Mini-and microsatellite mutations in children from Chernobyl accident cleanup workers

Slebos, Robbert J.C.; Little, Ruth E.; Umbach, David M.; Antipkin, Yurij; Zadaorozhnaja, Tamara D; Mendel, Nikola A; Sommer, Courtney A; Conway, Kathleen; Parrish, Eloise; Gulino, Sara E.; Taylor, Jack A.

doi:10.1016/j.mrgentox.2004.01.003

Cited by 47 publications

(30 citation statements)

References 16 publications

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“…In addition, a number of studies have failed to detect an increase in mutations among the children of Chernobyl cleanup workers (34)(35)(36)(37). This may be caused largely by the lack of useful tools and approaches to evaluate the potential for agents to produce heritable effects.…”

Section: Resultsmentioning

confidence: 99%

Sidestream tobacco smoke is a male germ cell mutagen

Marchetti

Rowan-Carroll

Williams

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Active cigarette smoking increases oxidative damage, DNA adducts, DNA strand breaks, chromosomal aberrations, and heritable mutations in sperm. However, little is known regarding the effects of second-hand smoke on the male germ line. We show here that short-term exposure to mainstream tobacco smoke or sidestream tobacco smoke (STS), the main component of secondhand smoke, induces mutations at an expanded simple tandem repeat locus (Ms6-hm) in mouse sperm. We further show that the response to STS is not linear and that, for both mainstream tobacco smoke and STS, doses that induced significant increases in expanded simple tandem repeat mutations in sperm did not increase the frequencies of micronucleated reticulocytes and erythrocytes in the bone marrow and blood of exposed mice. These data show that passive exposure to cigarette smoke can cause tandem repeat mutations in sperm under conditions that may not induce genetic damage in somatic cells. Although the relationship between noncoding tandem repeat instability and mutations in functional regions of the genome is unclear, our data suggest that paternal exposure to second-hand smoke may have reproductive consequences that go beyond the passive smoker.DNA mutation | micronuclei | germline | spermatogenesis D espite years of intense public campaigns to limit and reduce tobacco consumption, smoking is still widespread, and its health effects remain a significant public concern. Approximately 35% of men of reproductive age in the United States smoke cigarettes (1), and there is extensive evidence to suggest that tobacco smoking can result in abnormal reproductive outcomes such as spontaneous abortions and birth defects (2). Men who smoke are at high risk for several semen abnormalities, including reduced motility, sperm DNA damage such as DNA breaks and adducts, and chromosomal abnormalities (3). In mice, exposure to mainstream tobacco smoke (MTS) induces germ-line mutations in expanded simple tandem repeats (ESTR) that can be transmitted to the progeny, causing irreversible modifications in the genome of the offspring (4). Recently, the International Agency for Research on Cancer concluded that there is enough evidence to link paternal smoking in humans with increased risk of childhood cancer, suggesting that tobacco smoking causes heritable germ cell mutation in humans (5).Exposure to second-hand smoke also remains widespread, with an estimated 40% of nonsmokers being exposed to secondhand smoke (6). Much less is known about the health effects of second-hand (or passive) smoking, although evidence is rapidly accumulating that exposure to second-hand smoke can be as harmful and hazardous to human health as active smoking (6, 7), and that there may be no risk-free level of exposure (8). Sidestream tobacco smoke (STS), the main component of secondhand smoke, is a complex mixture of more than 4,000 chemicals, including at least 50 known carcinogens (8). Qualitative differences between MTS-the smoke inhaled by active smokers-and STS are small; however, some toxicants...

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Section: Resultsmentioning

confidence: 99%

Sidestream tobacco smoke is a male germ cell mutagen

Marchetti

Rowan-Carroll

Williams

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…We report mutation analysis results obtained with the tetranucleotide microsatellite marker D7S1482, which is a hypermutable marker in both germline and somatic cells (Temam et al, 2003;Slebos et al, 2004a). DNAs obtained from mouth rinses was diluted to near-single molecule levels and amplified using time-release PCR (Kebelmann-Betzing et al, 1998;Slebos et al, 2004b).…”

Section: Microsatellite Marker Analysesmentioning

confidence: 99%

Microsatellite mutations in buccal cells are associated with aging and head and neck carcinoma

Slebos

Vadivelu

et al. 2008

Br J Cancer

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Carcinogen exposure from tobacco smoking is the major cause of upper aerodigestive tract cancer, yet heavy smokers only have about a 10% life-time risk of developing one of these cancers. Current technologies allow only limited prediction of cancer risk and there are no approved screening methods applicable to the general population. We developed a method to assess somatic mutational load using small-pool PCR (SP-PCR) and analysed mutations in DNA isolated from cells obtained by mouth rinse. Mutation levels in the hypermutable tetranucleotide marker D7S1482 were analysed in specimens from 25 head and neck squamous carcinoma (HNSCC) cases and 31 controls and tested for associations with age, smoking history and cancer status. We found a significant association between mutation frequency and age (P ¼ 0.021, Generalized Linear Model (GLM), N ¼ 56), but no influence of smoking history. Cases had higher mutation frequencies than controls when corrected for the effects of age, a difference that was statistically significant in the subgroup of 10 HNSCC patients who were treated with surgery only (P ¼ 0.017, GLM, N ¼ 41). We also present evidence that cancer status is linked to levels of nonunique, and presumably clonally derived, mutations in D7S1482. Insertion mutations were observed in 833 (79%) of 1058 alleles, of which 457 (43%) could be explained by insertion of a single repeat unit; deletion mutations were found in 225 (21%) of tested alleles.In conclusion, we demonstrate that the sensitive detection of single molecule mutations in clinical specimens is feasible by SP-PCR. Our study confirms an earlier report that microsatellite mutations increase with age and is the first to provide evidence that these mutations may be associated with cancer status in individual subjects.

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“…Authors drew a conclusion about mutagenic influence of irradiation only at the spermatogenesis cycle at the meiosis stage. To test whether ionizing radiation can cause paternal genetic mutations that are transmitted to offspring, 88 families of Chernobyl clean-up workers exposed to ionizing radiation were studied [32]. Mutation via DNA blotting with the multi-locus minisatellite probes 33.6 and 33.15 and via PCR in a panel of six tetranucleotide repeats were analyzed.…”

Section: Chernobyl Experiences On Genomic Instabilitymentioning

confidence: 99%

Cytogenetic Biological Dosimetry Past, Present and Future Perspectives

Darroudi

2012

Sixth International Conference on Environmental Mutagens in Human Populations

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Abstract. Human risk assessments at the low doses, and low dose rates and high doses following acute exposure to ionizing radiation are of prime importance in radiation protection. These issues are of continuing importance in respect of social/economic policy relating to the industrial and medical uses of ionizing radiation, and for risk assessment among people occupationally are being exposed to low and/or high LET radiation, such as astronauts, pilots, stewardess and nuclear power plant workers, as well as victims of radiation accidents. Consequently, several biological assays were developed and attempts were made to investigate formation of radiation induced chromosome aberrations and induction of genomic instability in human lymphocytes and fibroblasts. Fluorescence in situ hybridization (FISH) technique using chromosome, chromosome-arm, chromosome region, centromere and telomere specific DNA libraries has improved the resolution of detecting all classes of radiation induced chromosomal inter-and intra-changes. Consequently, has increased significantly the accuracy and detection limit of biological dosimetry. Newly obtained data indicate that (a) Premature chromosome condensation assay is a unique method to be used for immediate dose assessment at low (5cGy) as well as high doses (≥3 Gy) and can accurately discriminate between whole-and partial-body exposure in case of mass casualties and accidental over-exposure to high doses of ionizing radiation (b) FISH-based translocation assay has the potential to assess acute as well as chronic exposure in cases of accidental as well as occupational exposure to ionizing radiation, either immediately following exposure, or retrospectively by defining accumulative effects to red bone marrows. (c) there are distinct finger-prints (such as insertions and complex translocations) for high LET radiation in comparison to low LET radiation. The importance of these findings and future perspectives for biological dosimetry are discussed.

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Mini-and microsatellite mutations in children from Chernobyl accident cleanup workers

Cited by 47 publications

References 16 publications

Sidestream tobacco smoke is a male germ cell mutagen

Sidestream tobacco smoke is a male germ cell mutagen

Microsatellite mutations in buccal cells are associated with aging and head and neck carcinoma

Cytogenetic Biological Dosimetry Past, Present and Future Perspectives

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