Widespread human exposure to arsenic through drinking water at levels in excess of the Environmental Protection Agency and World Health Organization minimum contaminant level of 10 ?g/L is a national and international concern. It is becoming increasingly appreciated that low and non-cytotoxic concentrations of arsenic can amplify the DNA damaging and carcinogenic potential of other genotoxic agents such as ultraviolet radiation, at least in part, through inhibition of DNA repair processes. The mechanisms by which arsenic inhibits DNA repair target proteins is central to understanding the carcinogenic and co-carcinogenic potential of arsenic and to identify avenues to reverse or prevent the adverse effects of arsenic exposure in human populations. The current project will test the hypothesis that arsenic-generated reactive oxygen and nitrogen species inhibits the activity of zinc finger DNA repair proteins through reaction with redox-sensitive cysteine residues of the zinc finger domains.
In Aim 1 we will investigate the impact of arsenic-mediated iNOS and NADPH oxidase (NOX) induction and subsequent nitric oxide and superoxide generation on the activity of two DNA repair proteins (XPA and PARP-1), DNA repair and genotoxicity in keratinocytes. Genetic and pharmacologic disruption of iNOS and NOX will define which pathway(s) are involved in arsenic-mediated inhibition of DNA repair.
Aim 2 will investigate the interaction of arsenic-generated reactive oxygen and nitrogen species with the zinc fingers of XPA and PARP-1 and apply analytical techniques to define specific modifications of the zinc finger domain and consequences with regard to zinc binding. Data generated by our laboratories and others indicate selectivity for arsenic binding to zinc finger structures and we find that arsenic- bound, but not zinc bound, zinc finger peptide is highly vulnerable to oxidation We will test whether arsenic binding to a zinc finger translates to targeted oxidative and nitrosative modification and loss of zinc finger protein function.
In Aim 3, we will test the iNOS and NOX dependence for the reported synergism between arsenic and ultraviolet radiation in DNA damage and skin tumorigenesis in vivo using genetic models. Thus, this project rigorously tests mechanisms of arsenic inhibition of key DNA repair target proteins using a multi- faceted approach. The outcomes from these studies will improve our understanding of mechanisms underlying arsenic disruption of zinc finger DNA repair protein function and may have significant impact on treatments or preventative interventions for arsenic exposed populations. Additionally, these studies may lead to testable hypotheses regarding potential arsenic targets in cancer and other arsenic-associated diseases.

Public Health Relevance

Arsenic in drinking water exceeds the current EPA maximum contaminant level (MCL) in several areas of the United States, notably the north central region and western states. Given the widespread public exposure to arsenic in municipal and private water supplies, there is interest and concern in observations that arsenic concentrations at or near the MCL greatly enhance the carcinogenic potential of other DNA damaging agents. Thus, arsenic may contribute to elevated cancer risk when individuals are exposed to other carcinogens through occupational, environmental or lifestyle exposures. This project will study mechanisms by which arsenic acts as a co-carcinogen to inform strategies to reverse or prevent the adverse health effects of arsenic exposure in human populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES021100-01A1
Application #
8369694
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Humble, Michael C
Project Start
2012-09-01
Project End
2017-05-31
Budget Start
2012-09-01
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$339,750
Indirect Cost
$114,750
Name
University of New Mexico Health Sciences Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
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Zhou, Xixi; Sun, Xi; Mobarak, Charlotte et al. (2014) Differential binding of monomethylarsonous acid compared to arsenite and arsenic trioxide with zinc finger peptides and proteins. Chem Res Toxicol 27:690-8
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Melak, Dawit; Ferreccio, Catterina; Kalman, David et al. (2014) Arsenic methylation and lung and bladder cancer in a case-control study in northern Chile. Toxicol Appl Pharmacol 274:225-31
Wang, Feng; Zhou, Xixi; Liu, Wenlan et al. (2013) Arsenite-induced ROS/RNS generation causes zinc loss and inhibits the activity of poly(ADP-ribose) polymerase-1. Free Radic Biol Med 61:249-56