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DNA strand breaks in mammalian tissues induced by methylarsenics
K Yamanaka1, A Hasegawa, R Sawamura
1College of Pharmacy, Nihon University, Tokyo, Japan.
Abstract:
DNA damage induced by administration of dimethylarsinic acid (DMAA) to rats and mice was investigated. At 12 h after administration of DMAA, DNA single-strand breaks were induced markedly in lung. The majority of dimethylarsine, one of the main metabolites, in the expired air was excreted within 6-18 h after administration of DMAA to rats. In vitro experiments using nuclei isolated from lung of mice indicated that DNA strand breaks were caused by dimethylarsine. Furthermore, the strand breaks after exposure to dimethylarsine were reduced in the presence of catalase and/or superoxide dismutase. These results strongly suggest that the strand breaks are induced not by dimethylarsine itself but by active oxygen, e.g., O2- and .OH, produced both by dimethylarsine and molecular oxygen. When DNA was exposed to dimethylarsine, thiobarbituric acid (TBA)-reactive intermediates and cis-thymine glycol were produced. Dimethylarsine appears to induce DNA damage by the mechanism similar to the damage produced by ionizing radiation.
Insights
Dimethylarsinic acid (DMAA) causes DNA damage, primarily in the lungs, through active oxygen species. This arsenic metabolite induces strand breaks similar to ionizing radiation.
Area of Science:
- Toxicology
- Molecular Biology
- Environmental Health
Background:
- Dimethylarsinic acid (DMAA) is a major metabolite of inorganic arsenic.
- Arsenic compounds are known environmental contaminants with potential health risks.
- Understanding the mechanisms of DMAA-induced toxicity is crucial for risk assessment.
Purpose of the Study:
- To investigate DNA damage induced by dimethylarsinic acid (DMAA) in mammalian models.
- To elucidate the role of metabolites and reactive oxygen species in DMAA-induced genotoxicity.
- To compare the DNA damage mechanism of DMAA with other known genotoxic agents.
Main Methods:
- Administration of DMAA to rats and mice.
- Analysis of DNA single-strand breaks in lung tissue.
- In vitro studies using isolated mouse lung nuclei exposed to dimethylarsine.
- Assessment of reactive oxygen species involvement using catalase and superoxide dismutase.
- Detection of DNA adducts like cis-thymine glycol and TBA-reactive intermediates.
Main Results:
- DMAA administration induced significant DNA single-strand breaks in lung tissue within 12 hours.
- Dimethylarsine, a DMAA metabolite, was identified as the causative agent for DNA strand breaks in vitro.
- The presence of catalase and superoxide dismutase reduced dimethylarsine-induced DNA strand breaks, indicating active oxygen involvement.
- DMAA exposure generated thiobarbituric acid (TBA)-reactive intermediates and cis-thymine glycol.
- Dimethylarsine excretion occurred primarily between 6-18 hours post-administration in rats.
Conclusions:
- Dimethylarsinic acid induces DNA damage, specifically single-strand breaks in lung tissue.
- The genotoxicity of DMAA is mediated by active oxygen species (superoxide and hydroxyl radicals) produced during dimethylarsine metabolism.
- The mechanism of DNA damage by dimethylarsine resembles that of ionizing radiation.