DNA double-strand breaks and DNA recombination in benzene metabolite-induced genotoxicity.
ABSTRACT In utero exposure to environmental carcinogens, including the ubiquitous pollutant benzene, may cause DNA damage in the fetus, leading to an increased risk for the development of childhood cancer. Benzene metabolite-induced DNA double-strand breaks (DSBs) may undergo erroneous repair, leading to chromosomal aberrations including chromosomal inversions and translocations. In this study, fetal murine hematopoietic cells from pZK1 transgenic mice were exposed to p-benzoquinone (BQ), a toxic metabolite of benzene, and assessed for DNA recombination, DNA damage including DNA DSBs as measured by γ-H2A.X foci and oxidative DNA damage, and reactive oxygen species (ROS) production. The pZK1 transgenic mouse model contains a DNA construct allowing for the detection of intrachromosomal recombination events. Using this model, a significant increase in recombination was observed following exposure to BQ (25 and 50μM) at various time points. Additionally, increased γ-H2A.X foci were observed following exposure to 25μM BQ for 30 min, 45 min, and 1 h, whereas this exposure did not significantly increase oxidative DNA damage. Pretreatment with 400 U/ml polyethylene glycol-conjugated-catalase attenuated increases in DNA recombination as compared with treatment with BQ alone. An increase in ROS production (30 min and 1 h), as measured by dichlorodihydrofluorescein diacetate fluorescence, was also observed following exposure to 25μM BQ. These studies indicate that BQ is able to induce DNA damage and recombination in fetal liver cells and that ROS may be important in the mechanism of toxicity.
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ABSTRACT: As an approach to understanding how mammals regulate H(2)O(2) toxicity, intracellular concentration to prevent its we analyzed the genome-wide mRNA profile changes of human cells after treatment with a non-toxic H(2)O(2) concentration. We identified a large and essentially late H(2)O(2) response of induced and repressed genes that unexpectedly comprise few or no antioxidants but mostly apoptosis and cell cycle control activities. The requirement of the p53 regulator for regulating about a third of this H(2)O(2) stimulon and the lack of an associated enhancement of total cellular H(2)O(2) scavenging activity further suggest that H(2)O(2) elicits a stress antiproliferative/repair response that does not increase antioxidant defenses. We conclude that mammalian antioxidant defenses are constitutive, a finding that contrasts with the oxidant-inducibility of such defenses in microorganisms. This finding might be important in understanding the role of H(2)O(2) as a key signaling molecule in mammals.Journal of Biological Chemistry 08/2004; 279(30):31157-63. · 4.65 Impact Factor
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ABSTRACT: Although overall incidence is rare, leukemia is the most common type of childhood cancer. It accounts for 30% of all cancers diagnosed in children younger than 15 years. Within this population, acute lymphocytic leukemia (ALL) occurs approximately five times more frequently than acute myelogenous leukemia (AML) and accounts for approximately 78% of all childhood leukemia diagnoses. Epidemiologic studies of acute leukemias in children have examined possible risk factors, including genetic, infectious, and environmental, in an attempt to determine etiology. Only one environmental risk factor (ionizing radiation) has been significantly linked to ALL or AML. Most environmental risk factors have been found to be weakly and inconsistently associated with either form of acute childhood leukemia. Our review focuses on the demographics of childhood leukemia and the risk factors that have been associated with the development of childhood ALL or AML. The environmental risk factors discussed include ionizing radiation, non-ionizing radiation, hydrocarbons, pesticides, alcohol use, cigarette smoking, and illicit drug use. Knowledge of these particular risk factors can be used to support measures to reduce potentially harmful exposures and decrease the risk of disease. We also review genetic and infectious risk factors and other variables, including maternal reproductive history and birth characteristics.Environmental Health Perspectives 02/2007; 115(1):138-45. · 7.26 Impact Factor
- Journal of Toxicology and Environmental Health Part A 12/2000; 61(5-6):357-72. · 1.73 Impact Factor