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COMPARATIVE GENOTOXIC RESPONSES TO ARSENITE IN GUINEA PIG, MOUSE, RAT AND HUMAN LYMPHOCYTES
Citation:
Kligerman, A D., B. Peng, AND M J. Mass. COMPARATIVE GENOTOXIC RESPONSES TO ARSENITE IN GUINEA PIG, MOUSE, RAT AND HUMAN LYMPHOCYTES. Presented at 4th Int'l Conf. on Arsenic & Health Effects, San Diego, CA, June 18-22, 2000.
Description:
Comparative genotoxic responses to arsenite in guinea pig, mouse, rat and human
lymphocytes.
Inorganic arsenic is a known human carcinogen causing skin, lung, and bladder cancer following chronic exposures. Yet, long-term laboratory animal carcinogenicity studies have generally yielded negative results. Inorganic arsenic induces both structural and numerical chromosome abnormalities apparently without acting directly on the genetic material, and this may, in part, be responsible for its carcinogenic activity. It has been postulated that the methylation of inorganic arsenic leads to detoxification and deactivation as a carcinogen; however, the role of methylation of arsenic in the carcinogenesis process is unknown. Rats and mice are more efficient methylators of inorganic arsenic than are humans, while guinea pigs are extremely poor methylators of inorganic arsenic.
With the above in mind, we decided to compare the induction of MN in lymphocytes of mice, rats, guinea pigs, and humans following treatment with sodium arsenite. Lymphocytes were isolated from the peripheral blood of all species and stimulated to divide using phytohemagglutinin. Cultures were harvested after 72 h following a 46 h treatment with cytochalasin B to induce binucleated cells. Several different arsenic treatment protocols were used to determine if there were differences in the induction of MN by sodium arsenite in the four species. Of great interest to us was the finding that lymphocytes from guinea pigs sustained the least amount of genotoxic damage; whereas, lymphocytes from humans sustained the most genotoxic damage. The difference in the amount of genotoxic damage between guinea pig and human was on the order of 10-fold, with human lymphocytes being the most sensitive. This result appears to correlate inversely with the known capacity of the guinea pig and human to methylate arsenic. These findings support the notion that increased arsenic methylation capacity may actually sensitize cells to arsenic carcinogenesis rather than protect against it.
This is an abstract of a proposed presentation and does not necessarily reflect the policy of the U.S. Environmental Protection Agency.