Journal article Open Access

Recent Advances in Arsenic Carcinogenesis: Modes of Action, Animal Model Systems and Methylated Arsenic Metabolites

Kitchin, Kirk T.

Recent advances in our knowledge of arsenic carcinogenesis include the development of rat or mouse models for all human organs in which inorganic arsenic is known to cause cancer -skin, lung, urinary bladder, liver and kidney. Tumors can be produced from either promotion of carcinogenesis protocols (mouse skin and lungs, rat bladder, kidney, liver and thyroid) or from complete carcinogenesis protocols (rat bladder and mouse lung). Experiments with p53 +1- and K610DC transgenic mice administered dimethylarsinic acid (DMA) or arsenite have shown some degree of carcinogenic, cocarcinogenic or promotional activity in skin or bladder. At present, with the possible exception of skin, the arsenic carcinogenesis models in wild type animals are more highly developed than in transgenic mice. Recent advances in arsenic metabolism have suggested that methylation of inorganic arsenic may be a toxification, rather than a detoxification pathway and that trivalent methylated arsenic metabolites particularly monomethylarsonous acid (MMA(III) and dimethylarsinous acid (DMA(III) have a great deal of biological activity. Accumulating evidence indicates that these trivalent, methylated and relatively less ionizable arsenic metabolites may be unusually capable of interacting with cellular targets such as proteins and even DNA. In risk assessment of environmental arsenic, it is important to know and utilize both the mode of carcinogenic action and the shape of the dose-response curve at low environmental arsenic concentrations. Although much progress has been recently made in the area of arsenic's possible mode(s) of carcinogenic action, a scientific concensus has not yet been reached. In this review, nine different possible modes of action of arsenic carcinogenesis are presented and discussed -induced chromosomal abnormalities, oxidative stress, altered DNA repair, altered DNA methylation patterns, altered growth factors, enhanced cell proliferation, promotion/progression, gene amplification and suppression.

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