Grantee Research Project Results
Arsenic Potentiates the Carcinogenicity of Hexavalent Chromium by Inhibiting the Repair of Cr(VI)-Induced DNA Double Strand Breaks Exacerbating Chromate-Induced Chromosome InstabilityEPA Grant Number: MA916977
Title: Arsenic Potentiates the Carcinogenicity of Hexavalent Chromium by Inhibiting the Repair of Cr(VI)-Induced DNA Double Strand Breaks Exacerbating Chromate-Induced Chromosome Instability
Investigators: Young, Jamie L.
Institution: University of Southern Maine
EPA Project Officer: Jones, Brandon
Project Period: September 1, 2008 through August 31, 2011
RFA: GRO Fellowships for Graduate Environmental Study (2008)
Research Category: Academic Fellowships
Potential exposure of the general public to hexavalent chromium (Cr(VI)) and arsenic is a significant concern because both of these environmental pollutants are known human lung carcinogens; however their carcinogenic mechanisms remain unknown. There is also very little known about the potential interactions between Cr(VI) and arsenic. Both of these metals are common contaminates in drinking water; therefore interactions between the two are probable. Because exposure to Cr(VI) and arsenic is widespread, it is imperative that both the potential carcinogenic mechanism and potential interactions between the two metals is better understood.
The objective of this research project is to develop a model for understanding the toxic interactions between the environmental contaminants Cr(VI) and arsenic. The research will specifically be aimed examining the co-interactions of chromate and arsenic in order to determine if arsenic potentiates the carcinogenicity of Cr(VI) by inhibiting the repair of Cr(VI)-induced DNA double strand breaks, resulting in exacerbate chromium induced chromosome instability.Approach:
In order to assess the interaction between Cr(VI) and arsenic, normal human bronchial fibroblasts and human lung epithelial cells will be used as a model. The chosen cell culture models will be treated with soluble (sodium chromate) and particulate (zinc chromate), both of which are prototypical Cr(VI) compounds. The cells will be co-treated with one of the above chromium compounds and arsenic as a mean of studying various endpoints. The ability of arsenic to potentiate chromate-induced DNA double strand breaks will be assessed using gamma-H2A.X foci production as a measure of double strand breaks. Next, the ability of arsenic to potentiate chromate-induced chromosome damage will be assessed using the aneuploidy assay. Subsequently, the ability of arsenic to potentiate chromium-induced carcinogenesis by inhibition DNA double strand break repair will be determined by using a neoplastic transformation assay which detects anchorage independent growth and loss of contact inhibition. Lastly the ability of arsenic to later gene expression in chromate-induced DNA double strand break repair genes will be assessed using microarray analysis.Expected Results:
Our laboratory has shown that Cr(VI) induces DNA double strand breaks, and numerical chromosome instability. It is expected that arsenic will significantly increase the number of cells with Cr(VI)-induced DNA double strand breaks; therefore, exacerbating the extent of numerical chromosome instability. Overall, co-exposure of Cr(VI) and arsenic will increase the carcinogenicity of Cr(VI) and alter the expression of DNA double strand break repair genes.
With the completion of this research will come a better understanding of the interactions between Cr(VI) and arsenic and therefore the ability to better asses the risks of exposure to these two metals. This research will also provide a human lung model for chemical interactions between other hazardous environmental contaminants.Supplemental Keywords:
chromium, arsenic, DNA double strand breaks, chromosome instability, transformation,