Hexavalent chromium (Cr(VI)), also known as chromate, is a major public health concern. Chromates, particularly the insoluble compounds, are well-established human lung carcinogens. Our study focuses on investigating the mechanisms of Cr(VI)-induced carcinogenesis, which are currently unknown. Recent studies indicate that particulate Cr(VI) induces chromosome instability, which is a hallmark of human lung tumors. However, how Cr(VI) induces chromosome instability is poorly understood. Our preliminary data show that chronic exposure to particulate Cr(VI) induces a DNA repair deficient phenotype that underlies the chromosome instability, and thus, the goal of this research is to characterize this repair deficiency and its impact and understand the mechanisms that cause it to occur. We will test the hypothesis that particulate Cr(VI) induces epigenetic changes inactivating homologous recombination repair of Cr(VI)-induced DNA double strand breaks resulting in increased chromosome instability and carcinogenesis. We will test this hypothesis through four interrelated specific aims.
Aim 1 will characterize the homologous recombination repair defect and show that particulate Cr(VI) causes cells to inactivate Rad51-mediated response and switch to lower fidelity non-homologous end joining (NHEJ) repair using immunoblotting, immunofluorescence and repair assays.
Aim 2 will show that the cells with particulate Cr(VI)-inactivated Rad51 response acquire chromosome instability and undergo neoplastic transformation using cytogenetic techniques and assays for contact- uninhibited and anchorage independent growth.
Aim 3 will identify an epigenetic change (increased acetylation) that causes the loss of Rad51 response by affecting E2F1, ATM, Rad51C and Rad51 with assays for acetylation status, gene expression, and protein interactions and localization. Finally, Aim 4 will characterize the mechanism for particulate Cr(VI)-induced acetylation changes studying Cr(VI) binding to acetyl groups using assays for acetylation and histone deacetylase activity.
Each aim will focus on human lung cells and confirm key findings in human Cr(VI) tumors. Results will lead to the first reports of detailed information of the interactions of Cr(VI with DNA double strand break machinery, acetylation status and the first characterizations of these aspects 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 with widespread occupational and environmental exposure. How Cr(VI) causes human cancer is unknown. Our study advances our basic understanding of the cellular and molecular mechanisms underlying how Cr(VI) causes cancer and informs us about how cells protect against Cr(VI)-induced genomic instability. Our findings will help us identify new potential treatment targets and approaches to reduce or prevent Cr(VI)-induced lung cancer and to better assess the risk of exposure to this major public health concern. 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 Cr(VI) and other agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES016893-06
Application #
8578064
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tyson, Frederick L
Project Start
2008-07-01
Project End
2018-12-31
Budget Start
2014-04-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern Maine
Department
Other Basic Sciences
Type
Other Specialized Schools
DUNS #
City
Portland
State
ME
Country
United States
Zip Code
04104
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; Holmes, Amie L; Liou, Louis et al. (2016) Hexavalent chromium induces chromosome instability in human urothelial cells. Toxicol Appl Pharmacol 296:54-60
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
Carnero, Amancio; Blanco-Aparicio, Carmen; Kondoh, Hiroshi et al. (2015) Disruptive chemicals, senescence and immortality. Carcinogenesis 36 Suppl 1:S19-37
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
Wise, Catherine F; Wise, Sandra S; Thompson, W Douglas et al. (2015) Chromium Is Elevated in Fin Whale (Balaenoptera physalus) Skin Tissue and Is Genotoxic to Fin Whale Skin Cells. Biol Trace Elem Res 166:108-17
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
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
Martino, Julieta; Holmes, Amie L; Xie, Hong et al. (2015) Chronic Exposure to Particulate Chromate Induces Premature Centrosome Separation and Centriole Disengagement in Human Lung Cells. Toxicol Sci 147:490-9
Qin, Qin; Xie, Hong; Wise, Sandra S et al. (2014) Homologous recombination repair signaling in chemical carcinogenesis: prolonged particulate hexavalent chromium exposure suppresses the Rad51 response in human lung cells. Toxicol Sci 142:117-25

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