Measures of genotoxicity in Gulf war I veterans exposed to depleted uranium

McDiarmid, Melissa A.; Albertini, Richard J.; Tucker, James D.; Vacek, Pamela M.; Carter, Elizabeth W.; Bakhmutsky, Marina V.; Oliver, Marc; Engelhardt, Susan M.; Squibb, Katherine S.

doi:10.1002/em.20658

Cited by 30 publications

(28 citation statements)

References 60 publications

(45 reference statements)

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“…An analysis of Gulf War I veterans exposed to alpha particle emitting depleted uranium has also identified a significant 50% increase in HPRT mutant frequency compared to a low exposure group [106] and a number of other studies have also observed the mutagenic and clastogenic potential of depleted uranium exposure [107,108]. …”

Section: Genetic Effectsmentioning

confidence: 99%

The Cellular and Molecular Carcinogenic Effects of Radon Exposure: A Review

Robertson

Allen

Laney

et al. 2013

IJMS

120

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Radon-222 is a naturally occurring radioactive gas that is responsible for approximately half of the human annual background radiation exposure globally. Chronic exposure to radon and its decay products is estimated to be the second leading cause of lung cancer behind smoking, and links to other forms of neoplasms have been postulated. Ionizing radiation emitted during the radioactive decay of radon and its progeny can induce a variety of cytogenetic effects that can be biologically damaging and result in an increased risk of carcinogenesis. Suggested effects produced as a result of alpha particle exposure from radon include mutations, chromosome aberrations, generation of reactive oxygen species, modification of the cell cycle, up or down regulation of cytokines and the increased production of proteins associated with cell-cycle regulation and carcinogenesis. A number of potential biomarkers of exposure, including translocations at codon 249 of TP53 in addition to HPRT mutations, have been suggested although, in conclusion, the evidence for such hotspots is insufficient. There is also substantial evidence of bystander effects, which may provide complications when calculating risk estimates as a result of exposure, particularly at low doses where cellular responses often appear to deviate from the linear, no-threshold hypothesis. At low doses, effects may also be dependent on cellular conditions as opposed to dose. The cellular and molecular carcinogenic effects of radon exposure have been observed to be both numerous and complex and the elevated chronic exposure of man may therefore pose a significant public health risk that may extend beyond the association with lung carcinogenesis.

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Section: Genetic Effectsmentioning

confidence: 99%

The Cellular and Molecular Carcinogenic Effects of Radon Exposure: A Review

Robertson

Allen

Laney

et al. 2013

IJMS

120

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“…Soluble uranyl ion has been found to be clastogenic, transforming, and aneugenic in cell culture [30–32]. Mutations at the hprt locus have been reported for soluble uranyl ion in Chinese Hamster Ovary (CHO) and V79 cells [8, 33], as well as in peripheral T-cells of gulf war veterans exposed to DU containing shrapnel [34]. Characterization of the mutagenic spectrum in CHO EM9 cells exposed to uranyl acetate (UA) showed more small multiexon 1–22 bp deletions and 1–2 bp insertions than were observed in either spontaneously-generated or H 2 O 2 -induced hprt mutants [35].…”

Section: Introductionmentioning

confidence: 99%

Analysis of heat-labile sites generated by reactions of depleted uranium and ascorbate in plasmid DNA

et al. 2013

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The goal of this study was to characterize how depleted uranium (DU) causes DNA damage. Procedures were developed to assess the ability of organic and inorganic DNA adducts to convert to single strand breaks (SSB) in pBR322 plasmid DNA in the presence of heat or piperidine. DNA adducts formed by methyl methanesulfonate (MMS), cis-platin (cis-Pt), and chromic chloride were compared to those formed by reaction of uranyl acetate (UA) and ascorbate (Asc). Uranyl ion in the presence of Asc produced U-DNA adducts that converted to SSB upon heating. Piperidine, which acted on DNA methylated by MMS to convert methyl-DNA adducts to SSB, served in the opposite fashion with U-DNA adducts by decreasing SSB. The observation that piperidine also decreased the gel shift for metal-DNA adducts formed by monofunctional cis-Pt and chromic chloride was interpreted to suggest that piperidine served to remove U-DNA adducts. Radical scavengers did not affect formation of U-induced SSB, suggesting that SSB arose from the presence of U-DNA adducts and not from free radicals. A model is proposed to predict how U-DNA adducts may serve as initial lesions that convert to SSB or AP sites. Results suggest that DU can act as a chemical genotoxin that does not require radiation for its mode of action. Characterizing the DNA lesions formed by DU is necessary to assess the relative importance of different DNA lesions in the formation of DU-induced mutations. Understanding mechanisms of formation of DU-induced mutations may contribute to identification of biomarkers of DU exposures in humans.

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“…For this day 1, and on the following days 3, 6, 8, and 10, the cells were counted and the GPI-a cloning assay was performed as described [McDiarmid et al 2011]. On each of the five days, 10 × 10 6 cells at 0.5 × 10 6 cells/ml were maintained in RPMI-10% CBS for the next day of analysis.…”

Section: Methodsmentioning

confidence: 99%

Both PIGA and PIGL mutations cause GPI‐a deficient isolates in the Tk6 cell line

Nicklas

Carter

Albertini

2015

Environ and Mol Mutagen

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Molecular analysis of proaerolysin selected glycosylphosphatidylinositol anchor (GPI-a) deficient isolates in the TK6 cell line was performed. Initial studies found that the expected X-linked PIGA mutations were rare among the spontaneous isolates but did increase modestly after ethyl methane sulfate (EMS) treatment (but to only 50% of isolates). To determine the molecular bases of the remaining GPI-a deficient isolates, real-time analysis for all the 25 autosomal GPI-a pathway genes was performed on the isolates without PIGA mutations, determining that PIGL mRNA was absent for many. Further analysis determined these isolates had several different homozygous deletions of the 5’ region of PIGL (17p12-p22) extending 5’ (telomeric) through NCOR1 and some into the TTC19 gene (total deletion >250,000bp). It was determined that the TK6 parent had a hemizygous deletion in 17p12-p22 (275,712bp) extending from PIGL intron 2 into TTC19 intron 7. Second hit deletions in the other allele in the GPI-a deficient isolates led to the detected homozygous deletions. Several of the deletion breakpoints including the original first hit deletion were sequenced. As strong support for TK6 having a deletion, a number of the isolates without PIGA mutations nor homozygous PIGL deletions had point mutations in the PIGL gene. These studies show that the GPI-a mutation studies using TK6 cell line could be a valuable assay detecting point and deletion mutations in two genes simultaneously.

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Measures of genotoxicity in Gulf war I veterans exposed to depleted uranium

Cited by 30 publications

References 60 publications

The Cellular and Molecular Carcinogenic Effects of Radon Exposure: A Review

The Cellular and Molecular Carcinogenic Effects of Radon Exposure: A Review

Analysis of heat-labile sites generated by reactions of depleted uranium and ascorbate in plasmid DNA

Both PIGA and PIGL mutations cause GPI‐a deficient isolates in the Tk6 cell line

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