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ToxSci Advance Access published online on June 16, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh200
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received February 13, 2004
Accepted June 10, 2004

Genetic Toxicology

TCDD Affects DNA Double Strand-Break Repair

Clara Y. Y. Chan 1, Perry M. Kim 1, Louise M. Winn 1*

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

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


  Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an environmental toxicant, elicits a spectrum of deleterious biological responses including carcinogenesis. We hypothesize that TCDD exposure exerts its carcinogenicity, in part, by affecting the repair of DNA DSBs through homologous recombination (HR), mediated by the AhR signaling pathway. To investigate this hypothesis we used a Chinese hamster ovary (CHO) cell line (CHO 33) containing a neo direct repeat recombination reporter substrate to determine whether TCDD affects DNA DSB repair. The Saccharomyces cerevisiae mitochondrial endonuclease I-SceI was used to induce a site specific DSB within the upstream neo recombination substrate in the CHO 33 cells. The cells were then exposed to 500 pM of TCDD in the presence or absence of the AhR antagonist {alpha}-naphthoflavone (0.1 µM) for 24 hr. Two weeks later HR frequencies were determined by counting the number of functional neo expressing, G418-resistant colonies per live cells plated. TCDD significantly increased HR frequency, demonstrating that it does in fact modulate the repair of DNA DSBs. Southern blot analysis of G418-resistant colonies using a cDNA neo probe determined that both gene conversion and gene deletion HR events occurred as a result of DNA DSB repair and TCDD exposure. Exposure of cells to {alpha}-naphthoflavone resulted in a significant decrease in TCDD-induced HR frequency. These results demonstrate that TCDD, potentially acting via the AhR, can modulate HR repair of DNA DSBs in CHO 33 cells.

Keywords: TCDD, homologous recombination, AhR, DNA repair
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