Lung cancer continues to be the leading cause of cancer death in the U.S. One of the key strategies to combating it is to better understand its causes. Hexavalent chromium [Cr(VI)] is a human lung carcinogen of major public health concern because exposure to it is common in the workplace and in the general environment. Our study focuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis, which are currently unknown. In particular, this work focuses on the particulate Cr(VI) compounds, because they are the most potent Cr(VI) carcinogens. Recent studies indicate particulate Cr(VI) induces chromosome instability and causes cells to evade DNA double strand break repair, which are hallmarks of human lung cancer. Thus, this research focuses on how particulate Cr(VI) induces cells to evade DNA double strand break repair leading to chromosome instability and carcinogenesis. Our data show prolonged exposure to particulate Cr(VI) specifically impacts the effector arm of homologous recombination (HR repair), disrupting RAD51 nucleoprotein filament formation, loss of which can cause chromosome instability. Therefore, the goal of this research is to characterize this impact on HR repair and the underlying changes in order to understand the mechanisms involved. Our hypothesis is: particulate Cr(VI) disrupts the underlying mechanisms of RAD51 nucleoprotein filament formation inactivating HR repair of Cr(VI)-induced DNA breaks resulting in CIN and neoplastic transformation. We will test this hypothesis through three interrelated specific aims.
Aim 1 will determine how Cr(VI) impacts BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 to disrupt RAD51 nucleoprotein filament formation in human lung cells.
Aim 2 determines the persistence and cellular heritability of disrupted RAD51 filament formation in human lung cells neoplastically transformed by Cr(VI), and the protein levels of BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 in lung tumors from human Cr(VI) workers.
Aim 3 determines the impact of Cr(VI) on protein levels of BRCA2, DSS1, RAD51B, RAD51C, RAD51D, RPA, and XRCC2 in the lungs and lung tumors of Cr(VI)-exposed animals. Results will lead to the first reports of detailed information of the interactions of Cr(VI) with the effector arm of HR repair at a cellular and molecular level and the first characterizations of these aspects in neoplastic outcomes including tumors from Cr(VI)-exposed workers. Results will also show which changes are transient and depend on exposure and which changes persist in cells that escape cell death and progress to neoplastic outcomes. This research is significant because it provides: 1) An understanding of Cr(VI)?s carcinogenic mechanism; 2) Essential information to better assess exposure risk to particulates; and 3) A mechanistic approach for further study of Cr(VI), other metals and lung cancer in general.

Public Health Relevance

Lung cancer is the number one cause of cancer death in the United States. Our study focuses on two hallmarks of lung cancer, chromosome instability and evading DNA double strand break repair, and advances our basic understanding of the cellular and molecular mechanisms underlying how Cr(VI) causes these outcomes as part of its carcinogenic mechanism. Our findings will help identify new mechanistic insights, which can spur new potential treatment targets, new approaches to reduce and prevent Cr(VI)-induced lung cancer, and new insights to better determine safer exposure levels for this major public health concern.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Systemic Injury by Environmental Exposure (SIEE)
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Tyson, Frederick L
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University of Louisville
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Wise, Sandra S; Aboueissa, Abou El-Makarim; Martino, Julieta et al. (2018) Hexavalent Chromium-Induced Chromosome Instability Drives Permanent and Heritable Numerical and Structural Changes and a DNA Repair-Deficient Phenotype. Cancer Res 78:4203-4214
Speer, Rachel M; Wise, Catherine F; Young, Jamie L et al. (2018) The cytotoxicity and genotoxicity of particulate and soluble hexavalent chromium in leatherback sea turtle lung cells. Aquat Toxicol 198:149-157
Wise Jr, John Pierce; Wise, James T F; Wise, Catherine F et al. (2018) A three year study of metal levels in skin biopsies of whales in the Gulf of Mexico after the Deepwater Horizon oil crisis. Comp Biochem Physiol C Toxicol Pharmacol 205:15-25
Browning, Cynthia L; Wise, Catherine F; Wise Sr, John Pierce (2017) Prolonged particulate chromate exposure does not inhibit homologous recombination repair in North Atlantic right whale (Eubalaena glacialis) lung cells. Toxicol Appl Pharmacol 331:18-23
Browning, Cynthia L; Wise Sr, John Pierce (2017) Prolonged exposure to particulate chromate inhibits RAD51 nuclear import mediator proteins. Toxicol Appl Pharmacol 331:101-107
Wise, Sandra S; Wise, Catherine; Xie, Hong et al. (2016) Hexavalent chromium is cytotoxic and genotoxic to American alligator cells. Aquat Toxicol 171:30-6
Wise, Sandra S; Holmes, Amie L; Liou, Louis et al. (2016) Hexavalent chromium induces chromosome instability in human urothelial cells. Toxicol Appl Pharmacol 296:54-60
Browning, Cynthia L; Qin, Qin; Kelly, Deborah F et al. (2016) Prolonged Particulate Hexavalent Chromium Exposure Suppresses Homologous Recombination Repair in Human Lung Cells. Toxicol Sci 153:70-8
Carnero, Amancio; Blanco-Aparicio, Carmen; Kondoh, Hiroshi et al. (2015) Disruptive chemicals, senescence and immortality. Carcinogenesis 36 Suppl 1:S19-37
Xie, Hong; Holmes, Amie L; Wise, Sandra S et al. (2015) Human Skin Cells Are More Sensitive than Human Lung Cells to the Cytotoxic and Cell Cycle Arresting Impacts of Particulate and Soluble Hexavalent Chromium. Biol Trace Elem Res 166:49-56

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