Genome-based, mechanism-driven computational modeling of risks of ionizing radiation: The next frontier in genetic risk estimation?

Sankaranarayanan, K.; Nikjoo, Hooshang

doi:10.1016/j.mrrev.2014.12.003

Cited by 9 publications

(7 citation statements)

References 129 publications

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“…It is known that there are differences in radiation sensitivity between human and mouse. For example, 1 Gy or less is the threshold of immature oocyte sensitivity to be sterile in mice, but about 5 Gy for humans 12,35 . Therefore, it doesn't mean that the mutations found in the mouse experiment are directly induced in humans.…”

Section: Discussionmentioning

confidence: 99%

“…However, in this study, we investigated the effect on mature oocytes as a maternal exposure model. This stage was selected because immature mouse oocytes are sensitive to the lethal effect of IR, which makes it difficult to assess the effect on the genome 12 , and the exposure of mice to 0.45 Gy of radiation causes a severe loss of small primordial follicles from the ovary 13 . Here, we characterized and quantified the de novo mutations, mainly base substitutions and small indels, on spermatogonia and mature oocytes through WGS and consider the transgenerational effects of IR at the genome-wide level.…”

mentioning

confidence: 99%

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Characteristics of induced mutations in offspring derived from irradiated mouse spermatogonia and mature oocytes

Satoh¹,

Asakawa²,

Nishimura³

et al. 2020

Sci Rep

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The exposure of germ cells to radiation introduces mutations in the genomes of offspring, and a previous whole-genome sequencing study indicated that the irradiation of mouse sperm induces insertions/deletions (indels) and multisite mutations (clustered single nucleotide variants and indels). However, the current knowledge on the mutation spectra is limited, and the effects of radiation exposure on germ cells at stages other than the sperm stage remain unknown. Here, we performed whole-genome sequencing experiments to investigate the exposure of spermatogonia and mature oocytes. We compared de novo mutations in a total of 24 F1 mice conceived before and after the irradiation of their parents. The results indicated that radiation exposure, 4 Gy of gamma rays, induced 9.6 indels and 2.5 multisite mutations in spermatogonia and 4.7 indels and 3.1 multisite mutations in mature oocytes in the autosomal regions of each F1 individual. Notably, we found two types of deletions, namely, small deletions (mainly 1~12 nucleotides) in non-repeat sequences, many of which showed microhomology at the breakpoint junction, and single-nucleotide deletions in mononucleotide repeat sequences. The results suggest that these deletions and multisite mutations could be a typical signature of mutations induced by parental irradiation in mammals.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Characteristics of induced mutations in offspring derived from irradiated mouse spermatogonia and mature oocytes

Satoh¹,

Asakawa²,

Nishimura³

et al. 2020

Sci Rep

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“…These high-energy waves or particles interact with the genetic material in the nucleus, damaging the DNA and triggering a cascade of signalling events and activities aimed at repairing the damage. This process, however, may result in not only the repair of the DNA, but also the formation of mutations (Sankaranarayanan & Nikjoo, 2015). Of note, radiation is not likely to impact only one gene; more often than not, the random nature of energy deposition by radiation results in mutations to many genes and genomic sites clustered in the same area (Sankaranarayanan & Nikjoo, 2015;.…”

Section: Biological Plausibilitymentioning

confidence: 99%

“…This process, however, may result in not only the repair of the DNA, but also the formation of mutations (Sankaranarayanan & Nikjoo, 2015). Of note, radiation is not likely to impact only one gene; more often than not, the random nature of energy deposition by radiation results in mutations to many genes and genomic sites clustered in the same area (Sankaranarayanan & Nikjoo, 2015;. Many of the radiation-induced mutations have been documented as deletions , often of differing sizes in a number of different genes (Sankaranarayanan & Nikjoo, 2015).…”

Section: Biological Plausibilitymentioning

confidence: 99%

Adverse Outcome Pathway on deposition of energy leading to lung cancer

2023

OECD Series on Adverse Outcome Pathways

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Despite its widespread recognition in chemical toxicology, the adverse outcome pathway (AOP) framework has not been fully explored in the radiation field to guide relevant research and subsequent risk assessment. Development of a radiation relevant AOP is described here using a case example of lung cancer. Lung cancer is a major public health problem world-wide, causing the deaths of an estimated 1.5 million people annually; it imposes a major health-care burden. Numerous environmental factors are known contributors including both chemical (e.g. asbestos, air pollution and arsenic) and radiation stressors (e.g. radon gas). Radon gas is the second leading cause of lung cancer in North America. Evidence suggests that environmental and indoor radon exposure constitutes a significant public health problem. The mechanism of lung cancer development from exposure to radon gas is unclear. Data suggest that cytogenetic damage from radon decay progeny may be an important contributor. This AOP defines a path to cancer using key events related to DNA damage response and repair. The molecular initiating event (MIE) which represents the first chemical interaction with the cell is identified as the deposition of ionizing energy. Energy deposited onto a cell can lead to multiple ionization events to targets such as DNA. This energy will break DNA double strands (KE1) and initiate double strand break (DSB) repair machinery. In higher eukaryotes, this occurs through nonhomologous end joining (NHEJ) which is a quick and efficient, but error-prone process (KE2). If DSBs occur in regions of the DNA transcribing critical genes, then mutations (KE3) generated through faulty repair may alter the function of these genes or may cause chromosomal aberrations (KE4), resulting in genomic instability. These events will alter the functions of many gene products and impact cellular pathways such as cell growth, cell cycling, and apoptosis. With these alterations, cell proliferation (KE5) will be promoted by escaping the regulatory control and form hyperplasia in lung epithelial cells, leading eventually to lung cancer (AO) induction and metastasis. The overall weight of evidence for this AOP is strong. The uncertainties and inconsistencies surrounding this AOP are centred on dose-response relationships associated with dose, dose-rates and radiation quality. The proposed AOP will act as a case example to motivate more researchers in the radiation field to use the AOP framework to effectively exchange knowledge and identify research gaps in the area of low dose risk assessment. 5 ContentsForeword .

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“…Furthermore, the baseless testimony by some scientists adversely affects the consensus formation between the administration and the public, which could be the field of trans-science [26]. The job of scientists is not to decide whether LD radiation is safe or dangerous but to provide evidence-based quantitative data for risk assessment [27] and publicize the data to the public in a fair and easy-to-understand manner.…”

Section: Why Have Low-dose Radiation Issues Not Been Resolved Despitmentioning

confidence: 99%

Effects of Radioactive Cesium-Containing Water on Mice

Nakajima

2019

Low-Dose Radiation Effects on Animals and Ecosystems

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To investigate the transgenerational effect of chronic low-dose-rate internal radiation exposure after the Fukushima Nuclear Power Plant accident in Japan, every generation of mice was maintained in a radioisotope facility with free access to drinking water containing 137 CsCl (100 Bq/ml). Descendent mice were assessed for γ-H2AX foci in hepatocytes, the micronucleus test and chromosome aberration analysis in bone marrow cells, DNA mutations in the liver, tumorigenicity in the lung, oxidative stress in blood plasma, and metabolome analysis in the heart. In this chapter, the author tries to introduce that animal experiments are useful to understand low-dose and low-dose-rate radiation effects.

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Genome-based, mechanism-driven computational modeling of risks of ionizing radiation: The next frontier in genetic risk estimation?

Cited by 9 publications

References 129 publications

Characteristics of induced mutations in offspring derived from irradiated mouse spermatogonia and mature oocytes

Characteristics of induced mutations in offspring derived from irradiated mouse spermatogonia and mature oocytes

Adverse Outcome Pathway on deposition of energy leading to lung cancer

Effects of Radioactive Cesium-Containing Water on Mice

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