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ToxSci Advance Access published online on February 18, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg008
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received September 11, 2002; accepted December 6, 2002
© 2003 Society of Toxicology

Molecular and Genetic Toxicology

Homologous Recombination Initiated by Benzene Metabolites: A Potential Role of Oxidative Stressa

Louise M. Winn 1*

1 Department of Pharmacology and Toxicology and School of Environmental Studies, Queen's University, Kingston, Ontario, Canada

* To whom correspondence should be addressed. E-mail: winnl{at}biology.queensu.ca.


  Abstract

Benzene is a ubiquitous pollutant and known human leukemogen. Benzene can be enzymatically bioactivated to reactive intermediates that can lead to increased formation of reactive oxygen species (ROS). ROS formation can directly induce DNA double strand breaks, and also oxidize nucleotides that are subsequently converted to double strand breaks during DNA replication. DNA double-strand breaks can be repaired through homologous recombination, which is not error free. Therefore increased DNA double-strand break levels may induce hyper-recombination, which can lead to deleterious genetic changes. To test the hypothesis that benzene and its metabolites initiate hyper-recombination and to investigate the potential role of ROS, a Chinese hamster ovary (CHO) cell line containing a neo direct repeat recombination substrate (CHO 3-6) was used to determine whether benzene or its metabolites phenol, hydroquinone, catechol or benzoquinone initiated increased homologous recombination and whether this increase could be diminished by the co-incubation of cells with the antioxidative enzyme catalase. Results demonstrated that cells exposed to benzene (1, 10, 30 or 100 µM) for 24 hr did not have increased homologous recombination. Increased recombination occurred with exposure to either phenol (1.8, 2.6, 2.9-fold), catechol (1.9, 2.5, 3.2-fold) or benzoquinone (2.7, 5.5, 6.9-fold) at 1, 10 and 30µM concentrations respectively and with exposure to hydroquinone at 10 and 30 µM (1.5, 1.9-fold) (p<0.05). Studies investigating the effects of catalase demonstrated that increased homologous recombination due to exposure to phenol, hydroquinone, catechol or benzoquinone (10 µM) could be completely abolished by the addition of catalase. These data supports the hypothesis that increased homologous recombination mediates benzene-initiated toxicity and supports a role for oxidative stress in this mechanism.


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