate biomarker for cancer risk, was increased after exposure to diagnostic X-rays, with particular interest in the ionizing radiation dose-response below the level of approximately 50 mGy. Chromosome translocation frequency data from three separately conducted occupational studies of ionizing radiation were pooled together.

Mitochondrial gene expression changes in normal and mitochondrial mutant cells after exposure to ionizing radiation.

Mitochondrial DNA (mtDNA) contains 13 genes that encode proteins of the oxidative phosphorylation complex that are involved in ATP generation. Leber's optic atrophy and Leigh's syndrome are diseases that are caused by point mutations in the mitochondrial genome and that have phenotypes associated with energy deprivation. We hypothesized that energy deficiency from mitochondrial mutations in these cells leads to radiation hypersensitivity.

Chromosome translocations and assessing human exposure to adverse environmental agents.

This article discusses the use of chromosome translocations for assessing adverse environmental exposure in humans. Translocations are a persistent biomarker of exposure and a biomarker of effect, making them the endpoint of choice for certain human exposure studies because they indicate a potential relationship between exposure and adverse health outcomes, particularly cancer and birth defects. Presented here are the different types of translocations, their origins and persistence, the strengths and limitations of using translocations for exposure assessments, the current state of the art for quantifying exposure including the importance of confounding effects, and the use of model organisms.

Bystander effects induced by chemicals and ionizing radiation: evaluation of changes in gene expression of downstream MAPK targets.

Radiation-induced bystander effects have been evaluated extensively, including the involvement of the mitogen-activated protein kinase (MAPK) pathways. However, few studies have examined the ability of chemicals to induce bystander effects, and the molecular mechanisms involved in chemical bystander effects have not been investigated. We have previously demonstrated the ability of mitomycin C (MMC) and phleomycin (PHL) to induce bystander effects in normal human lymphoblastoid cells.

Cigarette smoking during pregnancy: chromosome translocations and phenotypic susceptibility in mothers and newborns.

The effects of maternal cigarette smoking during pregnancy on structural chromosome aberrations were evaluated in peripheral lymphocytes from 239 mothers and their 241 newborns to determine whether smoking during pregnancy, genetic susceptibility, and race are associated with chromosome aberrations including translocations. Demographic information and cigarette smoking data were obtained via questionnaire. There were 119 Caucasian Americans, 118 African Americans, and 2 Asian Americans.