title: Arsenite causes DNA damage in keratinocytes via generation of hydroxyl radicals.
abstract: Arsenic is an environmental and occupational toxin. Dermatologic toxicities due to arsenic exposure are well-documented and include basal cell and squamous cell carcinomas. However, the mechanism of arsenic-induced skin cancer is not well-understood. Recent studies indicate that arsenic exposure results in the generation of reactive oxygen species (ROS) and oxidative stress. Here, we examined the chemical nature of the specific ROS, studied the interrelationship among these species, and identified the specific species that is responsible for the subsequent DNA damage in a spontaneously immortalized keratinocyte cell line. We detected the formation of O(2)(*)(-) and H(2)O(2) in keratinocytes incubated with arsenite [As(III)] but not with arsenate. As(III)-induced DNA damage was detected in a concentration-dependent manner and evident at low micromolar concentrations. Catalase, an H(2)O(2) scavenger, eliminated H(2)O(2) and reduced the As(III)-mediated DNA damage. Superoxide dismutase, by enhancing the production of H(2)O(2) and (*)OH, significantly increased the As(III)-mediated DNA damage. Sodium formate, a competitive scavenger for (*)OH, and deferoxamine, a metal chelator, both reduced the DNA damage. These results suggest that exposure to arsenite generates O(2)(*)(-) and H(2)O(2), and (*)OH, derived from H(2)O(2), is responsible, at least in part, for the observed DNA damage. These findings demonstrate arsenic-induced formation of specific ROS and provide the direct evidence of (*)OH-mediated DNA damage in keratinocytes, which may play an important role in the mechanism for arsenic-induced skin carcinogenicity.
authors.affiliation: Program in Toxicology, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA.
authors.forename: Honglian
authors.initials: H
authors.lastname: Shi
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Suwei
authors.initials: S
authors.lastname: Wang
authors.forename: Karen L
authors.initials: KL
authors.lastname: Cooper
authors.forename: Shimin
authors.initials: S
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002460:Cell Line; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D013481:Superoxides / Q000378:metabolism
chemical_list: D018053:Arsenites; D002274:Carcinogens, Environmental; D013481:Superoxides; D017665:Hydroxyl Radical; D004247:DNA; D006861:Hydrogen Peroxide; C015001:arsenite