Irradiation and Alterations in Hippocampal DNA Methylation
<p>Following exposure to ionizing irradiation as part of cancer treatment, a nuclear attack or incident at a power plant, or space missions, effects on DNA methylation in and outside the brain might involve the bi-directional gut–brain axis and reactive oxygen species (ROS) in mitochondria. Irradiation has been shown to increase the hippocampal levels of the DNMT3, TET 1, and TET 3 enzymes involved in DNA methylation. Alterations in levels of 5 mC and 5 hmC, in turn, might be related to the increased levels of the injury markers 8-OHDG and 4-HNE observed following irradiation. Figure was generated using Biorender.com software.</p> "> Figure 2
<p>Methylation and demethylation mechanisms. (<b>A</b>) Diagram depicts methyltransferase enzymes and their functional roles, as well as the TET family of methyl-hydroxylases. (<b>B</b>) TET-family enzymes actively demethylate 5mC via step-wise oxidation followed by TDG-mediated glycosylation and base-excision repair of the abasic site to cytosine. Figure was generated using Biorender.com software.</p> "> Figure 3
<p>Radiation studies in cancer patients and in preclinical models have highlighted that therapeutic strategies to control the tumor are often associated with behavioral alterations and cognitive injury, involving detrimental effects on synaptic function. It is recognized that simulated space irradiation is not only pertinent to astronauts during and following missions. There is increasing interest in the use of radiation as part of the space environment in cancer therapy, including the use of protons and carbon in cancer patients. Detrimental effects on the blood–brain barrier and neuroinflammation might be a large contributor to these detrimental effects as well. These detrimental effects are not limited to radiation therapy and are often seen following chemotherapy and immunotherapy as well. The effects of radiation on the brain, including those of often-used clinical radiation and simulated space irradiation, are associated with epigenetic alterations. The gut–brain axis and ROS might play a role in these pathways. Figure was generated using Biorender.com software.</p> "> Figure 4
<p>Diagram depicting proteins that bind to methylated DNA, sorted by the type of methylation. A “?” denotes conflicting evidence or a lack of validation by other studies. For 5mC, we have also indicated whether the protein interacts with CpG or CpA sites. Figure was generated using Biorender.com software.</p> "> Figure 5
<p>Behavioral and cognitive tests are often used to assess the effects of irradiation on the brain. Historically, the hippocampus has been the focus of studies assessing the effects of irradiation on the brain. For example, neurogenesis has been studied, and based on the susceptibility of the hippocampus to radiation effects, hippocampal sparing is being considered in radiation therapy. However, it is recognized that the effects of irradiation are seen at doses below those affecting neurogenesis. The quality of nest building is considered a measure related to the activities of daily life for humans. In the water maze, spatial navigation to a visible or hidden platform or spatial memory retention in a probe trial (no platform) is assessed. Fear learning and memory can be assessed in the fear conditioning test. Depending on the design, either hippocampus-dependent contextual and/or hippocampus-independent cued fear conditioning is assessed. In the acoustic startle response test, the response to an acoustic stimulus, sometimes in the presence of another aversive stimulus, is assessed. In the Y maze, hippocampus-dependent spatial alternation is assessed in a single trial. In the spatial Y maze version of this test, there are two trials. In the first trial, access to one arm is blocked. Following a delay, access to the originally blocked arm is made available, and visits to that arm and entries into that arm are analyzed. Alterations in behavioral and cognitive performance following irradiation are associated with epigenetic changes in pertinent brain regions. These epigenetic effects are not limited to the brain and are also seen in other tissues following irradiation. Figure was generated using Biorender.com software.</p> "> Figure 6
<p>Methodologies for genome-wide profiling of cytosine methylation. Bisulfite converts non-methylated bases to uracil, which is then converted to thymidine via library amplification. Conventional bisulfite-Seq fails to distinguish 5mC from 5hmC. TAB-Seq and other related approaches use β glucosyltransferase (βGT) to protect 5hmC, followed by enzymatic or chemical conversion of non-protected bases. In the case of TAB-Seq, TET is used to sequentially oxidize 5mC, followed by bisulfite treatment, which converts the resulting 5caC or 5fC to uracil but spares the protected 5hmC. MeDIP-Seq and MBD-Seq use antibodies, or methyl-binding domains, to pull down methylated chromatin fragments. MeDIP-Seq can interrogate 5mC, 5hmC, 5fc, or 5caC through the use of specific antibodies. MRE-Seq digests DNA with restriction enzymes that cut specific CpG sequences or are blocked by methylation of these CpG sequences. Sites that are resistant to digestion are scored as methylated. Recently, “nanopore” sequencing of DNA has been used to create genome-wide maps of 5mC and 5hmC at single-nucleotide resolution. Figure was generated using Biorender.com software.</p> "> Figure 7
<p>Selected genes from the “synapse” gene ontology were associated with increased 5hmC following <sup>65</sup>Fe and <sup>28</sup>Si irradiation of the mouse hippocampus. The genes highlighted in purple are radiation signature genes that were associated with increased 5hmc in response to a proton, <sup>65</sup>Fe, or <sup>28</sup>Si irradiation. Data were adapted and selected from [<a href="#B39-epigenomes-08-00027" class="html-bibr">39</a>].</p> ">
Abstract
:1. Introduction
2. Methylation and Demethylation—Modifications and Enzymes
3. Potential Mechanisms by Which Radiation Exposure Regulates DNA Methylation Enzymes
4. Regulation of Gene Expression
5. Cognitive Tests Typically Used in Radiation Studies
6. Effects of Radiation on Hippocampal DNA Methylation and Cognitive Measures: Association between Cognitive Injury, Hippocampal Networks, Brain Injury Biomarkers, and DNA Methylation
6.1. Cognitive Injury
6.2. DNA Methylation Changes Show a Tissue-Dependent Response; Neurodegenerative Pathways
7. Genome-Wide Methylation Analyses
8. Integrated Analyses of Radiation Effects on Hippocampal Cognitive and Molecular Measures: Overlapping DNA Methylation Changes across Various Doses and Ion Types
9. Summary
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Kim, M.; Zou, W. Ultra-high dose rate FLASH radiation therapy for cancer. Med. Phys. 2023, 50 (Suppl. 1), 58–61. [Google Scholar] [CrossRef] [PubMed]
- Tsang, D.; Patel, S. Proton beam therapy for cancer. CMAJ 2019, 191, E664–E666. [Google Scholar] [CrossRef] [PubMed]
- Wickert, R.; Tessonier, T.; Deng, M.H.; Adeberg, S.; Seidensaal, K.; Hoeltgen, L.; Debus, J.; Herfath, K.; Harrabi, S. Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma. Cancers 2022, 14, 5865. [Google Scholar] [CrossRef] [PubMed]
- Orlandi, E.; Barcellini, A.; Vischioni, B.; Fiore, M.R.; Vitolo, V.; Iannalfi, A.; Bonora, M.; Chalaszczyk, A.; Ingargiola, R.; Riva, G.; et al. The Role of Carbon Ion Therapy in the Changing Oncology Landscape—A Narrative Review of the Literature and the Decade of Carbon Ion Experience at the Italian National Center for Oncological Hadrontherapy. Cancers 2023, 15, 5068. [Google Scholar] [CrossRef] [PubMed]
- Mohan, R. A Review of Proton Therapy—Current Status and Future Directions. Precis. Radiat. Oncol. 2022, 6, 164–176. [Google Scholar] [CrossRef] [PubMed]
- Tessonnier, T.; Ecker, S.; Besuglow, J.; Naumann, J.; Mein, S.; Longarino, F.K.; Ellerbrock, M.; Ackermann, B.; Winter, M.; Brons, S.; et al. Commissioning of Helium Ion Therapy and the First Patient Treatment With Active Beam Delivery. Int. J. Radiat. Oncol. Biol. Phys. 2023, 116, 935–948. [Google Scholar] [CrossRef]
- Mairani, A.; Mein, S.; Blakely, E.; Debus, J.; Durante, M.; Ferrari, A.; Fuchs, H.; Georg, D.; Grosshans, D.R.; Guan, F.; et al. Roadmap: Helium ion therapy. Phys. Med. Biol. 2022, 67, 15TR02. [Google Scholar] [CrossRef] [PubMed]
- Bonaccorsi, S.G.; Tessonnier, T.; Hoeltgen, L.; Meixner, E.; Harrabi, S.; Hörner-Rieber, J.; Haberer, T.; Abdollahi, A.; Debus, J.; Mairani, A. Exploring Helium Ions’ Potential for Post-Mastectomy Left-Sided Breast Cancer Radiotherapy. Cancers 2024, 16, 410. [Google Scholar] [CrossRef] [PubMed]
- Chaklai, A.; Canaday, P.; O’Niel, A.; Cucinotta, F.A.; Sloop, A.; Gladstone, D.; Pogue, B.; Zhang, R.; Sunnerberg, J.; Kheirollah, A.; et al. Effects of UHDR and conventional irradiation on behavioral and cognitive performance and the percentage of Ly6G+ CD45+ cells in the hippocampus. Int. J. Mol. Sci. 2023, 24, 12497. [Google Scholar] [CrossRef]
- Williams, M.T.; Sugimoto, C.; Regan, S.L.; Pitzer, E.M.; Fritz, A.L.; Sertorio, M.; Mascia, A.E.; Vatner, R.E.; Perentesis, J.P.; Vorhees, C.V. Cognitive and behavioral effects of whole brain conventional or high dose rate (FLASH) proton irradiation in a neonatal Sprague Dawley rat model. PLoS ONE 2022, 17, e024007. [Google Scholar] [CrossRef]
- Montay-Gruel, P.; Bouchet, A.; Jaccard, M.; Patin, D.; Serduc, R.; Aim, W.; Petersson, K.; Petit, B.; Bailat, C.; Bourhis, J.; et al. X-rays can trigger the FLASH effect: Ultra-high dose-rate synchrotron light source prevents normal brain injury after whole brain irradiation in mice. Radiother. Oncol. 2018, 129, 582–588. [Google Scholar] [CrossRef]
- Alaghband, Y.; Cheeks, S.N.; Allen, B.D.; Montay-Gruel, P.; Doan, N.-L.; Petit, B.; Jorge, P.G.; Giedzinski, E.; Acharya, M.M.; Vozenin, M.-C.; et al. Neuroprotection of radiosensitive juvenile mice by ultra-high dose rate FLASH irradiation. Cancers 2020, 12, 1671. [Google Scholar] [CrossRef]
- Montay-Gruel, P.; Acharya, M.M.; Gonçalves Jorge, P.; Petit, B.; Petridis, I.G.; Fuchs, P.; Leavitt, R.; Petersson, K.; Gondré, M.; Ollivier, J.; et al. Hypofractionated FLASH-RT as an effective treatment against glioblastoma that reduces neurocognitive side effects in mice. Clin. Cancer Res. 2021, 27, 775–784. [Google Scholar] [CrossRef]
- Braby, L.A.; Raber, J.; Chang, P.; Dinges, D.; Goodhead, D.; Herr, D.W.; Hopewell, J.; Huff, J.; Krull, K.; Linnehan, R.; et al. Radiation Exposures in Space and the Potential for Central Nervous System Effects (Phase II); Ncrp SC 1-24P2 Report; National Council on Radiation Protection and Measurements: Bethesda, MD, USA, 2019. [Google Scholar]
- Raber, J.; Rola, R.; LeFevour, A.; Morhardt, D.; Curley, J.; Mizumatsu, S.; VandenBerg, S.R.; Fike, J.R. Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis. Radiat. Res. 2004, 162, 39–47. [Google Scholar] [CrossRef]
- Rola, R.; Raber, J.; Rizk, A.; Otsuka, S.; VandenBerg, S.R.; Morhardt, D.R.; Fike, J.R. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp. Neurol. 2004, 188, 316–330. [Google Scholar] [CrossRef]
- Rola, R.; Obenaus, A.; Nelson, G.A.; Otsuka, S.; Limoli, C.L.; Fike, J.R. High LET irradiation induced inflammation and persistent changes in markers of hippocampal neurogenesis. Radiat. Res. 2005, 164, 556–560. [Google Scholar] [CrossRef]
- Sweet, T.B.; Hurley, S.D.; Wu, M.D.; Olschowka, J.A.; Williams, J.P.; O’Banion, M.K. Neurogenic Effects of Low-Dose Whole-Body HZE (Fe) Ion and Gamma Irradiation. Radiat. Res. 2016, 186, 614–623. [Google Scholar] [CrossRef]
- Mao, X.W.; Favre, C.J.; Fike, J.R.; Kubinova, L.; Anderson, E.; Campbell-Beachler, M.; Jones, T.; Smith, A.; Rightnar, S.; Nelson, G.A. High-LET radiation-induced response of microvessels in the Hippocampus. Radiat. Res. 2010, 173, 486–493. [Google Scholar] [CrossRef]
- Allen, A.; Raber, J.; Chakraborti, A.; Sharma, S.; Fike, J.R. 56Fe irradiation alters spine density and dendritic complexity in the mouse hippocampus. Radiat. Res. 2015, 184, 586–594. [Google Scholar] [CrossRef] [PubMed]
- Raber, J.; Allen, A.R.; Sharma, S.; Allen, B.; Rosi, S.; Olsen, R.H.J.; Davis, M.J.; Eiwaz, M.; Fike, J.R.; Nelson, G.A. Effects of proton and combined proton and 56Fe irradiation on the hippocampus. Radiat. Res. 2016, 185, 20–30. [Google Scholar] [CrossRef] [PubMed]
- Raber, J.; Allen, A.; Weber, S.; Chakraborti, A.; Sharma, S.; Fike, J.R. Effect of behavioral testing on spine density of basal dendrites in the CA1 region of the hippocampus modulated by 56Fe irradiation. Behav. Brain Res. 2016, 302, 263–268. [Google Scholar] [CrossRef]
- Acharya, M.; Baulch, J.E.; Kllein, P.; Baddour, A.; Apodaca, L.; Kramar, E.; Alikhani, L.; Garcia, C.; Angulo, M.; Batra, R.; et al. New concerns for neurocognitive function during deep space exposures to chronic, low dose-rate, neutron radiation. eNeuro 2019, 6. [Google Scholar] [CrossRef]
- Parihar, V.K.; Allen, B.; Tran, K.; Macaraeg, T.; Chu, E.; Kwok, S.; Chmielewski, N.; Craver, B.; Baulch, J.; Achaya, M.; et al. What happens to your brain on the way to Mars? Sci. Adv. 2015, 1, e1400256. [Google Scholar] [CrossRef]
- Begolly, S.; Shrager, P.G.; Olschowka, J.A.; Williams, J.P.; O’Banion, M.K. Fractionation Spares Mice From Radiation-Induced Reductions in Weight Gain But Does Not Prevent Late Oligodendrocyte Lineage Side Effects. Int. J. Radiat. Oncol. Biol. Phys. 2016, 96, 449–457. [Google Scholar] [CrossRef]
- Raber, J.; Yamazaki, J.; Torres, E.; Kirchoff, N.; Stagaman, K.; Sharpton, T.J.; Turker, M.; Kronenberg, A. Combined effects of three high energy charged particle beams important for space flight on brain, behavioral and cognitive endpoints in B6D2F1 female and male mice. Frontiers 2019, 10, 179. [Google Scholar] [CrossRef]
- Raber, J.; Fuentes Anaya, A.; Torres, E.; Lee, J.; Boutros, S.; Grygoryev, D.; Hammer, A.; Kasschau, K.; Sharpton, T.; Turker, M.; et al. Effects of Six Sequential Charged Particle Beams on Behavioral and Cognitive Performance in B6D2F1 Female and Male Mice. Front. Physiol. 2020, 11, 959. [Google Scholar] [CrossRef]
- Lenarczyk, M.; Kronenberg, A.; Mader, M.; Komorowski, R.; Hopewell, J.; Baker, J. Exposure to multiple ion beams, broadly representative of galactic cosmic rays, causes perivascular cardiac fibrosis in mature male rats. PLoS ONE 2023, 18, e0283877. [Google Scholar] [CrossRef]
- Weil, M.M.; Ray, F.A.; Genik, P.C.; Yu, Y.; McCarthy, M.; Fallgren, C.M.; Ullrich, R.L. Effects of 28Si ions, 56Fe ions, and protons on the induction of murine acute myeloid leukemia and hepatocellular carcinoma. PLoS ONE 2014, 9, e104819. [Google Scholar] [CrossRef]
- Nzabarushimana, E.; Miousse, I.R.; Shao, L.; Chang, J.; Allen, A.R.; Turner, J.; Stewart, B.; Raber, J.; Koturbash, I. Long-term epigenetic effects of exposure to low doses of Fe-56 in the mouse lung. J. Radiat. Res. 2014, 55, 823–828. [Google Scholar] [CrossRef] [PubMed]
- Miousse, I.; Kutanzi, K.; Koturbash, I. Effects of Ionizing Radiation on DNA Methylation: From Experimental Biology to Clinical Applications. Int. J. Radiat. Biol. 2017, 93, 457–469. [Google Scholar] [CrossRef] [PubMed]
- Koturbash, I.; Miousse, I.R.; Sridharan, V.; Nzabarushimana, E.; Skinner, C.M.; Melnyk, S.B.; Pavliv, O.; Hauer-Jensen, M.; Nelson, G.A.; Boerma, M. Radiation-induced changes in DNA methylation of repetitive elements in the mouse heart. Mutat. Res./Fundam. Mol. Mech. Mutagen. 2016, 787, 43–53. [Google Scholar] [CrossRef]
- Prior, S.; Miousse, I.R.; Nzabarushimana, E.; Pathak, R.; Skinner, C.; Kutanzi, K.R.; Allen, A.R.; Raber, J.; Tackett, A.J.; Hauer-Jensen, M.; et al. Densely ionizing radiation affects DNA methylation of selective LINE-1 elements. Environ. Res. 2016, 150, 470–481. [Google Scholar] [CrossRef]
- Christofidou-Solomidou, M.; Pietrofesa, R.A.; Arguiri, E.; Schweitzer, K.S.; Berdyshev, E.V.; McCarthy, M.; Corbitt, A.; Alwood, J.S.; Yu, Y.; Globus, R.K.; et al. Space radiation-associated lung injury in a murine model. Am. J. Physiol. Lung Cell Mol. Physiol. 2015, 308, L416–L428. [Google Scholar] [CrossRef]
- Du, J.; Kageyama, S.I.; Yamashita, R.; Tanaka, K.; Okumura, M.; Motegi, A.; Hojo, H.; Nakamura, M.; Hirata, H.; Sunakawa, H.; et al. Transposable elements potentiate radiotherapy-induced cellular immune reactions via RIG-I-mediated virus-sensing pathways. Comm. Biol. 2023, 6, 818. [Google Scholar] [CrossRef]
- Impey, S.; Pelz, C.; Tafessu, A.; Marzulla, T.; Turker, M.S.; Raber, J. Proton irradiation induces persistent and tissue-specific DNA methylation changes in the left ventricle and hippocampus. BMC Genom. 2016, 17, 273. [Google Scholar] [CrossRef]
- Impey, S.; Jopson, T.; Pelz, C.; Tafessu, A.; Fareh, F.; Zuloaga, D.; Marzulla, T.; Riparip, L.-K.; Stewart, B.; Rosi, S.; et al. Bi-directional and shared epigenomic signatures following proton and 56Fe irradiation. Sci. Rep. 2017, 7, 10227. [Google Scholar] [CrossRef]
- Torres, E.R.; Hall, R.; Choi, J.; Impey, S.; Pelz, C.; Lindner, J.; Stevens, J.; Raber, J. Integrated metabolomics-DNA methylation analysis reveals significant long-term tissue-dependent directional alterations in aminoacyl-tRNA biosynthesis in the left ventricle of the heart and hippocampus following proton irradiation. Front. Mol. Biosci. 2019, 6, 77. [Google Scholar] [CrossRef]
- Impey, S.; Pelz, C.; Riparip, L.K.; Tafessu, A.; Fareh, F.; Zuloaga, D.G.; Marzulla, T.; Stewart, B.; Rosi, S.; Turker, M.S.; et al. Postsynaptic density radiation signature following space irradiation. Front. Physiol. 2023, 14, 1215535. [Google Scholar] [CrossRef]
- Impey, S.; Jopson, T.; Pelz, C.; Tafessu, A.; Fareh, F.; Zuloaga, D.; Marzulla, T.; Riparip, L.-L.; Stewart, B.; Rosi, S.; et al. Short- and long-term effects of 56Fe irradiation on cognition and hippocampal DNA methylation and gene expression. BMC Genom. 2016, 17, 825. [Google Scholar] [CrossRef] [PubMed]
- Suzuki, M.M.; Bird, A. DNA methylation landscapes: Provocative insights from epigenomics. Nat. Rev. Genet. 2008, 9, 465–476. [Google Scholar] [CrossRef] [PubMed]
- Mattei, A.L.; Bailly, N.; Meissner, A. DNA methylation: A historical perspective. Trends Genet. 2022, 38, 676–707. [Google Scholar] [CrossRef] [PubMed]
- Xie, W.; Barr, C.L.; Kim, A.; Yue, F.; Lee, A.Y.; Eubanks, J.; Dempster, E.L.; Ren, B. Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell 2012, 148, 816–831. [Google Scholar] [CrossRef]
- Varley, K.E.; Gertz, J.; Bowling, K.M.; Parker, S.L.; Reddy, T.E.; Pauli-Behn, F.; Cross, M.K.; Williams, B.A.; Stamatoyannopoulos, J.A.; Crawford, G.E.; et al. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res. 2013, 23, 555–567. [Google Scholar] [CrossRef] [PubMed]
- Arand, J.; Spieler, D.; Karius, T.; Branco, M.R.; Meilinger, D.; Meissner, A.; Jenuwein, T.; Xu, G.; Leonhardt, H.; Wolf, V.; et al. In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet. 2012, 8, e1002750. [Google Scholar] [CrossRef]
- Tahiliani, M.; Koh, K.P.; Shen, Y.; Pastor, W.A.; Bandukwala, H.; Brudno, Y.; Agarwal, S.; Iyer, L.M.; Liu, D.R.; Aravind, L.; et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009, 324, 930–935. [Google Scholar] [CrossRef]
- Ito, S.; Shen, L.; Dai, Q.; Wu, S.C.; Collins, L.B.; Swenberg, J.A.; He, C.; Zhang, Y. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 2011, 333, 1300–1303. [Google Scholar] [CrossRef]
- Munzel, M.; Globisch, D.; Bruckl, T.; Wagner, M.; Welzmiller, V.; Michalakis, S.; Muller, M.; Biel, M.; Carell, T. Quantification of the sixth DNA base hydroxymethylcytosine in the brain. Angew. Chem. Int. Ed. Engl. 2010, 49, 5375–5377. [Google Scholar] [CrossRef] [PubMed]
- He, Y.F.; Li, B.Z.; Li, Z.; Liu, P.; Wang, Y.; Tang, Q.; Ding, J.; Jia, Y.; Chen, Z.; Li, L.; et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 2011, 333, 1303–1307. [Google Scholar] [CrossRef]
- Wu, X.; Zhang, Y. TET-mediated active DNA demethylation: Mechanism, function and beyond. Nat. Rev. Genet. 2017, 18, 517–534. [Google Scholar] [CrossRef]
- Acharya, M.; Baddour, A.; Kawashita, T.; Allen, B.; Syage, A.; Nguyen, T.; Yoon, N.; Giedzinski, E.; Yu, L.; Parihar, V.K.; et al. Epigenetic determinants of space radiation-induced cognitive dysfunction. Sci. Rep. 2017, 7, 42885. [Google Scholar] [CrossRef]
- Balaban, R.; Nemoto, S.; Finkel, T. Mitochondria, oxidants, and aging. Cell 2005, 120, 483–495. [Google Scholar] [CrossRef]
- Szumiel, I. Ionizing radiation-induced oxidative stress, epigenetic changes and genomic instability: The pivotal role of mitochondria. Int. J. Radiat. Biol. 2015, 91, 1–12. [Google Scholar] [CrossRef]
- Mahmood, J.; Jelveh, S.; Calveley, V.; Zaidi, A.; Doctrow, S.R.; Hill, R. Mitigation of radiation induced lung injury by genestein and EUK-207. Int. J. Radiat. Biol. 2011, 87, 889–901. [Google Scholar] [CrossRef]
- Doctrow, S.R.; Lopez, A.; Schock, A.M.; Duncan, N.E.; Jourdan, M.M.; Olasz, E.B.; Moulder, J.E.; Fish, B.L.; Mader, M.; Lazar, J.; et al. A Synthetic Superoxide Dismutase/Catalase Mimetic EUK-207 Mitigates Radiation Dermatitis and Promotes Wound Healing in Irradiated Rat Skin. J. Investig. Dermatol. 2012, 133, 1088–1096. [Google Scholar] [CrossRef]
- Gao, F.; Fish, B.; Szabo, A.; Doctrow, S.; Kma, L.; Molthen, R.; Moulder, J.; Jacobs, E.; Medhora, M. Short-term treatment with a SOD/Catalase mimetic, EUK-207, mitigates pneumonitis and fibrosis after single-dose total-body or whole-thoracic irradiation. Radiat. Res. 2012, 178, 468–480. [Google Scholar] [CrossRef]
- Raber, J.; Davis, M.; Pfankuch, T.; Rosenthal, R.; Doctrow, S.; Moulder, J. Mitigating effecr of EUK-207 on radiation-induced cognitive impairments. Behav. Brain Res. 2017, 320, 457–463. [Google Scholar] [CrossRef]
- Rola, R.; Zou, Y.; Huang, T.-T.; Fishman, K.; Baure, J.; Rosi, S.; Milliken, H.; Limoli, C.L.; Fike, J.R. Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radic. Biol. Med. 2007, 42, 1133–1145. [Google Scholar] [CrossRef]
- Kaur, H.; Singh, Y.; Singh, S.; Sing, R. Gut microbiome-mediated epigenetic regulation of brain disorder and application of machine learning for multi-omics data analysis. Genome 2020, 64, 355–371. [Google Scholar] [CrossRef]
- Casero, D.; Gill, K.; Sridharan, V.; Kotrubash, I.; Nelson, G.; Hauer-Jensen, M.; Boerma, M.; Braun, J.; Cheema, A. Space-type radiation induces multimodal responses in the mouse gut microbiome and metabolome. Microbiome 2017, 5, 105. [Google Scholar] [CrossRef] [PubMed]
- Smith, Z.D.; Meissner, A. DNA methylation: Roles in mammalian development. Nat. Rev. Genet. 2013, 14, 204–220. [Google Scholar] [CrossRef] [PubMed]
- Xu, Y.; Wu, F.; Tan, L.; Kong, L.; Xiong, L.; Deng, J.; Barbera, A.J.; Zheng, L.; Zhang, H.; Huang, S.; et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol. Cell 2011, 42, 451–464. [Google Scholar] [CrossRef] [PubMed]
- Wu, H.; Zhang, Y. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes. Dev. 2011, 25, 2436–2452. [Google Scholar] [CrossRef] [PubMed]
- Arab, K.; Karaulanov, E.; Musheev, M.; Trnka, P.; Schafer, A.; Grummt, I.; Niehrs, C. GADD45A binds R-loops and recruits TET1 to CpG island promoters. Nat. Genet. 2019, 51, 217–223. [Google Scholar] [CrossRef] [PubMed]
- Cortellino, S.; Xu, J.; Sannai, M.; Moore, R.; Caretti, E.; Cigliano, A.; Le Coz, M.; Devarajan, K.; Wessels, A.; Soprano, D.; et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 2011, 146, 67–79. [Google Scholar] [CrossRef] [PubMed]
- Henry, R.A.; Mancuso, P.; Kuo, Y.M.; Tricarico, R.; Tini, M.; Cole, P.A.; Bellacosa, A.; Andrews, A.J. Interaction with the DNA Repair Protein Thymine DNA Glycosylase Regulates Histone Acetylation by p300. Biochemistry 2016, 55, 6766–6775. [Google Scholar] [CrossRef] [PubMed]
- Prasad, R.; Yen, T.J.; Bellacosa, A. Active DNA demethylation-The epigenetic gatekeeper of development, immunity, and cancer. Adv. Genet. 2021, 2, e10033. [Google Scholar] [CrossRef] [PubMed]
- Rausch, C.; Hastert, F.; Cardoso, M. DNA Modification Readers and Writers and Their Interplay. J. Mol. Biol. 2020, 432, 1731–1746. [Google Scholar] [CrossRef] [PubMed]
- Sharifi, O.; Yasui, D.H. The Molecular Functions of MeCP2 in Rett Syndrome Pathology. Front. Genet. 2021, 12, 624290. [Google Scholar] [CrossRef] [PubMed]
- Boxer, L.D.; Renthal, W.; Greben, A.W.; Whitwam, T.; Silberfeld, A.; Stroud, H.; Li, E.; Yang, M.G.; Kinde, B.; Griffith, E.C.; et al. MeCP2 Represses the Rate of Transcriptional Initiation of Highly Methylated Long Genes. Mol. Cell 2020, 77, 294–309.e9. [Google Scholar] [CrossRef] [PubMed]
- Spruijt, C.G.; Gnerlich, F.; Smits, A.H.; Pfaffeneder, T.; Jansen, P.W.; Bauer, C.; Münzel, M.; Wagner, M.; Müller, M.; Khan, F.; et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 2013, 152, 1146–1159. [Google Scholar] [CrossRef]
- Iurlaro, M.; Ficz, G.; Oxley, D.; Raiber, E.-A.; Bachman, M.; Booth, M.; Andrews, S.; Balasubramanian, S.; Reik, W. A screen for hydroxymethylcytosine and formylcytosine binding proteins suggests functions in transcription and chromatin regulation. Gen. Biol. 2013, 14, R1119. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.; Xu, B.; Yang, J.; He, L.; Zhang, Z.; Cheng, X.; Yu, H.; Liu, X.; Jin, T.; Peng, Y.; et al. UHRF2 commissions the completion of DNA demethylation through allosteric activation by 5hmC and K33-linked ubiquitination of XRCC1. Mol. Cell 2021, 81, 2960–2974. [Google Scholar] [CrossRef] [PubMed]
- Butler, R.W.; Hill, J.M.; Steinherz, P.G.; Meyers, P.A.; Finlay, J.L. Neuropsychologic effects of cranial irradiation, intrathecal methotrexate, and systemic methotrexate in childhood cancer. J. Clin. Oncol. 1994, 12, 2621–2629. [Google Scholar] [CrossRef]
- Smibert, E.; Anderson, V.; Godber, T.; Ekert, H. Risk factors for intellectual and educational sequelae of cranial irradiation in childhood acute lymphoblastic leukaemia. Br. J. Cancer 1996, 73, 825–830. [Google Scholar] [CrossRef] [PubMed]
- Duffner, P.K. Long-term effects of radiation therapy on cognitive and endocrine function in children with leukemia and brain tumors. Neurologist 2004, 10, 293–310. [Google Scholar] [CrossRef] [PubMed]
- Mulhern, R.K.; Merchant, T.E.; Gajjar, A.; Reddick, W.E.; Kun, L.E. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol. 2004, 5, 399–408. [Google Scholar] [CrossRef] [PubMed]
- Butler, R.W.; Haser, J.K. Neurocognitive effects of treatment for childhood cancer. Ment. Retard. Dev. Disabil. Res. Rev. 2006, 12, 184–191. [Google Scholar] [CrossRef] [PubMed]
- Caveness, W.F. Pathology of radiation damage to the normal brain of the monkey. Natl. Cancer Inst. Monogr. 1977, 46, 57–76. [Google Scholar] [PubMed]
- Dauer, L.T.; Walsh, L.; Mumma, M.T.; Cohen, S.S.; Golden, A.P.; Howard, S.C.; Roemer, G.E.; Boice, J.D., Jr. Moon, Mars and Minds: Evaluating Parkinson’s disease mortality among U.S. radiation workers and veterans in the million person study of low-dose effects. Z. Med. Phys. 2024, 34, 100–110. [Google Scholar] [CrossRef]
- Azizova, T.; Bannikova, M.; Grigoryaeva, E.; Rybkina, V.; Hamada, N. Occupational exposure to chronic ionizing radiation increases risk of Parkinson’s diseasecincidence in Russian Mayak workers. Int. J. Epidem 2020, 2020, 435–447. [Google Scholar] [CrossRef]
- Abayomi, O.K. Pathogenesis of irradiation-induced cognitive dysfunction. Acta Oncol. 1996, 35, 659–663. [Google Scholar] [CrossRef] [PubMed]
- Pokhrel, D.; Sood, S.; McClinton, C.; Shen, X.; Lominska, C.; Saleh, H.; Badkul, R.; Jiang, H.; Mitchell, M.; Wang, F. Treatment planning strategy for whole-brain radiotherapy with hippocampal sparing and simultaneous integrated boost for multiple brain metastases using intensity-modulated arc therapy. Med. Dosim. 2016, 41, 315–322. [Google Scholar] [CrossRef] [PubMed]
- Mizumatsu, S.; Monje, M.L.; Morhardt, D.R.; Rola, R.; Palmer, T.D.; Fike, J.R. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res. 2003, 63, 4021–4027. [Google Scholar] [PubMed]
- Rola, R.; Otsuka, S.; Obenaus, A.; Nelson, G.A.; Limoli, C.L.; VandenBerg, S.R.; Fike, J.R. Indicators of Hippocampal Neurogenesis are Altered by (56)Fe-Particle Irradiation in a Dose-Dependent Manner. Radiat. Res. 2004, 162, 442–446. [Google Scholar] [CrossRef] [PubMed]
- Begolly, S.; Olschowka, J.A.; Love, T.; Williams, J.P.; O’Banion, M.K. Fractionation enhances acute oligodendrocyte progenitor cell radiation sensitivity and leads to long term depletion. Glia 2017, 66, 846–861. [Google Scholar] [CrossRef] [PubMed]
- Daxinger, L.; Whitelaw, E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat. Rev. Genet. 2012, 13, 153–162. [Google Scholar] [CrossRef] [PubMed]
- Voutounou, M.; Glen, C.D.; Dubrova, Y.E. The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice. Mutat. Res. 2012, 734, 1–4. [Google Scholar] [CrossRef]
- Bohacek, J.; Gapp, K.; Saab, B.J.; Mansuy, I.M. Transgenerational epigenetic effects on brain functions. Biol. Psychiatry 2013, 73, 313–320. [Google Scholar] [CrossRef] [PubMed]
- Brookes, E.; Shi, Y. Diverse epigenetic mechanisms of human disease. Annu. Rev. Genet. 2014, 48, 237–268. [Google Scholar] [CrossRef]
- Guerrero-Bosagna, C.; Skinner, M.K. Environmentally induced epigenetic transgenerational inheritance of male infertility. Curr. Opin. Genet. Dev. 2014, 26, 79–88. [Google Scholar] [CrossRef]
- Skinner, M.K. Environmental stress and epigenetic transgenerational inheritance. BMC Med. 2014, 12, 153. [Google Scholar] [CrossRef] [PubMed]
- Wei, Y.; Schatten, H.; Sun, Q.Y. Environmental epigenetic inheritance through gametes and implications for human reproduction. Hum. Reprod. Update 2015, 21, 194–208. [Google Scholar] [CrossRef] [PubMed]
- Bowers, M.E.; Yehuda, R. Intergenerational Transmission of Stress in Humans. Neuropsychopharmacology 2016, 41, 232–244. [Google Scholar] [CrossRef] [PubMed]
- Gomes, A.M.; Barber, R.C.; Dubrova, Y.E. Paternal irradiation perturbs the expression of circadian genes in offspring. Mutat. Res. 2015, 775, 33–37. [Google Scholar] [CrossRef]
- Kim, G.H.; Kim, J.E.; Rhie, S.J.; Yoon, S. The Role of Oxidative Stress in Neurodegenerative Diseases. Exp. Neurobiol. 2015, 24, 325–340. [Google Scholar] [CrossRef] [PubMed]
- Chiang, C.S.; McBride, W.H.; Withers, H.R. Radiation-induced astrocytic and microglial responses in mouse brain. Radiother. Oncol. 1993, 29, 60–68. [Google Scholar] [CrossRef] [PubMed]
- Nakagawa, M.; Bellinzona, M.; Seilhan, T.M.; Gobbel, G.T.; Lamborn, K.R.; Fike, J.R. Microglial responses after focal radiation-induced-injury are affected by a-difluoromethylornithine. Int. J. Radiat. Oncol. Biol. Phys. 1996, 36, 113–123. [Google Scholar] [CrossRef] [PubMed]
- Rola, R.; Fishman, K.; Baure, J.; Rosi, S.; Lamborn, K.R.; Obenaus, A.; Nelson, G.A.; Fike, J.R. Hippocampal neurogenesis and neuroinflammation after cranial irradiation with (56)Fe particles. Radiat. Res. 2008, 169, 626–632. [Google Scholar] [CrossRef]
- Moravan, M.J.; Olschowka, J.A.; Williams, J.P.; O’Banion, M.K. Cranial irradiation leads to acute and persistent neuroinflammation with delayed increases in T-cell infiltration and CD11c expression in C57BL/6 mouse brain. Radiat. Res. 2011, 176, 459–473. [Google Scholar] [CrossRef]
- Li, S.; Tollefsbol, T.O. DNA methylation methods: Global DNA methylation and methylomic analyses. Methods 2021, 187, 28–43. [Google Scholar] [CrossRef]
- Wang, T.; Loo, C.E.; Kohli, R.M. Enzymatic approaches for profiling cytosine methylation and hydroxymethylation. Mol. Metab. 2022, 57, 101314. [Google Scholar] [CrossRef] [PubMed]
- Yu, M.; Hon, G.; Szulwach, K.; Song, C.; Zhang, L.; Kim, A.; Li, X.; Dai, Q.; Shen, Y.; Park, B.; et al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 2012, 149, 1368–1380. [Google Scholar] [CrossRef] [PubMed]
- Booth, M.; Branco, M.; Ficz, G.; Oxley, D.; Krueger, F.; Reik, W.; Balasubramanian, S. Quantative sequencinf of 5-mthylcytosie and 5 hydroxymethylcytosine at single-base resolution. Science 2012, 336, 934–937. [Google Scholar] [CrossRef] [PubMed]
- Schutsky, E.K.; DeNizio, J.E.; Hu, P.; Liu, M.Y.; Nabel, C.S.; Fabyanic, E.B.; Hwang, Y.; Bushman, F.D.; Wu, H.; Kohli, R.M. Nondestructive, base-resolution sequencing of 5-hydroxymethylcytosine using a DNA deaminase. Nat. Biotechnol. 2018, 10, 1038. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Siejka-Zielinska, P.; Velikova, G.; Bi, Y.; Yuan, F.; Tomkova, M.; Bai, C.; Chen, L.; Schuster-Bockler, B.; Song, C.X. Bisulfite-free direct detection of 5-methylcytosine and 5-hydroxymethylcytosine at base resolution. Nat. Biotechnol. 2019, 37, 424–429. [Google Scholar] [CrossRef] [PubMed]
- Jain, M.; Koren, S.; Miga, K.H.; Quick, J.; Rand, A.C.; Sasani, T.A.; Tyson, J.R.; Beggs, A.D.; Dilthey, A.T.; Fiddes, I.T.; et al. Nanopore sequencing and assembly of a human genome with ultra-long reads. Nat. Biotechnol. 2018, 36, 338–345. [Google Scholar] [CrossRef] [PubMed]
- Xu, H.; Liu, Y.; Li, Y.; Diao, L.; Xun, Z.; Zhang, Y.; Wang, Z.; Li, D. RadAtlas 1.0: A knowledgebase focusing on radiation-associated genes. Int. J. Radiat. Biol. 2020, 96, 980–987. [Google Scholar] [CrossRef] [PubMed]
- Iwakawa, M.; Hamada, N.; Imadome, K.; Funayama, T.; Sakashita, T.; Kobayashi, Y.; Imai, T. Expression profiles are different in carbon ion-irradiated normal human fibroblasts and their bystander cells. Mutat. Res. 2008, 642, 57–67. [Google Scholar] [CrossRef]
- Machida, M.; Lonart, G.; Britten, R.A. Low (60 cGy) doses of (56)Fe HZE-particle radiation lead to a persistent reduction in the glutamatergic readily releasable pool in rat hippocampal synaptosomes. Radiat. Res. 2010, 174, 618–623. [Google Scholar] [CrossRef]
- Parihar, V.K.; Parsha, J.; Tran, K.; Craver, B.; Acharya, M.; Limoli, C.L. Persistent changes in neuronal structure and synaptic plasticity caused by proton irradiation. Brain Struct. Funct. 2015, 220, 1161–1171. [Google Scholar] [CrossRef]
- Sokolova, I.; Schneider, C.; Bezaire, M.; Soltesz, I.; Vlkolinsky, R.; Nelson, G. Proton radiation alters intrinsic and synaptic properties of CA1 pyramidal neurons of the mouse hippocampus. Radiat. Res. 2015, 183, 208–218. [Google Scholar] [CrossRef] [PubMed]
- Parihar, V.; Allen, B.; Caressi, C.; Kwok, S.; Chu, E.; Tran, K.; Chmielewski, N.; Giedzinski, E.; Acharya, M.; Britten, R.; et al. Cosmic radiation exposure and persistent cognitive dysfunction. Sci. Rep. 2016, 6, 34774. [Google Scholar] [CrossRef] [PubMed]
- Krukowski, K.; Grue, K.; Frias, E.; Pietrykowski, J.; Jones, T.; Nelson, G.; Rosi, S. Female mice are protected from space-radiation-induced maladaptive responses. Brain Beh Immun. 2018, 74, 106–120. [Google Scholar] [CrossRef] [PubMed]
Radiation Type | Energy | Dose (Gy) | Hippocampal Dissection Time Point |
---|---|---|---|
56Fe | 600 MeV/n | 0, 0.1, 0.2, and 0.4 | 5 and 23 weeks following irradiation or sham-irradiation |
28Si | 600 MeV/n | 0, 0.3, 0.6, and 0.9 | 5 and 23 weeks following irradiation or sham-irradiation |
Protons | 150 MeV/n | 1 | 5 and 23 weeks following irradiation or sham-irradiation |
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Impey, S.; Raber, J. Irradiation and Alterations in Hippocampal DNA Methylation. Epigenomes 2024, 8, 27. https://doi.org/10.3390/epigenomes8030027
Impey S, Raber J. Irradiation and Alterations in Hippocampal DNA Methylation. Epigenomes. 2024; 8(3):27. https://doi.org/10.3390/epigenomes8030027
Chicago/Turabian StyleImpey, Soren, and Jacob Raber. 2024. "Irradiation and Alterations in Hippocampal DNA Methylation" Epigenomes 8, no. 3: 27. https://doi.org/10.3390/epigenomes8030027
APA StyleImpey, S., & Raber, J. (2024). Irradiation and Alterations in Hippocampal DNA Methylation. Epigenomes, 8(3), 27. https://doi.org/10.3390/epigenomes8030027