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PILOT STUDY FOR ARSENIC CARCINOGENESIS IN P53 HETEROZYGOTE DEFICIENT MICE
Impact/Purpose:
The objective is to find an animal model for arsenic carcinogensis that could be used to determine shape of the dose-response curve for arsenic induced cancer. The study attempted to find the most active arsenical in carcinogenesis in p53 heterozygous deficient mice among arsenite, arsenate, monomethylarsonic acid and dimethylarsenic acid.
Description:
40 p53 heterozygous knockout mice and 40 p53 wild-type controls were exposed to 4 arsenicals in drinking water at a single dose, the maximum tolerated dose (MTD), in a chronic lifetime tumor bioassay, and animals were subjected to necropsy and limited pathologic examination of the most common neoplasms. The experiments were designed to test the carcinogenicity of sodium arsenite, sodium arsenate, monomethyl- and dimethyl-arsenic derivatives. Positive data would signal that the model should be explored in a more detailed fashion at a later date. The p53 knockout mice used were genetically engineered animals that have a single copy of the p53 gene instead of the normal 2 copies. The p53 gene is tumor suppressor gene that when absent, suppressed, or mutated at specific sites can result in tumorigenesis. In humans the p53 gene is known to be mutated in approximately 50% of all tumors. The presence of one normal copy of the p53 gene in the knockout mice maintains normal tumor suppressor function, however, they are at increased risk for expressing p53 alterations when exposed to carcinogens.
At present there is no reproducible animal model for arsenic induced cancer that is relevant to human exposure scenarios. This longstanding problem has made it difficult to test hypotheses in the laboratory regarding low-dose extrapolation for arsenic carcinogenesis, identify the active species in arsenic carcinogenesis, couple insights regarding the metabolism of arsenic with carcinogenesis. All of these could potentially impact the risk assessment for arsenic, especially if it is found that there is support (in an animal model) for non-linear low dose-response, and that the active species is not arsenite.