This article may be too technical for most readers to understand.(October 2013) |
Studies with protons and HZE nuclei of relative biological effectiveness for molecular, cellular, and tissue endpoints, including tumor induction, demonstrate risk from space radiation exposure. [1] [2] [3] This evidence may be extrapolated to applicable chronic conditions that are found in space and from the heavy ion beams that are used at accelerators.
A necessary step for improving space radiation cancer risk assessment is to perform studies on the molecular pathways that can cause cancer initiation and progression, and to extend these studies to learn how such pathways can be disrupted by HZE ions, including both genetic and epigenetic modifications that are noted as the hallmarks of cancer (Figure 4-8). The goal of this research is to establish a more mechanistic approach to estimating risk and to answer questions, including whether HZE effects can be scaled from those of gamma rays, whether risk is linear with low dose-rate, and how individual radiation sensitivity impacts the risks for astronauts, a population that is selected for many factors related to excellence in health.
Energy deposition by HZE ions is highly heterogeneous with a localized contribution along the trajectory of each particle and lateral diffusion of energetic electrons (delta rays) that are many micrometers from the ion's path. [5] [6] These particles are, therefore, characterized by a high-LET, however, they contain a low-LET component fur to high-energy electrons that are ejected by ions as they traverse tissue. Biophysical models have shown that the energy deposition events by high-LET radiation produce differential DNA lesions, including complex DNA breaks, and that there are qualitative differences between high- and low-LET radiation, in both the induction and the repair of DNA damage. [7] [8] [9] The number of DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) that are produced by radiation varies little with radiation type: however, for high-LET radiation, a higher fraction of DNA damages are complex; i.e., clusters containing mixtures of two or more of the various types of damages (SSB, DSB, etc.) within a localized region of DNA. Complex damage is uncommon for endogenous damage or low-LET radiation, and has been associated with the increased RBE of densely ionizing radiation. The repair of DSB is known to occur through direct end-joining and homologous recombination processes. Indications are that:
or
While the high effectiveness in cell killing provides the rationale for heavy ion cancer therapy (hadron therapy), residual damage in surviving cells is of concern for carcinogenesis.
Heavy charged particles are very effective at producing chromosomal exchanges with RBE values exceeding 30 in interphase (as visualized using premature chromosome condensation) and 10 at the post-irradiation mitosis for energetic iron (Fe) ions. [10] The detailed RBE vs. LET relationship that was found for total exchanges is similar to that of earlier studies of mutation [11] [12] and in vitro neoplastic transformation. [13] For all of these endpoints, RBE peaks at around 100 to 200 keV/μm before it decreases at very high-LET. However, the quality of chromosome damage is different when heavy ions are compared to sparsely ionizing radiation. Large differences in gene expression are observed between x-rays and HZE ions, thus reflecting differences in damages response pathways. [14] [15] Qualitative differences in the type of gene mutations have also been reported. [16] [17] Novel multicolor fluorescence painting techniques of human chromosomes have clearly demonstrated that high-LET α-particles and Fe-ions induce many more complex rearrangements will ultimately lead to cell death. In fact, only a small fraction of the initial damage is transduction of late chromosomal damage has also been measured in the progeny of human lymphocytes that were exposed with much higher frequency in the progeny of cells that were exposed to heavy ions compared to gamma rays. [18]
Genomic instability has been observed both in vitro and in vivo in the progeny of cells that are irradiated with heavy ions in several model systems. [19] The presence of chromosomes that are lacking telomeres in the progeny of cells that were exposed to heavy ions is particularly interesting. Sabatier et al. [20] [21] found that rearrangements involving telomere regions are associated with chromosomal instability in human fibroblasts that occur many generations after exposure to accelerated heavy ions. Telomere dysfunction plays a crucial role in initiating or sustaining genomic instability, which is a major step in cancer progression. Heavy-ion-induced effects on telomere stability have also been studied using siRNA (small interfering ribonucleic acid) knockdown for components of DNA-dependent protein kinase (DNA-PK) in human lymphoblasts. Differential results were found for gamma rays and HZE nuclei, with iron nuclei being much more effective in producing DSB-telomere fusions after knockdown of DNA-PK. [22] Cells containing telomere-deficient chromosomes will either senesce or undergo breakage-fusion-bridge (B/F/B) cycles, thereby promoting genetic instability. The fate of normal cells that contain a single terminal deletion is unknown, but it has been shown that the loss of a single telomere in cancer cells can result in instability in multiple chromosomes. [23] [24] These recent results suggest that telomere instability could be an important early event in the pathway to cancer induction by HZE nuclei.
Animal studies have not conclusively demonstrated that HZE nuclei have higher carcinogenic effectiveness than low-LET radiation. Studies of animal carcinogenesis with HZE nuclei are extremely limited in number and the use of tumor-prone animals introduces bias into the results. Relative biological effectiveness factors comparing gamma rays to HZE ions were measured in mice or rats for tumors of the skin [25] and of the Harderian [26] [27] or mammary gland, [28] reaching values as high as 25 to 50 at low doses. However, the risk and detriment of cancer will not be fully characterized until the relationship between radiation quality and latency, where tumors appear earlier after high-LET irradiation, is adequately described. The earlier latency and increasing effectiveness that is found with HZE ions that are similar to those in earlier studies with neutrons, [29] [30] together with the lack of response of gamma rays that is seen in many low-dose studies, suggests that the scaling concepts that are used in current risk assessment approaches are unable to describe important qualitative effects, and that relative biological effectiveness factors may, in principle, be indefinable or a faulty concept.
Tumor Model | End-point | HZE type | Reference |
---|---|---|---|
Mice (B6CF1) | Life-shortening | C, Ar, Fe | Ainsworth (1986) [31] |
Mice (B6CH1) | Harderian gland | He, C, Ar, Fe | Fry et al. (1985) [26] |
Mice (B6CH1) | Harderian gland | He, Ne, Fe, Nb | Alpen et al. (1993) [27] |
Rat (Sprague-Dawley) | Skin tumors | Ne, Ar, Fe | Burns (1992) [25] |
Rat (Sprague-Dawley) | Mammary tumors | Fe | Dicello et al. (2004) [28] |
Mice (carcinoma-bearing animal (CBA)) | Leukemia, liver tumors | Fe, p, Si | Ullrich, in preparation [29] |
Recent studies have debated the relative importance of DNA damage and mutation or extracellular matrix remodeling and other non-targets effects as initiators of carcinogenesis. [32] Tissue effects that are independent of DNA damage and that have been associated with cancer initiation or progression include genomic instability, [33] extracellular matrix remodeling, persistent inflammation, and oxidative damage. [34] Other studies are exploring possible relationships between radiation and the activation of dormant tumors and the modulation of angiogenesis. [35]
So-called bystander or non-targeted effects may have enormous consequences for space exploration. Non-targeted effects may lead to a supra-linear dose-response curve at low doses, perhaps reducing the effectiveness of spacecraft shielding; but it may also provide protection by removing damaged cells from the organism. Both effects challenge the conventional linear no-threshold risk model assumption, which is currently adopted for radioprotection on Earth and in space. These effects also suggest important targets for biological countermeasures that are likely to be more effective than are countermeasures that target DNA damage.
Results in tissues suggest that differences in biological response between high- and low-LET differ depending on the model context that is considered (i.e., 2D vs. 3D vs. animal). As a result of the many types of particles, energies, and doses of interest that are in space, extensive animal experimentation has been prohibited by costs in the past. More recently, however, studies in 3D human coculture are proving to be an effective method with which to study cancer risks in a more realistic context. [32] [36]
In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in animals, such mutagens can therefore be carcinogens, although not all necessarily are. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes.
A telomere is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Telomeres are a widespread genetic feature most commonly found in eukaryotes. In most, if not all species possessing them, they protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the very ends of the DNA strand for a double-strand break.
Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.
Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic substances are not mutagenic. The alteration can have direct or indirect effects on the DNA: the induction of mutations, mistimed event activation, and direct DNA damage leading to mutations. The permanent, heritable changes can affect either somatic cells of the organism or germ cells to be passed on to future generations. Cells prevent expression of the genotoxic mutation by either DNA repair or apoptosis; however, the damage may not always be fixed leading to mutagenesis.
Radiation hormesis is the hypothesis that low doses of ionizing radiation are beneficial, stimulating the activation of repair mechanisms that protect against disease, that are not activated in absence of ionizing radiation. The reserve repair mechanisms are hypothesized to be sufficiently effective when stimulated as to not only cancel the detrimental effects of ionizing radiation but also inhibit disease not related to radiation exposure. It has been a mainstream concept since at least 2009.
A clastogen is a mutagenic agent that disturbs normal DNA related processes or directly causes DNA strand breakages, thus causing the deletion, insertion, or rearrangement of entire chromosome sections. These processes are a form of mutagenesis which if left unrepaired, or improperly repaired, can lead to cancer. Known clastogens include acridine yellow, benzene, ethylene oxide, arsenic, phosphine, mimosine, actinomycin D, camptothecin, methotrexate, methyl acrylate, resorcinol and 5-fluorodeoxyuridine. Additionally, 1,2-dimethylhydrazine is a known colon carcinogen and shows signs of possessing clastogenic activity. There are many clastogens not listed here and research is ongoing to discover new clastogens. Some known clastogens only exhibit clastogenic activity in certain cell types, such as caffeine which exhibits clastogenic activity in plant cells. Researchers are interested in clastogens for researching cancer, as well as for other human health concerns such as the inheritability of clastogen effected paternal germ cells that lead to fetus developmental defects.
DNA repair protein XRCC4 also known as X-ray repair cross-complementing protein 4 or XRCC4 is a protein that in humans is encoded by the XRCC4 gene. In addition to humans, the XRCC4 protein is also expressed in many other metazoans, fungi and in plants. The X-ray repair cross-complementing protein 4 is one of several core proteins involved in the non-homologous end joining (NHEJ) pathway to repair DNA double strand breaks (DSBs).
Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the NBN gene.
Particle therapy is a form of external beam radiotherapy using beams of energetic neutrons, protons, or other heavier positive ions for cancer treatment. The most common type of particle therapy as of August 2021 is proton therapy.
Health threats from cosmic rays are the dangers posed by cosmic rays to astronauts on interplanetary missions or any missions that venture through the Van-Allen Belts or outside the Earth's magnetosphere. They are one of the greatest barriers standing in the way of plans for interplanetary travel by crewed spacecraft, but space radiation health risks also occur for missions in low Earth orbit such as the International Space Station (ISS).
In radiobiology, the relative biological effectiveness is the ratio of biological effectiveness of one type of ionizing radiation relative to another, given the same amount of absorbed energy. The RBE is an empirical value that varies depending on the type of ionizing radiation, the energies involved, the biological effects being considered such as cell death, and the oxygen tension of the tissues or so-called oxygen effect.
The MRN complex is a protein complex consisting of Mre11, Rad50 and Nbs1. In eukaryotes, the MRN/X complex plays an important role in the initial processing of double-strand DNA breaks prior to repair by homologous recombination or non-homologous end joining. The MRN complex binds avidly to double-strand breaks both in vitro and in vivo and may serve to tether broken ends prior to repair by non-homologous end joining or to initiate DNA end resection prior to repair by homologous recombination. The MRN complex also participates in activating the checkpoint kinase ATM in response to DNA damage. Production of short single-strand oligonucleotides by Mre11 endonuclease activity has been implicated in ATM activation by the MRN complex.
Telomere-binding proteins function to bind telomeric DNA in various species. In particular, telomere-binding protein refers to TTAGGG repeat binding factor-1 (TERF1) and TTAGGG repeat binding factor-2 (TERF2). Telomere sequences in humans are composed of TTAGGG sequences which provide protection and replication of chromosome ends to prevent degradation. Telomere-binding proteins can generate a T-loop to protect chromosome ends. TRFs are double-stranded proteins which are known to induce bending, looping, and pairing of DNA which aids in the formation of T-loops. They directly bind to TTAGGG repeat sequence in the DNA. There are also subtelomeric regions present for regulation. However, in humans, there are six subunits forming a complex known as shelterin.
Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the SMC1B gene. SMC proteins engage in chromosome organization and can be broken into 3 groups based on function which are cohesins, condensins, and DNA repair.SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis. SMC1ß protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.
Astronauts are exposed to approximately 50-2,000 millisieverts (mSv) while on six-month-duration missions to the International Space Station (ISS), the Moon and beyond. The risk of cancer caused by ionizing radiation is well documented at radiation doses beginning at 100mSv and above.
HZE ions are the high-energy nuclei component of galactic cosmic rays (GCRs) which have an electric charge of +3 e or greater – that is, they must be the nuclei of elements heavier than hydrogen or helium.
Chromosomal instability (CIN) is a type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. More specifically, CIN refers to the increase in rate of addition or loss of entire chromosomes or sections of them. The unequal distribution of DNA to daughter cells upon mitosis results in a failure to maintain euploidy leading to aneuploidy. In other words, the daughter cells do not have the same number of chromosomes as the cell they originated from. Chromosomal instability is the most common form of genetic instability and cause of aneuploidy.
Travel outside the Earth's protective atmosphere, magnetosphere, and in free fall can harm human health, and understanding such harm is essential for successful crewed spaceflight. Potential effects on the central nervous system (CNS) are particularly important. A vigorous ground-based cellular and animal model research program will help quantify the risk to the CNS from space radiation exposure on future long distance space missions and promote the development of optimized countermeasures.
Telomeres, the caps on the ends of eukaryotic chromosomes, play critical roles in cellular aging and cancer. An important facet to how telomeres function in these roles is their involvement in cell cycle regulation.
Jan Karlseder is an Austrian molecular biologist, a professor in the Molecular and Cellular Biology Laboratory, the Director of the Paul F. Glenn Center for Biology of Aging Research and the holder of the Donald and Darlene Shiley Chair at the Salk Institute for Biological Studies.
{{cite book}}
: CS1 maint: multiple names: authors list (link){{cite book}}
: |journal=
ignored (help)This article incorporates public domain material from Human Health and Performance Risks of Space Exploration Missions (PDF). National Aeronautics and Space Administration. (NASA SP-2009-3405, pp. 141-144).