Nuclear Weapons Tests and Human Germline Mutation Rate

Dubrova, Yuri E.; Bersimbaev, R. I.; Djansugurova, Leyla; Tankimanova, Maira; Mamyrbaeva, Z; Mustonen, R; Lindholm, Carita; Hultén, Maj; Salomaa, Sisko

doi:10.1126/science.1068102

Cited by 128 publications

(70 citation statements)

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“…Despite the ubiquitous presence of known mutagens and carcinogens in our day-to-day environment, extensive animal data showing induction and transmission of germ cell mutations (27), human studies showing increased genetic and chromosomal damage in sperm of older men (28) and patients receiving chemotherapy (29), and reports on increases in mutations rates in the children of parents exposed to radioactive contamination (30)(31)(32)(33), no germ cell mutagen has been identified conclusively in humans. 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).…”

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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“…Owing to the high spontaneous germline mutation rate of some minisatellites (41000 Â higher than most protein-coding loci), a PPI effect could be detected in a substantially smaller population than required to detect mutations in protein-coding loci (Dubrova et al, 1993(Dubrova et al, , 1996(Dubrova et al, , 1997. Studies of two different populations, one exposed to IR from radionuclide-contaminated land following the Chernobyl accident (B0.5 Gy, Dubrova et al, 1996Dubrova et al, , 1997Dubrova et al, , 2002a, the other from the fallout of nuclear weapons tests (41 Sv; Dubrova et al, 2002b), revealed an approximate doubling in germline minisatellite mutation rates due to PPI. These and other data suggest that minisatellite mutation rates may be useful biomarkers of germline genetic effects caused by environmental mutagens such as IR (Yauk, 2004;Bouffler et al, 2006).…”

mentioning

confidence: 99%

New germline mutations in the hypervariable minisatellite CEB1 in the parents of children with leukaemia

et al. 2007

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Gardner and co-workers advanced the hypothesis that the Seascale leukaemia cluster could have been caused by new mutations in germ cells, induced by paternal preconceptional irradiation (PPI) exposure at the Sellafield nuclear installation. Since evidence has shown that PPI can increase the de novo germline mutation rate in hypervariable minisatellite loci, we investigated the hypothesis that sporadic childhood leukaemia might be associated with an increased parental germline minisatellite mutation rate. To test this hypothesis, we compared de novo germline mutation rates in the hypervariable minisatellite locus, CEB1, in family trios (both parents and their child) of children with leukaemia (n ¼ 135) compared with unaffected control families (n ¼ 124). The majority of case and control germline mutations were paternal (94%); the mean paternal germline mutation rates of children with leukaemia (0.083) and control children (0.156) were not significantly different (odds ratio, 95% confidence interval: 0.50, 0.23 -1.08; P ¼ 0.11). There were no significant differences in case and control parental allele sizes, case and control germline mutation progenitor allele sizes (2.74 vs 2.54 kb; P ¼ 0.56), case and control mutant allele sizes (2.71 vs 2.67 kb; P ¼ 0.90), mutant allele size changes (0.13 vs 0.26 kb; P ¼ 0.10), or mutational spectra. Within the limitation of the number of families available for study, we conclude that childhood leukaemia is unlikely to be associated with increased germline minisatellite instability.

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“…The authors consider that the initial acute exposure was responsible for the increase and since spontaneous minisatellite mutation in humans occurs mainly by meiotic recombination, the effect is attributable to an induced instability resulting in later destabilisation of minisatellites during meiosis which persists from the time of the accident until 1995. However, in another FSU study (Dubrova et al, 2002b) the mutation rate for minisatellite loci decreased with post-irradiation year of birth, implying that transgenerational destabilisation of these loci is not a consistently expressed effect.…”

Section: Mouse Data Amentioning

confidence: 99%

“…Some FSU studies indicate positive results (Dubrova et al, 1996(Dubrova et al, , 1997(Dubrova et al, , 2002a(Dubrova et al, , 2002b, while others are equivocal or negative (Livshits et al, 2001;Kiuru et al, 2003). b No consistent pattern of response is evident (ie of human germline minisatellite mutations to low dose ionising radiation).…”

Section: Human Data Amentioning

confidence: 99%

“…These data are not considered to be consistent with the hypothesis of direct targeting of any specific gene(s) in the F 0 male causing destabilisation of the F 1 and F 2 germlines and point in the direction of an epigenetic instability mechanism such as might be attributed to DNA methylation changes. (9) A study of germline mutations in minisatellites among the inhabitants of regions of Ukraine which were heavily contaminated by radionuclides after the Chernobyl accident has been reported (Dubrova et al, 2002b). The control group was composed of 98 children conceived before the Chernobyl accident and born between 1976 and 1986.…”

Section: Mouse Data Amentioning

confidence: 99%

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