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) 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.
authors.affiliation: U.S. Army Research Laboratory, Weapons and Materials Research Directorate, B434 Mulberry Road, Aberdeen Proving Ground, MD 21005-5609, USA.
authors.forename: B E
authors.initials: BE
authors.lastname: Schuster
authors.forename: L E
authors.initials: LE
authors.lastname: Roszell
authors.forename: L E
authors.initials: LE
authors.lastname: Murr
authors.forename: D A
authors.initials: DA
authors.lastname: Ramirez
authors.forename: J D
authors.initials: JD
authors.lastname: Demaree
authors.forename: B R
authors.initials: BR
authors.lastname: Klotz
authors.forename: A B
authors.initials: AB
authors.lastname: Rosencrance
authors.forename: W E
authors.initials: WE
authors.lastname: Dennis
authors.forename: W
authors.initials: W
authors.lastname: Bao
authors.forename: E J
authors.initials: EJ
authors.lastname: Perkins
authors.forename: J F
authors.initials: JF
authors.lastname: Dillman
authors.forename: D I
authors.initials: DI
authors.lastname: Bannon
mesh_terms: D000497:Alloys / Q000633:toxicity; D000818:Animals; D002273:Carcinogens; D003035:Cobalt / Q000633:toxicity; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004343:Drug Implants; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D007273:Injections, Intramuscular; D008297:Male; D008670:Metals / Q000633:toxicity / Q000652:urine; D051379:Mice; D046228:Microarray Analysis; D019042:Muscle Neoplasms / Q000139:chemically induced / Q000473:pathology; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D009532:Nickel / Q000633:toxicity; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D012208:Rhabdomyosarcoma / Q000139:chemically induced / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014414:Tungsten / Q000633:toxicity* / Q000652:urine
chemical_list: D000497:Alloys; D002273:Carcinogens; D004343:Drug Implants; D007202:Indicators and Reagents; D008670:Metals; D003035:Cobalt; D009532:Nickel; D051736:Proto-Oncogene Proteins c-mdm2; D051358:Cyclin-Dependent Kinase 4; D014414:Tungsten