Paternal exposure to ethylnitrosourea results in transgenerational genomic instability in mice

Dubrova, Yuri E.; Hickenbotham, Peter; Glen, Colin D.; Monger, Karen; Wong, Hiu-Pak; Barber, Ruth

doi:10.1002/em.20385

Cited by 43 publications

(42 citation statements)

References 21 publications

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“…2B). Thus, our data support our previously reported notion that that transgenerational instability is not attributable to specific subset of DNA lesions, such as double-strand DNA breaks, but rather is triggered by generalized DNA damage in male germ cells (10). Indeed, irradiation results in a wide spectrum of DNA lesions, ranging from base damage to double-strand DNA breaks (19), whereas exposure to ethylnitrosourea mainly causes alkylation of DNA (20).…”

Section: Discussionsupporting

confidence: 91%

“…Recent mouse studies have shown that the genetic effects of exposure to ionizing radiation and some chemical mutagens might not be restricted to the directly affected parental germ line, but also can manifest in their offspring (6)(7)(8)(9)(10). One of the key aspects of transgenerational effects is destabilization of the offspring's genomes, detectable across at least two generations.…”

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confidence: 99%

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Exposure to anticancer drugs can result in transgenerational genomic instability in mice

Glen

Dubrova

2012

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

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The genetic effects of human exposure to anticancer drugs remain poorly understood. To establish whether exposure to anticancer drugs can result not only in mutation induction in the germ line of treated animals, but also in altered mutation rates in their offspring, we evaluated mutation rates in the offspring of male mice treated with three commonly used chemotherapeutic agents: cyclophosphamide, mitomycin C, and procarbazine. The doses of paternal exposure were approximately equivalent to those used clinically. Using single-molecule PCR, the frequency of mutation at the mouse expanded simple tandem repeat locus Ms6-hm was established in DNA samples extracted from sperm and bone marrow of the offspring of treated males. After paternal exposure to any one of these three drugs, expanded simple tandem repeat mutation frequencies were significantly elevated in the germ line (sperm) and bone marrow of their offspring. This observed transgenerational instability was attributed to elevated mutation rates at the alleles derived from both the exposed fathers and from the nonexposed mothers, thus implying a genome-wide destabilization. Our results suggest that paternal exposure to a wide variety of mutagens can result in transgenerational instability manifesting in their offspring. Our data also raise important issues concerning delayed transgenerational effects in the children of survivors of anticancer therapy.epigenetic | genetic risk

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Exposure to anticancer drugs can result in transgenerational genomic instability in mice

Glen

Dubrova

2012

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

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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%

“…Germ cell mutation is critically important to public health because increases in heritable mutations may result in an increased burden of genetic disease in subsequent generations. Previous studies have shown that paternal exposures to chemical mutagens (20), ionizing radiation (38,39), and particulate air pollution (40) increase ESTR mutation frequencies in sperm, and, more importantly, induce persistent genomic instability in the F1 and F2 offspring of exposed mice (32,38,41). Although not directly assessed in the present study, the observation that the mutated alleles are already present in the sperm of exposed mice at frequencies that match those observed in their offspring (16,20) lends support to the notion that the tobacco smokeinduced germ-line mutations reported here would be passed on to the next generation.…”

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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“…To date, there is very strong evidence for transgenerational effects following paternal exposure to mutagens such as IR, chemicals and anticancer drugs (Barber et al, 2006a;Barber et al, 2009;Dubrova et al, 2000b;Dubrova et al, 2008;Glen et al, 2008;Vilarino-Guell et al, 2003) but the role of several non-mutagens that have been linked to genomic instability has not been thoroughly investigated and remains comparatively indeterminate.…”

Section: Transgenerational Instabilitymentioning

confidence: 99%

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

Voutounou

Glen

Dubrova

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Paternal exposure to ethylnitrosourea results in transgenerational genomic instability in mice

Cited by 43 publications

References 21 publications

Exposure to anticancer drugs can result in transgenerational genomic instability in mice

Exposure to anticancer drugs can result in transgenerational genomic instability in mice

Sidestream tobacco smoke is a male germ cell mutagen

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

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