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GENE METHYLATION CHANGES IN TUMOR SUPPRESSOR GENES INDUCED BY ARSENIC
Impact/Purpose:
The objective is to determine whether previous observations on the ability of arsenic to act as a modifier of DNA methylation in the promoter of the human p53 gene also apply to other tumor suppressor genes and oncogenes. This work seeks to determine carcinogenic mechanisms that are concordant with its activity at the molecular biologic level.
Description:
The choice of a dose-response model used for extrapolation can be influenced by knowledge of mechanism of action. We have already showed that arsenic affects methylation of the human p53 gene promoter. Evidence that genes other than the p53 tumor suppressor gene are affected would be an indication that arsenic effects on DNA methylation and gene expression are widespread in the genome and would further implicate this as a consequential mechanism in arsenic carcinogenesis. Although it is already known that arsenic does not damage DNA directly, it has the ability to produce chromosome damage by unknown mechanisms. Such damage could occur by suppression of tumor suppressor gene function. Use of the altered DNA methylation hypothesis for arsenic may justify the use of a non-linear model for low dose extrapolation for use in setting the MCL.