X-rays induce distinct patterns of somatic mutation in fetal versus adult hematopoietic cells

Title: X-rays induce distinct patterns of somatic mutation in fetal versus adult hematopoietic cells

Author: Li Liang, Li Deng, Marc S. Mendonca, Yanping Chen, Betty Zheng, Peter J. Stambrook, Changshun Shao, Jay A. Tischfield

Reference: DNA Repair, Volume 6, Issue 9, 1 September 2007, Pages 1380–1385

DOI: http://dx.doi.org/10.1016/j.dnarep.2007.04.005

Keywords: Ionizing radiation; Prenatal exposure; Mitotic recombination; Base excision repair; Developmental stage

Abstract: There are a variety of mechanisms and pathways whereby cells safeguard their genomes in the face of environmental insults that damage DNA. Whether each of these pathways is equally robust at specific developmental stages in mammals and whether they are also modulated in a tissue-specific manner, however, are unclear. Here, we report that ionizing radiation (IR) produces different types of somatic mutations in fetal cells compared with adult cells of the same lineage. While 1 Gy of X-ray significantly induced intragenic point mutations in T cells of adult mice, no point mutational effect was observed when applied to fetuses. Fetal exposure to IR, on the other hand, led to a significant elevation of mitotic recombination in T cells, which was not observed in adults. Base excision repair (BER) activity was significantly lower in fetal hematopoietic cells than in adult cells, due to a low level of DNA polymerase β, the rate-limiting enzyme in BER. In fetal hematopoietic cells, this low BER activity, together with a high rate of proliferation, causes X-ray-induced DNA lesions, such as base damage, single strand breaks and double strand breaks, to be repaired by homologous recombination, which we observe as mitotic recombination. Higher BER activity and a relatively lower rate of cell proliferation likely contribute to the significant induction of DNA point mutations in adults. Thus, the mutational response to IR is at least partly determined by the availability of specific repair pathways and other developmentally regulated phenotypes, such as mitotic index.

ＵＲＬ：http://www.sciencedirect.com/science/article/pii/S1568786407001693

Extreme sensitivity of adult neurogenesis to low doses of X-irradiation

Author: S. Mizumatsu, M.L. Monje, D.R. Morhardt et al.

Reference: Cancer Res. ― 2003. ― Vol. 63, № 14. ― P. 4021–4027.

Keywords: cognitive impairment, subgranular zone, hippocampal dentate gyrus, X-ray

Abstract: Therapeutic irradiation of the brain is associated with a number of adverse effects, including cognitive impairment. Although the pathogenesis of radiation-induced cognitive injury is unknown, it may involve loss of neural precursor cells from the subgranular zone (SGZ) of the hippocampal dentate gyrus and alterations in new cell production (neurogenesis). Young adult male C57BL mice received whole brain irradiation, and 6-48 h later, hippocampal tissue was assessed using immunohistochemistry for detection of apoptosis and numbers of proliferating cells and immature neurons. Apoptosis peaked 12 h after irradiation, and its extent was dose dependent. Forty-eight h after irradiation, proliferating SGZ cells were reduced by 93-96%; immature neurons were decreased from 40 to 60% in a dose-dependent fashion. To determine whether acute cell sensitivity translated into long-term changes, we quantified neurogenesis 2 months after irradiation with 0, 2, 5, or 10 Gy. Multiple injections of BrdUrd were given to label proliferating cells, and 3 weeks later, confocal microscopy was used to determine the percentage of BrdUrd-labeled cells that showed mature cell phenotypes. The production of new neurons was significantly reduced by X-rays; that change was dose dependent. In contrast, there were no apparent effects on the production of new astrocytes or oligodendrocytes. Measures of activated microglia indicated that changes in neurogenesis were associated with a significant inflammatory response. Given the known effects of radiation on cognitive function and the relationship between hippocampal neurogenesis and associated memory formation, our data suggest that precursor cell radiation response and altered neurogenesis may play a contributory if not causative role in radiation-induced cognitive impairment.

URL: http://www.ncbi.nlm.nih.gov/pubmed/12874001