Radiobiology and Reproduction—What Can We Learn from Mammalian Females? (original) (raw)
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The genome-wide effects of ionizing radiation on mutation induction in the mammalian germline
The ability to predict the genetic consequences of human exposure to ionizing radiation has been a long-standing goal of human genetics in the past 50 years. Here we present the results of an unbiased, comprehensive genome-wide survey of the range of germline mutations induced in laboratory mice after parental exposure to ionizing radiation and show irradiation markedly alters the frequency and spectrum of de novo mutations. Here we show that the frequency of de novo copy number variants (CNVs) and insertion/deletion events (indels) is significantly elevated in offspring of exposed fathers. We also show that the spectrum of induced de novo single-nucleotide variants (SNVs) is strikingly different; with clustered mutations being significantly over-represented in the offspring of irradiated males. Our study highlights the specific classes of radiation-induced DNA lesions that evade repair and result in germline mutation and paves the way for similarly comprehensive characterizations of other germline mutagens.
Sex-specific differences in fetal germ cell apoptosis induced by ionizing radiation
Human Reproduction, 2008
We have previously shown that male human fetal germ cells are highly radiosensitive and that their death depends on p53 activation. Male germ cell apoptosis was initiated with doses as low as 0.1 Gy and was prevented by pifithrin a, a p53 inhibitor. In this study, we investigated the radiosensitivity of early female and male fetal proliferating germ cells. methods and results: Both male and female fetal germ cells displayed a similar number of gH2AX foci in response to ionizing radiation (IR). In organ culture of human fetal ovaries, the germ cells underwent apoptosis only when exposed to high doses of IR (1.5 Gy and above). Accumulation of p53 was detected in irradiated male human fetal germ cells but not in female ones. Inhibition of p53 with pifithrin a did not affect oogonia apoptosis following irradiation. IR induced apoptosis similarly in mouse fetal ovaries in organ culture and in vivo during oogonial proliferation. Germ cell survival in testes from p53 knockout or p63 knockout mice exposed to IR was better than wild-type, whereas female germ cell survival was unaffected by p53 or p63 knockout.
Avicenna journal of medical biotechnology, 2014
Genome instability is a main cause of chromosomal alterations in both somatic and germ cells when exposed to environmental, physical and chemical genotoxicants. Germ cells especially spermatozoa are more vulnerable to suffering from DNA damaging agents during spermatogenesis and also more potent in transmitting genome instability to next generation. To investigate the effects of γ-rays on inducing abnormalities manifested as numerical Chromosome Aberrations (CA) and Micronucleus (MN) in preimplantation embryos, adult male NMRI mice were irradiated with 4 Gy of γ-rays. They were then mated at weekly intervals with superovulated, non-irradiated female mice in 6 successive weeks. About 68 hr post coitous, four to eight cell embryos were retrieved and fixed on slides using standard methods in order to screen for CA and MN. In embryos generated from irradiated mice, the frequency of aneuploidy and MN increased dramatically at all post-irradiation sampling times as compared to the control...
Ovarian Modifications in Mice Exposed to Whole-Body Irradiation
2013
This experiment was designed to determine the involvement of varying levels of whole-body irradiation on ovarian follicular and corpora luteal development in mice. Previous research has indicated reduced counts of ovarian follicles and corpora lutea in mice flown in space. These differences may be the result of microgravity, increased exposure to radiation, or some combination of both. Fifty-six mice were divided into three groups (apocynin-treated, nox2 knockout, and wild-type control) before exposure to 0 Gy, 0.5 Gy, or 2.0 Gy radiation. The tissues were harvested, preserved, run through the appropriate paraffin embedding procedures, serially sectioned, mounted on microscope slides, and stained using a standard H&E staining technique. Total and mean follicular and corpora luteal counts were accessed and compared across treatment groups. Mean ovarian weight, mean total reproductive weight, mean ovarian weight percentage of total body weight, mean total reproductive weight percentage of total body weight, and the apparent estrous phase of the animals were also compared. Radiation from 0.5-2.0 Gy had no significant effect on mean ovarian weight, mean total reproductive weight, mean ovarian weight percentage of total body weight, or mean total reproductive weight percentage of total body weight. Radiation from 0.5-2.0 Gy significantly increased mean early-stage follicular count in the wildtype group only. Radiation of 2.0 Gy increased late-stage follicular count across all groups after accounting for mean ovarian percent of total body weight. Radiation of 2.0 Gy significantly increased mean corpora lutea count in the wildtype group only. This result not only suggests that low-dose radiation accelerates oocyte development in the murine ovary, but also that the inaction of NADPH-oxidase (via apocynin inhibition or genetic knockout) may ameliorate some of these effects.
Gamma-irradiation increased meiotic crossovers in mouse spermatocytes
Mutagenesis, 2011
In mice, the occurrence of immunofluorescent foci for mismatch repair protein MLH1 correlates closely with the occurrence of crossovers, as detected genetically, and MLH1 foci represent virtually all prospective crossover positions. To examine the effects of g-irradiation on meiotic crossovers in mouse spermatocytes, male mice were subjected to wholebody g-irradiation at different sub-stages of meiotic prophase and crossovers on synaptonemal complexes (SCs) were analysed by visualising and quantifying the immunofluorescent MLH1 foci. At both 24 and 48 h after exposure, significant dose-dependent increases in the number of total MLH1 foci per spermatocyte were observed at late zygotene-early pachytene with the gradient increase of radiation dose from 0, 1.5, 3-6 Gy. Furthermore, irradiation at preleptoteneleptotene still led to significant dose-dependent increased meiotic crossovers in the spermatocytes analysed 120 h after exposure. In further analysis, these dose-dependent increases in the number of total MLH1 foci per cell were attributed to significant dose-dependent decreases in autosomal SCs with 0 MLH1 focus, and the dose-dependent increases in autosomal SCs with 2 MLH1 foci and the percentage of cells with MLH1 focus on XY bivalent. The increased number of cells with an MLH1 focus on the pseudoautosomal regions (PARs) may indicate that there is a delay in meiotic progression in the irradiated cells. Although significant dose-dependent increases in the number of total MLH1 foci per cell were examined 24, 48 or 120 h after exposure with the gradient increase of radiation doses, these increases were mild compared to the control groups. This suggests that there is tight control of crossover formation (at least with respect to MLH1 foci number). The mechanisms underlying irradiationinduced DNA lesion repair, cellular responses independent of DNA damage and meiotic crossover homeostasis in mammals will be the subjects of future study.
Proceedings of the National Academy of Sciences, 1998
Germ-line mutation induction at mouse minisatellite loci by acute irradiation with x-rays was studied at premeiotic and postmeiotic stages of spermatogenesis. An elevated paternal mutation rate was found after irradiation of premeiotic spermatogonia and stem cells, whereas the frequency of minisatellite mutation after postmeiotic irradiation of spermatids was similar to that in control litters. In contrast, paternal irradiation did not affect the maternal mutation rate. A linear dose-response curve for paternal mutation induced at premeiotic stages was found, with a doubling dose of 0.33 Gy, a value close to those obtained in mice after acute spermatogonia irradiation using other systems for mutation detection. High frequencies of spontaneous and induced mutations at minisatellite loci allow mutation induction to be evaluated at low doses of exposure in very small population samples, which currently makes minisatellite DNA the most powerful tool for monitoring radiation-induced germ-line mutation.
Biology of Reproduction, 2019
Radiation induces ovarian damage and accelerates reproductive aging. Inbred mouse strains exhibit differential sensitivity to lethality induced by total body irradiation (TBI), with the BALB/cAnNCrl (BALB/c) strain being more sensitive than the 129S2/SvPasCrl (129) strain. However, whether TBI-induced ovarian damage follows a similar pattern of strain sensitivity is unknown. To examine this possibility, female BALB/c and 129 mice were exposed to a single dose of 1 Gy (Cesium-137 γ) TBI at 5 weeks of age, and ovarian tissue was harvested for histological and gene expression analyses two weeks post-exposure. Sham-treated mice served as controls. 1 Gy radiation nearly eradicated the primordial follicles and dramatically decreased the primary follicles in both strains. In contrast, larger growing follicles were less affected in the 129 relative to BALB/c strain. Although this TBI paradigm did not induce detectable ovarian fibrosis in either of the strains, we did observe strain-dependen...
Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2005
In vivo studies on X-irradiated mice have shown that structural chromosome aberrations can be induced in female germ cells and that the radiation-induced chromosomal damage strongly depends on the stage of maturation reached by the oocytes at the time of irradiation. In the present study, the sensitivity of oocytes to induction of chromosome damage by radiation was evaluated at two different stages, by use of a recently developed method of in vitro culture covering a crucial period of follicle/oocyte growth and maturation. A key feature of this system is that growth and development of all follicles is perfectly synchronized, due to the selection of a narrow class of follicles in the start-off culture. This allows irradiation of well-characterized and homogenous populations of follicles, in contrast to the situation prevailing in vivo. Follicles were X-irradiated with either 2 or 4 Gy, on day 0 of culture (early preantral follicles with one to two cell layers) or on day 12, 3 h after hormonal stimulation of ovulation (antral Graafian follicles). Ovulated oocytes, blocked in metaphase I (MI) by colchicine, were fixed 16 h after hormonal stimulation and analyzed for chromosome aberrations. The results confirm the high radiosensitivity of oocytes at 2 weeks prior to ovulation and the even higher radiosensitivity of those irradiated a few hours before ovulation, underlining the suitability of the in vitro system for further studies on the genetic effects of ionising radiation in female mammals.