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Cytogenetic insights into DNA damage and repair of lesions induced by a monomethylated trivalent arsenical
Citation:
KLIGERMAN, A. D., J. A. Campbell, AND S. I. Malik. Cytogenetic insights into DNA damage and repair of lesions induced by a monomethylated trivalent arsenical. MUTATION RESEARCH. Elsevier Science Ltd, New York, NY, 695(1-2):2-8, (2010).
Impact/Purpose:
This presentation will help risk assessors understand the process in determining when a mode of action should be deemed "Mutagenic"
Description:
Arsenic is a human carcinogen, and only recently have animal models been developed that are useful in investigating its carcinogenic mode ofaction (MOA). However, how arsenic induces cancer is still an open question. In a previous paper, we proposed a model detailing how arsenic might induce DNA lesions leading to cytogenetic damage [Kligerman and Tennant, Tox Appl Pharma 222:281-288 (2007)]. Inthis model we hypothesized that arsenic does not induce chromosome damage via DNA adduction but induces short-lasting lesions from the action of reactive oxygen species (ROS). These lesions cause single-strand breaks (SSB) that induce chromosome breakage when treatment is in S-phase or late Gi phase. However, if treatment is confined to the early G1-or Go-phase ofthe cell cycle, it is predicted that little or no cytogenetic damage will result at the subsequent metaphase. Here, we describe the results from testing this model using monomethylarsonous acid (MMAffi) and cytosine arabinoside (araC), a DNA chain, terminator, to extend the time that DNA lesions remain open during repair to allow the lesions to reach S-phase or interact to form DNA exchanges that would lead to exchange aberrations at metaphase. The results of our study only partially confirmed our hypothesis. Instead, the results indicated that the lesions induced by MMAIll are quickly repaired through base excision repair, that there is little chance for araC to extend the life ofthe lesions, and thus the DNA damage induced by arsenicals that leads to chromosome aberrations is very short lived.
