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NRF2 Oxidative Stress Induced by Heavy Metals is Cell Type Dependent
SIMMONS, S., F. Chung-Yang, K. Yeoman, J. Wakefield, AND T. V. RAMABHADRAN. NRF2 Oxidative Stress Induced by Heavy Metals is Cell Type Dependent. Current Chemical Genomics. Bentham Science Publishers, Ltd., Oak Park, IL, (5):1-12, (2011).
This study focused on metal-induced Nrf2-mediated oxidative stress responsive in human cells. In the course of our work, we observed dramatic differences in Nrf2 response between human cell lines to a common set of metal toxicants.
Exposure to metallic environmental toxicants has been demonstrated to induce a variety of oxidative stress responses in mammalian cells. The transcription factor Nrf2 is activated in response to oxidative stress and coordinates the expression of antioxidant gene products. In this study, we describe the development of an Nrf2-specific reporter gene assay that can be used to study the oxidative stress response in multiple cell types. Using five different cell lines, the Nrf2-activating potency of twenty metals was assessed across a range of concentrations. While ten of the metals tested (cadmium, cobalt, copper, gold, iron, lead, mercury, silver, sodium arsenite and zinc) stimulated Nrf2-dependent transcriptional activity in at least three of the engineered cell lines, only three (cadmium, copper and sodium arsenite) were active in all five cell lines. A comparison of metal induced Nrf2 transcriptional activation revealed significant differences in the absolute magnitude of activation as well as the relative potencies between the cell lines· tested. However, there was no direct correlation between activity and potency. Taken together, these results show that the capacity to stimulate Nrf2 activity and relative potencies of these test compounds are highly dependent on the cell type tested. Since oxidative stress is thought to be involved in the mode of action of many toxicological studies, this observation may inform the design of paradigms for toxicity testing for toxicant prioritization and characterization.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
GENETIC AND CELLULAR TOXICOLOGY BRANCH