Chromium(VI) compounds cause pulmonary, hepatic, renal, and gastrointestinal toxicity. Inhalation is a common form of exposure and is associated with occupational asthma, chronic bronchitis, fibrosis, chronic obstructive pulmonary disease, and cancer. Occupational and environmental exposures result from the vast amounts of Cr(VI) used industrially, the extensive release of Cr wastes, and fossil fuel combustion. The EPA includes Cr(VI) on the list of 17 chemicals that pose the greatest threat to human health. Many of the effects of Cr(VI) exposure are consistent with oxidant-like damage. The intracellular reduction of Cr(VI) generates reactive species and is required for toxicity. Our long-term goals are to understand the toxicological consequences of the intracellular reductive activation of Cr(VI). Intracellular Cr(VI) reduction generates multiple reactive species over prolonged periods, including Cr(V), superoxide, and a stoichiometric excess of hydroxyl radical. This implies the potential for pronounced and prolonged redox stress, which we have found results in the oxidation of the mitochondrial and cytosolic thioredoxins (Trx), and the inhibition of Trx reductases (TrxR). Reduced Trx is critical for cell survival, for maintaining thiol redox balance, and for controlling redox-dependent signaling events. Trx oxidation has the potential to induce stress responses, including the upregulation of inflammatory mediators and promoting cell death, both of which are likely contributors to the types of diseases associated with Cr(VI) exposure. The initiating events in these outcomes are not well understood, however. Trx oxidation represents a new paradigm for Cr(VI) toxicity, and could represent a key initiating event that ultimately leads to the toxic effects. The overriding hypothesis is that Cr(VI)-induced oxidants result in Trx oxidation, which will activate apoptosis-signal regulating kinase (ASK1) and downstream stress-activated kinases (JNK and p38 MAPK), and that these events will promote apoptosis and the induction of inflammatory mediators. Studies with purified proteins and with normal bronchial epithelial cells will determine which of the reactive Cr and oxygen species mediate TrxR/Trx inhibition/oxidation, and will determine the relationships between Trx oxidation, the activation of ASK1 and p38/JNK, and the induction of inflammatory mediators and apoptosis. The role of ASK1, p38, and JNK in the cellular responses will be tested using selective inhibitors and dominant negative mutants. The contribution of specific Trx and TrxR isoforms to the cells response to Cr(VI) will be explored by manipulating the expression of each protein. This approach will also determine if overexpression of TrxR and/or Trx provides a mechanism to avoid Cr(VI)-induced cell death. Together, these studies will provide a detailed analysis of previously unexplored mechanisms of Cr(VI)-induced oxidant stress, and provide a deeper understanding of the mechanisms underlying Cr(VI) toxicity. Given the ubiquitous nature of the thioredoxin system, and the ability of Cr(VI) to impact other organs, these mechanisms could prove relevant to the effects of Cr(VI) on other tissues and organs.

Public Health Relevance

Hexavalent chromium compounds are among the chemicals that pose the greatest threat to human health. Inhalation is a common form of exposure and is associated with various lung diseases including occupational asthma, chronic bronchitis, chronic obstructive pulmonary disease, cancer, fibrosis, and cancer. Occupational and environmental exposures result from the vast amounts of chromium used in some industries, the extensive release of chromium wastes, and the combustion of fossil fuels. This proposal examines previously unexplored mechanisms of how chromium disrupts one of the essential antioxidant defenses in the lungs, and how this leads to events that promote inflammation and the death of cells that line the airways.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1-DKUS-C (90))
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Nadadur, Srikanth
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Medical College of Wisconsin
Schools of Medicine
United States
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