Mutagenicity monitoring following battlefield exposures: Longitudinal study of HPRT mutations in Gulf War I veterans exposed to depleted uranium.
A total of 70 military Veterans have been monitored for HPRT T-cell mutations in five separate studies at 2-year intervals over an 8-year period. Systemic depleted uranium (DU) levels were measured at the time of each study by determining urinary uranium (uU) excretion. Each HPRT study included 30-40 Veterans, several with retained DU-containing shrapnel. Forty-nine Veterans were evaluated in multiple studies, including 14 who were in all five studies. This permitted a characterization of the HPRT mutation assay over time to assess the effects of age, smoking and non-selected cloning efficiencies, as well as the inter- and intra-individual variability across time points. Molecular analyses identified the HPRT mutation and T-cell receptor (TCR) gene rearrangement in 1,377 mutant isolates. An unexpected finding was that in vivo clones of HPRT mutant T-cells were present in some Veterans, and could persist over several years of the study. The calculated HPRT mutant frequencies (MFs) were repeatedly elevated in replicate studies in three outlier Veterans with elevated urinary uranium excretion levels. However, these three outlier Veterans also harbored large and persistent in vivo HPRT mutant T-cell clones, each of which was represented by a single founder mutation. Correction for in vivo clonality allowed calculation of HPRT T-cell mutation frequencies (MutFs). Despite earlier reports of DU associated increases in HPRT MFs in some Veterans, the results presented here demonstrate that HPRT mutations are not increased by systemic DU exposure. Additional battlefield exposures were also evaluated for associations with HPRT mutations and none were found.
Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont.
Richard J
RJ
Albertini
Medical Biostatistics Unit, University of Vermont College of Medicine, Burlington, Vermont.
Pamela M
PM
Vacek
Center for Clinical and Translational Science-Biomedical Informatics Unit, University of Vermont, Burlington, Vermont.
Elizabeth W
EW
Carter
Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont.
Janice A
JA
Nicklas
Occupational Health Program, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
Katherine S
KS
Squibb
Occupational Health Program, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
Patricia W
PW
Gucer
Department of Veterans Affairs Medical Center, Baltimore, Maryland.
Susan M
SM
Engelhardt
Occupational Health Program, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
Melissa A
MA
McDiarmid
D000328:Adult; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D047830:Gulf War; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008889:Military Personnel; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation; D016273:Occupational Exposure; D014501:Uranium / Q000633:toxicity* / Q000652:urine; D055815:Young Adult
D009153:Mutagens; D014501:Uranium; D007041:Hypoxanthine Phosphoribosyltransferase
HPRT; biomarkers of genotoxicity; depleted uranium; mutation; urine uranium