Centers

Project Title: Arsenic-Induced Epigenetic Modifications and Risk for As-Induced Premalignant Skin Lesions

Principal Investigator: Mary V. Gamble, PhD (Dept. of Environmental Health Sciences)

Year: 2007

Award Amount: $25,000

Abstract: Epigenetic modifications are defined as processes that influence the genome and/or gene activity without changing the DNA sequence. They can be altered by environmental factors such as metals and diet. DNA methylation displays a distinct pattern in the genome such that the majority of cytosines in CpGs are methylated (genomic DNA [gDNA] methylation), whereas CpGs in CpG-rich regions located in promoter regions (gene-specific DNA [gsDNA] methylation) are generally not methylated. Alterations in this pattern are associated with disease outcomes including cancer. In a study of Bangladeshi adults chronically exposed to arsenic (As) in drinking water, we have previously found that As was associated with increased gDNA, and furthermore, this association was only observed in people having adequate folate nutritional status. We speculate that the observed increase in DNA methylation may be a protective response to arsenic exposure, as our preliminary analyses from a nested-case control study suggest that participants who are similarly exposed but have decreased methylation of gDNA are at higher risk for arsenic-induced skin lesions. In the latter study, As exposure was associated with increased gDNA methylation of PBL DNA in controls, but not in cases. The regulation of gDNA methylation is complex and incompletely understood, but decreased methylation of gDNA is often associated with increased gene specific methylation, and the latter can lead to alterations in gene expression which may influence risk for cancer outcomes. Methods. We have DNA samples that were collected as part of a nested case-control study in Araihazar, Bangladesh. A total of 316 SL cases (i.e. cases were free of SLs at baseline, but developed SLs by 2 years after recruitment) and 316 controls were individually matched for gender and age (within 5 years), and frequency matched for water As (within 100 μg/L). This NIH funded study was designed to determine whether folate deficiency and/or hyperhomocysteinemia are risk factors for subsequent development of As-induced skin lesions, and it lends itself ideally to test the hypotheses that gDNA hypomethylation, and gsDNA hypermethylation of candidate genes are associated with an increased risk for As-induced skin lesions. We selected a panel of candidate genes which have been reported to be influenced by arsenic exposure in prior experiments, including p53, p16INK4A, RASSF1A, and PRSS3.