Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis

Xu, Guogang; Intano, Gabriel W.; McCarrey, John R.; Walter, Ronald B.; McMahan, C. Alex; Walter, Christi A.

doi:10.1016/j.mrgentox.2008.05.012

Cited by 26 publications

(23 citation statements)

References 52 publications

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“…Many studies have indicated that germ cells and pluripotent cells use mechanisms to specifically limit the initial occurrence of spontaneous point mutations based on elevated levels of DNA repair pathways that ameliorate most potentially mutagenic DNA damage [16][17][18][19][20][21][22][23][24][25][26][27][28][29]. These findings all support the disposable soma theory in that they suggest that a more stringent mechanism to maintain genetic integrity operating in germ cells or pluripotent cells leads to a lower mutational load than that found in somatic cells or differentiated cells, respectively.…”

Section: Introductionmentioning

confidence: 74%

“…Several studies of DNA repair and cell death pathways have confirmed that these activities are elevated in germ cells relative to somatic cells [16][17][18][19][20][21][22][23][24]. Spontaneous DNA damage in spermatogenic cells is largely repaired through the base excision repair pathway or during replication by the mismatch repair system.…”

Section: Genetic Integrity In Germ Cellsmentioning

confidence: 99%

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Enhanced Genetic Integrity in Mouse Germ Cells1

Murphey

McLean

McMahan

et al. 2013

Biology of Reproduction

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Genetically based diseases constitute a major human health burden, and de novo germline mutations represent a source of heritable genetic alterations that can cause such disorders in offspring. The availability of transgenic rodent systems with recoverable, mutation reporter genes has been used to assess the occurrence of spontaneous point mutations in germline cells. Previous studies using the lacI mutation reporter transgenic mouse system showed that the frequency of spontaneous mutations is significantly lower in advanced male germ cells than in somatic cell types from the same individuals. Here we used this same mutation reporter transgene system to show that female germ cells also display a mutation frequency that is lower than that in corresponding somatic cells and similar to that seen in male germ cells, indicating this is a common feature of germ cells in both sexes. In addition, we showed that statistically significant differences in mutation frequencies are evident between germ cells and somatic cells in both sexes as early as mid-fetal stages in the mouse. Finally, a comparison of the mutation frequency in a general population of early type A spermatogonia with that in a population enriched for Thy-1-positive spermatogonia suggests there is heterogeneity among the early spermatogonial population such that a subset of these cells are predestined to form true spermatogonial stem cells. Taken together, these results support the disposable soma theory, which posits that genetic integrity is normally maintained more stringently in the germ line than in the soma and suggests that this is achieved by minimizing the initial occurrence of mutations in early germline cells and their subsequent gametogenic progeny relative to that in somatic cells.

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Section: Introductionmentioning

confidence: 74%

Section: Genetic Integrity In Germ Cellsmentioning

confidence: 99%

Enhanced Genetic Integrity in Mouse Germ Cells1

Murphey

McLean

McMahan

et al. 2013

Biology of Reproduction

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“…Mutation frequency declines during spermatogenic differentiation [Walter et al, 1998;Xu et al, 2008] suggesting that mechanisms have evolved to prevent germ cell transmission of genetic damage. Mutations induced by irradiation of A/B spermatogonia were shown to decline with cell differentiation, probably because of delayed apoptosis [Xu et al, 2008[Xu et al, , 2010. However, this protective process during spermatogenesis does not prevent all damaged cells from reaching the sperm stage, as shown by our studies and by others.…”

Section: Discussionmentioning

confidence: 99%

Direct and delayed X‐ray‐induced DNA damage in male mouse germ cells

Cordelli¹,

Eleuteri²,

Grollino³

et al. 2012

Environ and Mol Mutagen

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Sperm DNA integrity is essential for the accurate transmission of paternal genetic information. Various stages of spermatogenesis are characterized by large differences in radiosensitivity. Differentiating spermatogonia are susceptible to radiationinduced cell killing, but some of them can repair DNA damage and progress through differentiation. In this study, we applied the neutral comet assay, immunodetection of phosphorylated H2AX (g-H2AX) and the Sperm Chromatin Structure Assay (SCSA) to detect DNA strand breaks in testicular cells and spermatozoa at different times following in vivo X-ray irradiation. Radiation produced DNA strand breaks in testicular cells that were repaired within the first few hours after exposure. Spermatozoa were resistant to the induction of DNA damage, but non-targeted DNA lesions were detected in spermatozoa derived from surviving irradiated spermatogonia. These lesions formed while round spermatids started to elongate within the testicular seminiferous tubules. The transcription of pro-apoptotic genes at this time was also enhanced, suggesting that an apoptotic-like process was involved in DNA break production. Our results suggest that proliferating spermatogonia retain a memory of the radiation insult that is recognized at a later developmental stage and activates a process leading to DNA fragmentation. Environ. Mol. Mutagen. 53:429-439, 2012. V V C 2012 Wiley Periodicals, Inc.

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“…Primitive type A (collected from 6-day-old mice) and type A spermatogonia (collected from 8-day-old mice) have the highest spontaneous mutant frequencies, followed by type B spermatogonia, preleptotene spermatocytes, leptotene and zygotene spermatocytes, pachytene spermatocytes, round spermatids, and epididymal spermatozoa, all of which display a similarly low mutant frequency [1]. Ionizing radiation (IR) induces an increased mutant frequency that also declines as cells progress through spermatogenesis [3]. These data clearly show that one or more mechanisms reduce mutation load during spermatogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…It is unlikely, however, that DNA repair can mediate a decline in mutant frequency for fixed mutations. Apoptosis is another mechanism that may function in male germ cells to mediate a decline in mutant frequency during spermatogenesis by removing cells with a high mutant frequency [1,3]. However, little is known about the quantitative effects of apoptosis on mutant frequency, particularly in the germline.…”

Section: Introductionmentioning

confidence: 99%

BAX and Tumor Suppressor TRP53 Are Important in Regulating Mutagenesis in Spermatogenic Cells in Mice1

Vogel

McMahan

Herbert

et al. 2010

Biology of Reproduction

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During the first wave of spermatogenesis, and in response to ionizing radiation, elevated mutant frequencies are reduced to a low level by unidentified mechanisms. Apoptosis is occurring in the same time frame that the mutant frequency declines. We examined the role of apoptosis in regulating mutant frequency during spermatogenesis. Apoptosis and mutant frequencies were determined in spermatogenic cells obtained from Bax-null or Trp53-null mice. The results showed that spermatogenic lineage apoptosis was markedly decreased in Bax-null mice and was accompanied by a significantly increased spontaneous mutant frequency in seminiferous tubule cells compared to that of wild-type mice. Apoptosis profiles in the seminiferous tubules for Trp53-null were similar to control mice. Spontaneous mutant frequencies in pachytene spermatocytes and in round spermatids from Trp53-null mice were not significantly different from those of wild-type mice. However, epididymal spermatozoa from Trp53-null mice displayed a greater spontaneous mutant frequency compared to that from wild-type mice. A greater proportion of spontaneous transversions and a greater proportion of insertions/deletions 15 days after ionizing radiation were observed in Trp53-null mice compared to wild-type mice. Base excision repair activity in mixed germ cell nuclear extracts prepared from Trp53-null mice was significantly lower than that for wild-type controls. These data indicate that BAX-mediated apoptosis plays a significant role in regulating spontaneous mutagenesis in seminiferous tubule cells obtained from neonatal mice, whereas tumor suppressor TRP53 plays a significant role in regulating spontaneous mutagenesis between postmeiotic round spermatid and epididymal spermatozoon stages of spermiogenesis.

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Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis

Cited by 26 publications

References 52 publications

Enhanced Genetic Integrity in Mouse Germ Cells1

Enhanced Genetic Integrity in Mouse Germ Cells1

Direct and delayed X‐ray‐induced DNA damage in male mouse germ cells

BAX and Tumor Suppressor TRP53 Are Important in Regulating Mutagenesis in Spermatogenic Cells in Mice1

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