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Title: In vivo corrosion, tumor outcome, and microarray gene expression for two types of muscle-implanted tungsten alloys

Abstract

Tungsten alloys are composed of tungsten microparticles embedded in a solid matrix of transition metals such as nickel, cobalt, or iron. To understand the toxicology of these alloys, male F344 rats were intramuscularly implanted with pellets of tungsten/nickel/cobalt, tungsten/nickel/iron, or pure tungsten, with tantalum pellets as a negative control. Between 6 and 12 months, aggressive rhabdomyosarcomas formed around tungsten/nickel/cobalt pellets, while those of tungsten/nickel/iron or pure tungsten did not cause cancers. Electron microscopy showed a progressive corrosion of the matrix phase of tungsten/nickel/cobalt pellets over 6 months, accompanied by high urinary concentrations of nickel and cobalt. In contrast, non-carcinogenic tungsten/nickel/iron pellets were minimally corroded and urinary metals were low; these pellets having developed a surface oxide layer in vivo that may have restricted the mobilization of carcinogenic nickel. Microarray analysis of tumors revealed large changes in gene expression compared with normal muscle, with biological processes involving the cell cycle significantly up‐regulated and those involved with muscle development and differentiation significantly down‐regulated. Top KEGG pathways disrupted were adherens junction, p53 signaling, and the cell cycle. Chromosomal enrichment analysis of genes showed a highly significant impact at cytoband 7q22 (chromosome 7) which included mouse double minute (MDM2) and cyclin‐dependant kinase (CDK4) asmore » well as other genes associated with human sarcomas. In conclusion, the tumorigenic potential of implanted tungsten alloys is related to mobilization of carcinogenic metals nickel and cobalt from corroding pellets, while gene expression changes in the consequent tumors are similar to radiation induced animal sarcomas as well as sporadic human sarcomas. -- Highlights: ► Tungsten/nickel/cobalt, tungsten/nickel/iron, and pure tungsten were studied. ► Male Fischer rats implanted with pellets in gastrocnemius muscle of each hind leg. ► Aggressive rhabdomyosarcomas developed from tungsten/nickel/cobalt pellets only. ► Microarray gene expression analysis was carried out on selected tumors. ► Pellet degradation, urinary metal concentration, and sarcoma were correlated.« less

Authors:
 [1];  [2]; ;  [3];  [1];  [4]; ;  [5];  [6];  [7];  [8];  [2]
  1. U.S. Army Research Laboratory, Weapons and Materials Research Directorate, B434 Mulberry Road, Aberdeen Proving Ground, MD 21005-5609 (United States)
  2. U.S. Army Institute of Public Health, 5158 Blackhawk Road, Aberdeen Proving Ground, MD 21010‐5403 (United States)
  3. Department of Metallurgical and Materials Engineering, University of Texas, El Paso, TX 79968 (United States)
  4. Dynamic Science Inc., Aberdeen Proving Ground, MD 21005‐5609 (United States)
  5. U.S. Army Center for Environmental Health Research, Department of Chemistry, Ft. Detrick, MD 21702‐5010 (United States)
  6. SAS Institute, Inc. SAS Campus Drive, Cary, NC 27513 (United States)
  7. U.S. Army Engineer Research and Development Center, 3909 Hall Ferry Road, Vicksburg MS 39180 (United States)
  8. U.S. Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010‐5400 (United States)
Publication Date:
OSTI Identifier:
22215982
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 265; Journal Issue: 1; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARCINOGENS; CELL CYCLE; COBALT; CONNECTIVE TISSUE; CORROSION; GENES; IN VIVO; IRON; MICE; MUSCLES; NICKEL; OXIDES; RATS; RHABDOMYOSARCOMAS; TANTALUM; TUNGSTEN; TUNGSTEN ALLOYS

Citation Formats

Schuster, B.E., Roszell, L.E., Murr, L.E., Ramirez, D.A., Demaree, J.D., Klotz, B.R., Rosencrance, A.B., Dennis, W.E., Bao, W., Perkins, E.J., Dillman, J.F., and Bannon, D.I., E-mail: desmond.bannon@us.army.mil. In vivo corrosion, tumor outcome, and microarray gene expression for two types of muscle-implanted tungsten alloys. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.08.025.
Schuster, B.E., Roszell, L.E., Murr, L.E., Ramirez, D.A., Demaree, J.D., Klotz, B.R., Rosencrance, A.B., Dennis, W.E., Bao, W., Perkins, E.J., Dillman, J.F., & Bannon, D.I., E-mail: desmond.bannon@us.army.mil. In vivo corrosion, tumor outcome, and microarray gene expression for two types of muscle-implanted tungsten alloys. United States. doi:10.1016/J.TAAP.2012.08.025.
Schuster, B.E., Roszell, L.E., Murr, L.E., Ramirez, D.A., Demaree, J.D., Klotz, B.R., Rosencrance, A.B., Dennis, W.E., Bao, W., Perkins, E.J., Dillman, J.F., and Bannon, D.I., E-mail: desmond.bannon@us.army.mil. Thu . "In vivo corrosion, tumor outcome, and microarray gene expression for two types of muscle-implanted tungsten alloys". United States. doi:10.1016/J.TAAP.2012.08.025.
@article{osti_22215982,
title = {In vivo corrosion, tumor outcome, and microarray gene expression for two types of muscle-implanted tungsten alloys},
author = {Schuster, B.E. and Roszell, L.E. and Murr, L.E. and Ramirez, D.A. and Demaree, J.D. and Klotz, B.R. and Rosencrance, A.B. and Dennis, W.E. and Bao, W. and Perkins, E.J. and Dillman, J.F. and Bannon, D.I., E-mail: desmond.bannon@us.army.mil},
abstractNote = {Tungsten alloys are composed of tungsten microparticles embedded in a solid matrix of transition metals such as nickel, cobalt, or iron. To understand the toxicology of these alloys, male F344 rats were intramuscularly implanted with pellets of tungsten/nickel/cobalt, tungsten/nickel/iron, or pure tungsten, with tantalum pellets as a negative control. Between 6 and 12 months, aggressive rhabdomyosarcomas formed around tungsten/nickel/cobalt pellets, while those of tungsten/nickel/iron or pure tungsten did not cause cancers. Electron microscopy showed a progressive corrosion of the matrix phase of tungsten/nickel/cobalt pellets over 6 months, accompanied by high urinary concentrations of nickel and cobalt. In contrast, non-carcinogenic tungsten/nickel/iron pellets were minimally corroded and urinary metals were low; these pellets having developed a surface oxide layer in vivo that may have restricted the mobilization of carcinogenic nickel. Microarray analysis of tumors revealed large changes in gene expression compared with normal muscle, with biological processes involving the cell cycle significantly up‐regulated and those involved with muscle development and differentiation significantly down‐regulated. Top KEGG pathways disrupted were adherens junction, p53 signaling, and the cell cycle. Chromosomal enrichment analysis of genes showed a highly significant impact at cytoband 7q22 (chromosome 7) which included mouse double minute (MDM2) and cyclin‐dependant kinase (CDK4) as well as other genes associated with human sarcomas. In conclusion, the tumorigenic potential of implanted tungsten alloys is related to mobilization of carcinogenic metals nickel and cobalt from corroding pellets, while gene expression changes in the consequent tumors are similar to radiation induced animal sarcomas as well as sporadic human sarcomas. -- Highlights: ► Tungsten/nickel/cobalt, tungsten/nickel/iron, and pure tungsten were studied. ► Male Fischer rats implanted with pellets in gastrocnemius muscle of each hind leg. ► Aggressive rhabdomyosarcomas developed from tungsten/nickel/cobalt pellets only. ► Microarray gene expression analysis was carried out on selected tumors. ► Pellet degradation, urinary metal concentration, and sarcoma were correlated.},
doi = {10.1016/J.TAAP.2012.08.025},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 265,
place = {United States},
year = {2012},
month = {11}
}