DNA double-strand breaks and DNA recombination in benzene metabolite-induced genotoxicity

• Published in: Toxicological sciences Vol. 126; no. 2; pp. 569 - 577
• Main Authors: Tung, Emily W Y, Philbrook, Nicola A, Macdonald, Katharine D D, Winn, Louise M
• Format: Journal Article
• Language: English
• Published: United States 01.04.2012
• Subjects: Animals; Base Sequence; Benzene - toxicity; DNA Damage; DNA Primers; Mice; Mice, Inbred C57BL; Mutagens - toxicity; Mutation; Reactive Oxygen Species - metabolism; Recombination, Genetic
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfs001

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.