Cytogenetic insights into DNA damage and repair of lesions induced by a monomethylated trivalent arsenical.
Arsenic is a human carcinogen, and only recently animal models have been developed that are useful in investigating its carcinogenic mode of action (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 [A.D. Kligerman, A.H. Tennant, Toxicol. Appl. Pharmacol. 222 (2007) 281-288]. In this 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 late G(1)- or S-phase. However, if treatment is confined to the G(0)- or early G(1)-phase of the 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 (MMA(III)) 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 MMA(III) are quickly repaired through base excision repair, that there is little chance for araC to extend the life of the lesions, and thus the DNA damage induced by arsenicals that leads to chromosome aberrations is very short lived.
Kligerman
Andrew D
AD
Integrated Systems Toxicology Division, MD 143-06, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. kligerman.andrew@epa.gov
Malik
Shaukat I
SI
Campbell
James A
JA
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001151:Arsenic / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D019457:Chromosome Breakage / Q000187:drug effects*; D003561:Cytarabine / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D005260:Female; D008297:Male; D008741:Methyl Methanesulfonate / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000633:toxicity*; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D009942:Organometallic Compounds; C406082:monomethylarsonous acid; D003561:Cytarabine; D008741:Methyl Methanesulfonate; D001151:Arsenic