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.

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

“…Accumulating evidence suggests that oxidative stress occurs in response to arsenic exposure [5,6] and may be one factor in dermal arsenic carcinogenesis. Indeed, evidence of arsenic-induced oxidative DNA damage has been observed in cells [7][8][9][10][11][12], in rodents [13] and in humans [14].…”

Effect of Aqueous Extracts of Green Tea in Arsenic induced Toxicity in Mice

“…Arsenic causes cellular toxicity by damaging the body's oxidative defense mechanisms [12].Chronic arsenic exposure causes excessive free radical generation in the body [13][14][15][16], Arsenic induced oxidative stress generates the superoxide radical and the hydroxyl radical primarily associated with mitochondria, microsomes and peroxisomes [17]. As a result, cells under oxidative stress display various dysfunctions due to lesions caused by reactive oxygen species (ROS) to lipids, proteins and DNA [18].…”

Fragmentation of the DNA Repair Enzyme, OGG1, in Mouse Nonparenchymal Liver Cells by Arsenic Compounds

“…As for arsenic compounds, many reports have indicated that they increased oxidative DNA damage in cultured cells (6,7). For example, hydroxyl radical-induced oxidative DNA damage was generated in arsenic trioxide-treated keratinocyes (10). In addition, elevated levels of 8-OH-dG were observed in the urine of the patients with arsenic poisoning (8,9).…”

“…It was also reported that the urinary 8-OH-dG level is increased with exposure to arsenic compounds (8,9). The DNA damage induced by arsenic compounds was extensively investigated, and the contributions of reactive oxygen species (ROS) and nitric oxide generated by arsenic compounds to the carcinogenic mechanisms have been suggested (10)(11)(12). However, the exact role of DNA damage in arsenic compound-related carcinogenesis is still unclear.…”