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Project 4 : Determinants of individual variability in arsenic cytotoxicity
Walter Klimecki, DVM, PhD
The effect of arsenic on an individual may be affected by that person’s genes. Research into individual variability may explain why two people exposed to the same amount of arsenic could have very different outcomes.
Dr. Walt Klimecki, is investigating genetic variation and arsenic susceptibility. By studying people exposed to arsenic in their drinking water, his laboratory group has shown that slight differences in the DNA sequence of a gene that is the key player in arsenic metabolism can affect the amount of a toxic metabolite produced in the urine, which can affect their risk of disease. To make matters more complicated, the effect of these slight differences in DNA sequence can be greater or smaller, depending on the age and sex of the person carrying the slightly different DNA sequence.
The situation is further complicated by the fact that differences in metabolism cannot explain all of the variation seen in a population. Ongoing work in the Klimecki laboratory is using a cell culture model to study sensitivity or resistance to cell death caused by arsenic. Human blood cells with different genetic backgrounds are grown in the laboratory and treated with the same amount of arsenic, an amount which may kill some cell types. Cells cannot metabolize arsenic on their own (ie, outside of the whole body); thus, differences seen are expected to be due not to genetic differences in metabolism, but differences in the way cells handle a toxic insult. By measuring the expression of genes in cells that do or do not die, the cellular pathways affecting response to arsenic exposure can be determined. Importantly, the next step will be to look for such genetic differences in actual humans exposed to arsenic in their drinking water.
These studies will determine cellular mechanisms that confer arsenic resistance, and provide quantifiable biomarkers that can be tested for their ability to predict disease risk in arsenic-exposed populations. An important outcome of identifying individual risk of arsenic-induced disease is to be able to identify those most in need of protection, and to provide better tools for environmental risk analysis for public health professionals as well as policy makers.
1. Characterize the arsenic-responsive, genome-wide gene expression patterns in a series of lymphoblastoid cell lines (LBLs) representing phenotypic extremes of susceptibility to arsenic-induced cytotoxicity.
2. Functionally validate candidate genes from Objective 1 for their capacity to modulate arsenic sensitivity.
3. Characterize the role of arsenic-resistance genes in peripheral blood lymphocytes from arsenic-exposed humans.
Project 4 publications resulting from research conducted under the Superfund Research Program.
NIEHS Research Briefs resulting from research conducted under the Superfund Research Program:
Research Brief 135: The Human Genetics of Arsenic Biotransformation