The Dose and Dose-Rate Effects of Paternal Irradiation on Transgenerational Instability in Mice: A Radiotherapy Connection (original) (raw)
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In this briefing note we review health effects in offspring of human populations exposed as a result of radiotherapy and some groups exposed to chemotherapy. We also assess risks in offspring of other radiation-exposed groups, in particular those of the Japanese atomic bomb survivors and occupationally and environmentally exposed groups. Experimental findings are also briefly surveyed. Animal and cellular studies tend to suggest that the irradiation of males, at least at high doses (mostly 1 Gy and above), can lead to observable effects (including both genetic and epigenetic) in the somatic cells of their offspring over several generations that are not attributable to the inheritance of a simple mutation through the parental germ line. However, studies of disease in the offspring of irradiated humans have not identified any effects on health. The available evidence therefore suggests that human health has not been significantly affected by transgenerational effects of radiation. It ...
The long-term genetic effects of maternal irradiation remain poorly understood. To establish the effects of radiation exposure on mutation induction in the germline of directly exposed females and the possibility of transgenerational effects in their non-exposed offspring, adult female BALB/c and CBA/Ca mice were given 1 Gy of acute X-rays and mated with control males. The frequency of mutation at expanded simple tandem repeat (ESTR) loci in the germline of directly exposed females did not differ from that of controls. Using a single-molecule PCR approach, ESTR mutation frequency was also established for both germline and somatic tissues in the first-generation offspring of irradiated parents. While the frequency of ESTR mutation in the offspring of irradiated males was significantly elevated, maternal irradiation did not affect stability in their F 1 offspring. Considering these data and the results of our previous study, we propose that, in sharp contrast to paternal exposure to ionising radiation, the transgenerational effects of maternal high-dose acute irradiation are likely to be negligible.
Multisite de novo mutations in human offspring after paternal exposure to ionizing radiation
Scientific reports, 2018
A genome-wide evaluation of the effects of ionizing radiation on mutation induction in the mouse germline has identified multisite de novo mutations (MSDNs) as marker for previous exposure. Here we present the results of a small pilot study of whole genome sequencing in offspring of soldiers who served in radar units on weapon systems that were emitting high-frequency radiation. We found cases of exceptionally high MSDN rates as well as an increased mean in our cohort: While a MSDN mutation is detected in average in 1 out of 5 offspring of unexposed controls, we observed 12 MSDNs in altogether 18 offspring, including a family with 6 MSDNs in 3 offspring. Moreover, we found two translocations, also resulting from neighboring mutations. Our findings indicate that MSDNs might be suited in principle for the assessment of DNA damage from ionizing radiation also in humans. However, as exact person-related dose values in risk groups are usually not available, the interpretation of MSDNs in...
Radiation-induced transgenerational instability
Oncogene, 2003
To date, the analysis of mutation induction has provided an irrefutable evidence for an elevated germline mutation rate in the parents directly exposed to ionizing radiation and a number of chemical mutagens. However, the results of numerous publications suggest that radiation may also have an indirect effect on genome stability, which is transmitted through the germ line of irradiated parents to their offspring. This review describes the phenomenon of transgenerational instability and focuses on the data showing increased cancer incidence and elevated mutation rates in the germ line and somatic tissues of the offspring of irradiated parents. The possible mechanisms of transgenerational instability are also discussed.
Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident
Science, 2021
Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987–2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.
Transgenerational Transmission of Radiation Damage: Genomic Instability and Congenital Malformation
Journal of Radiation Research, 2006
The congenital malformation gastroschisis has a genetic disposition in the inbred mouse strain HLG/ Zte. It is increased after preconceptional irradiation of males or females. Radiation exposures during the meiotic stages are most efficient. This malformation can also be induced by ionising radiation when the exposure takes place during the preimplantation period especially during the zygote stage. This latter effect can be transmitted to the next mouse generation. Other macroscopically visible or skeletal malformations are not significantly induced under these experimental conditions. These latter malformations are increased by radiation exposures during major organogenesis. The mechanisms for the development of the effects are different. Radiation exposure of the mouse zygote (1 to 3 hours p.c.) also leads to the induction of genomic instability in skin fibroblasts of the fetus. This phenomenon also occurs in a mouse strain (C57BL/6J) which is not susceptible to radiation-induced gastroschisis during the preimplantation period. The genomic instability is transmitted to the next mouse generation. During genomic instability chromatide breaks are dominating as in non-exposed cells. With respect to "spontaneous" malformations gastroschisis is dominating in HLG/Zte mice. Late radiation effects seem to have similar patterns as observed in non-exposed subjects, however, the rates are increased after irradiation.
Genetic Radiation Risks-A Neglected Topic in the Low Dose Dabate
Environmental Health and Toxicology, 2016
The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) as well as the International Commission on Radiological Protection (ICRP) present very low risk factor for hereditary diseases in humans based on experiments in mice. The claim is based on reportedly absent genetic effects in the acute exposed Japanese A-bomb survivors. We question the safety of these assumptions and have made a compilation of findings about early deaths, congenital malformations, Down´s syndrome, cancer and other genetic effects observed in humans after the exposure of parents. We review evidence from occupationally exposed groups, from studies in populations exposed to Chernobyl fallout and from the descendants of liquidators and nuclear test veterans. Nearly all types of hereditary defects were found at very low doses. We discuss this clash between risk models and observation on the basis of knowledge of biological mechanisms and the effect of assumptions about linear relations between dose and end point in neonatal epidemiology. Using data from Chernobyl effects we derive an Excess Relative Risk for all Malformations of 1.0 per 10mSv cumulative exposure to fission product contamination. The dose response is non-linear "hogs-back" or biphasic and saturates at doses above 10mSv
Revisiting Next Generation Effects of Ionizing Radiation
2021
We have long wondered whether ionizing radiation to parents, before conception, can cause gene mutations leading to adverse effects in the next generations<sup>1</sup>. Animal experiments suggest that de novo gene mutations (DNM) occur with a doubling dose of about one Gy.<sup>1</sup> To address this question in humans, Yeager and colleagues<sup>2</sup> used whole genome sequencing (WGS) to study DNM in children of parents exposed to Chernobyl radiation before conception. The DNMs detected were predominantly single nucleotide variants (SNV), which did not increase in frequency with estimated parental radiation doses. These negative results were consistent with earlier studies in humans<sup>3,4</sup> and mice<sup>5</sup>. However, the exoneration of SNV as mediators of transgenerational radiation effects does not show that such effects do not exist. Indeed, it is much more plausible that radiation would mediate its mutationa...