Hexavalent chromium (Cr(VI)) or chromate is a major public health concern. Chromates, particularly the insoluble compounds, are well-established human lung carcinogens. The proposed research focuses on the mechanisms of Cr(VI)-induced carcinogenesis, which are currently unknown. Recent studies indicate that particulate Cr(VI) induces chromosome instability, which is often seen in human lung tumors. However, studies of the mechanisms of Cr(VI)-induced chromosome instability have not been done. Our preliminary data show that chronic exposure to particulate Cr(VI) induces centrosome amplification and spindle assembly checkpoint bypass, and thus, the goal of this research is to understand the mechanisms that cause these events leading to Cr(VI)-induced chromosome instability and carcinogenesis. We will test the hypothesis that particulate Cr(VI) induces prolonged G2/M arrest leading to centrosome amplification and spindle assembly checkpoint bypass resulting in chromosome instability and carcinogenesis through four interrelated specific aims: 1) Demonstrate that particulate Cr(VI)-induced DNA double strand breaks cause prolonged G2/M arrest leading to centrosome amplification;2) Identify the molecular mechanisms of how Cr(VI)-induced G2/M arrest uncouples centrosome and cell division causing centrosome amplification focusing on Mps1 and Nek2A;3) Determine the role of Nek2A, Mad1 and Mad2 interactions in particulate Cr(VI)-induced spindle assembly checkpoint bypass;and 4) Identify those cellular and molecular phenotypic changes revealed in Specific Aims 1-3 that occur in cells that escape Cr(VI)-induced death and growth arrest and in cells that are neoplastically transformed by Cr(VI). These four aims will use a combination of established and state-of-the-art toxicological, cytogenetic, and molecular biological techniques with the following approach: 1) Cr(VI)-induced centrosome amplification and spindle assembly checkpoint bypass will be measured with immunofluorescence and cytogenetic assays;2) Gene expression, immunolocalization and RNAi studies will be used to determine the mechanisms of centrosome amplification and checkpoint bypass;and 3) Cell growth and neoplastic transformation assays and studies in human tumors will be used to determine the fate of cells with particulate Cr(VI)-induced chromosome instability. Results will lead to the first reports of detailed information of the interactions of Cr(VI) with centrosome duplication machinery, spindle assembly checkpoint and the first characterizations of chromosome instability in tumors from Cr(VI)-exposed workers. This research is significant because it will provide: 1) An understanding of particulate Cr(VI)'s carcinogenic mechanism;2) Essential information to better assess the risk of exposure to particulates;and 3) A mechanistic approach for further study of Cr(VI), other metals, and lung cancer in general.

Public Health Relevance

Hexavalent chromium (Cr(VI)) is a human lung carcinogen. These studies will advance our basic understanding of the cellular and molecular mechanisms of how cells protect against Cr(VI)-induced genomic instability. Our findings will help us design new treatments and approaches to reduce or prevent Cr(VI)-induced lung cancer and possibly other metals, which continue to be major public health concerns. Finally, we will have established a mechanistic model in a human lung cell system that will allow us to conduct studies for other factors important for preventing human lung cancer both generally and by other agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016893-04
Application #
8240082
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Reinlib, Leslie J
Project Start
2009-07-06
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$329,682
Indirect Cost
$109,159
Name
University of Southern Maine
Department
Other Basic Sciences
Type
Other Domestic Higher Education
DUNS #
077469567
City
Portland
State
ME
Country
United States
Zip Code
04104
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
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
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
Young, Jamie L; Wise, Sandra S; Xie, Hong et al. (2015) Comparative cytotoxicity and genotoxicity of soluble and particulate hexavalent chromium in human and hawksbill sea turtle (Eretmochelys imbricata) skin cells. Comp Biochem Physiol C Toxicol Pharmacol 178:145-55
Goodson 3rd, William H; Lowe, Leroy; Carpenter, David O et al. (2015) Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 36 Suppl 1:S254-96

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