Low dose radiation effects on the brain – from mechanisms and behavioral outcomes to mitigation strategies

References

• Frankenberg-Schwager M. Induction, repair and biological relevance of radiation-induced DNA lesions in eukaryotic cells. Radiat Environmental Biophys 1990; 29:273-92; PMID:2281134; https://doi.org/10.1007/BF01210408
   PubMed Web of Science ®Google Scholar
• Lomax ME, Folkes LK, O'Neill P. Biological consequences of radiation-induced DNA damage: relevance to radiotherapy. Clin Oncol 2013; 25:578-85; PMID:23849504; https://doi.org/10.1016/j.clon.2013.06.007
   PubMed Web of Science ®Google Scholar
• 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; PMID:24937368; https://doi.org/10.3109/09553002.2014.934929
   PubMed Web of Science ®Google Scholar
• Sowa M, Arthurs BJ, Estes BJ, Morgan WF. Effects of ionizing radiation on cellular structures, induced instability and carcinogenesis. EXS 2006; 96:293-301; PMID:16383023
   PubMedGoogle Scholar
• Merrifield M, Kovalchuk O. Epigenetics in radiation biology: a new research frontier. Frontiers Genetics 2013; 4:40; PMID:23577019; https://doi.org/10.3389/fgene.2013.00040
   PubMedGoogle Scholar
• Kovalchuk O, Baulch JE. Epigenetic changes and nontargeted radiation effects–is there a link? Environmental Mol Mutagenesis 2008; 49:16-25; PMID:18172877; https://doi.org/10.1002/em.20361
   PubMed Web of Science ®Google Scholar
• Koturbash I, Zemp F, Kolb B, Kovalchuk O. Sex-specific radiation-induced microRNAome responses in the hippocampus, cerebellum and frontal cortex in a mouse model. Mutat Res 2011; 722:114-8; PMID:20478395; https://doi.org/10.1016/j.mrgentox.2010.05.007
   PubMed Web of Science ®Google Scholar
• Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 2003; 63:4021-7; PMID:12874001
   PubMed Web of Science ®Google Scholar
• Lawrence YR, Li XA, el Naqa I, Hahn CA, Marks LB, Merchant TE, Dicker AP. Radiation dose-volume effects in the brain. Int J Radiat Oncol Biol Phys 2010; 76:S20-7; PMID:20171513; https://doi.org/10.1016/j.ijrobp.2009.02.091
   PubMed Web of Science ®Google Scholar
• Britten RA, Davis LK, Johnson AM, Keeney S, Siegel A, Sanford LD, Singletary SJ, Lonart G. Low (20 cGy) doses of 1 GeV/u (56)Fe–particle radiation lead to a persistent reduction in the spatial learning ability of rats. Radiat Res 2012; 177:146-51; PMID:22077338; https://doi.org/10.1667/RR2637.1
   PubMed Web of Science ®Google Scholar
• Hudson D, Kovalchuk I, Koturbash I, Kolb B, Martin OA, Kovalchuk O. Induction and persistence of radiation-induced DNA damage is more pronounced in young animals than in old animals. Aging (Albany NY) 2011; 3:609-20; PMID:21685513; https://doi.org/10.18632/aging.100340
   PubMedGoogle Scholar
• Silasi G, Diaz-Heijtz R, Besplug J, Rodriguez-Juarez R, Titov V, Kolb B, Kovalchuk O. Selective brain responses to acute and chronic low-dose X-ray irradiation in males and females. Biochem Biophys Res Communications 2004; 325:1223-35; PMID:15555557; https://doi.org/10.1016/j.bbrc.2004.10.166
   PubMed Web of Science ®Google Scholar
• Andres-Mach M, Rola R, Fike JR. Radiation effects on neural precursor cells in the dentate gyrus. Cell Tissue Res 2008; 331:251-62; PMID:17786480; https://doi.org/10.1007/s00441-007-0480-9
   PubMed Web of Science ®Google Scholar
• Mizumatsu S, Monje ML, Morhardt DR, Rola R, Palmer TD, Fike JR. Extreme sensitivity of adult neurogenesis to low doses of X-irradiation. Cancer Res 2003; 63:4021-7; PMID:12874001
   PubMed Web of Science ®Google Scholar
• Madsen TM, Kristjansen PE, Bolwig TG, Wortwein G. Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat. Neuroscience 2003; 119:635-42; PMID:12809684; https://doi.org/10.1016/S0306-4522(03)00199-4
   PubMed Web of Science ®Google Scholar
• Fike JR, Rola R, Limoli CL. Radiation response of neural precursor cells. Neurosurg Clin N Am 2007; 18:115-+; PMID:17244559; https://doi.org/10.1016/j.nec.2006.10.010
   PubMed Web of Science ®Google Scholar
• Rola R, Raber J, Rizk A, Otsuka S, VandenBerg SR, Morhardt DR, Fike JR. Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice. Exp Neurol 2004; 188:316-30; PMID:15246832; https://doi.org/10.1016/j.expneurol.2004.05.005
   PubMed Web of Science ®Google Scholar
• Kornev MA, Kulikova EA, Kul'bakh OS. The cellular composition of the cerebral cortex of rat fetuses after fractionated low-dose irradiation. Neurosci Behav Physiol 2005; 35:635-8; PMID:16342621; https://doi.org/10.1007/s11055-005-0104-3
   PubMedGoogle Scholar
• Christian KM, Song H, Ming GL. Functions and dysfunctions of adult hippocampal neurogenesis. Annu Rev Neurosci 2014; 37:243-62; PMID:24905596; https://doi.org/10.1146/annurev-neuro-071013-014134
   PubMed Web of Science ®Google Scholar
• Palmer TD, Takahashi J, Gage FH. The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 1997; 8:389-404; PMID:9143557; https://doi.org/10.1006/mcne.1996.0595
   PubMed Web of Science ®Google Scholar
• Kolb B, Mychasiuk R, Muhammad A, Li Y, Frost DO, Gibb R. Experience and the developing prefrontal cortex. Proc Natl Acad Sci U S A 2012; 109 Suppl 2:17186-93; PMID:23045653; https://doi.org/10.1073/pnas.1121251109
   PubMed Web of Science ®Google Scholar
• Mothersill C, Seymour CB. Radiation-induced bystander effects–implications for cancer. Nat Rev Cancer 2004; 4:158-64; PMID:14964312; https://doi.org/10.1038/nrc1277
   PubMed Web of Science ®Google Scholar
• Morgan WF, Sowa MB. Non-targeted bystander effects induced by ionizing radiation. Mutat Res 2007; 616:159-64; PMID:17134726; https://doi.org/10.1016/j.mrfmmm.2006.11.009
   PubMed Web of Science ®Google Scholar
• Marozik P, Mothersill C, Seymour CB, Mosse I, Melnov S. Bystander effects induced by serum from survivors of the Chernobyl accident. Exp Hematol 2007; 35:55-63; PMID:17379088; https://doi.org/10.1016/j.exphem.2007.01.029
   PubMed Web of Science ®Google Scholar
• Pant GS, Kamada N. Chromosome aberrations in normal leukocytes induced by the plasma of exposed individuals. Hiroshima J Medical Sci 1977; 26:149-54; PMID:591380
   PubMed Web of Science ®Google Scholar
• Khan MA, Van Dyk J, Yeung IW, Hill RP. Partial volume rat lung irradiation; assessment of early DNA damage in different lung regions and effect of radical scavengers. Radiother Oncol 2003; 66:95-102; PMID:12559526; https://doi.org/10.1016/S0167-8140(02)00325-0
   PubMed Web of Science ®Google Scholar
• Brooks AL. Evidence for 'bystander effects' in vivo. Hum Exp Toxicol 2004; 23:67-70; PMID:15070062; https://doi.org/10.1191/0960327104ht419oa
   PubMed Web of Science ®Google Scholar
• Koturbash I, Boyko A, Rodriguez-Juarez R, McDonald RJ, Tryndyak VP, Kovalchuk I, Pogribny IP, Kovalchuk O. Role of epigenetic effectors in maintenance of the long-term persistent bystander effect in spleen in vivo. Carcinogenesis 2007; 28:1831-8; PMID:17347136; https://doi.org/10.1093/carcin/bgm053
   PubMed Web of Science ®Google Scholar
• Koturbash I, Rugo RE, Hendricks CA, Loree J, Thibault B, Kutanzi K, Pogribny I, Yanch JC, Engelward BP, Kovalchuk O. Irradiation induces DNA damage and modulates epigenetic effectors in distant bystander tissue in vivo. Oncogene 2006; 25:4267-75; PMID:16532033; https://doi.org/10.1038/sj.onc.1209467
   PubMed Web of Science ®Google Scholar
• Tamminga J, Koturbash I, Baker M, Kutanzi K, Kathiria P, Pogribny IP, Sutherland RJ, Kovalchuk O. Paternal cranial irradiation induces distant bystander DNA damage in the germline and leads to epigenetic alterations in the offspring. Cell Cycle 2008; 7:1238-45; PMID:18418050; https://doi.org/10.4161/cc.7.9.5806
   PubMed Web of Science ®Google Scholar
• Koturbash I, Loree J, Kutanzi K, Koganow C, Pogribny I, Kovalchuk O. In vivo bystander effect: cranial X-irradiation leads to elevated DNA damage, altered cellular proliferation and apoptosis, and increased p53 levels in shielded spleen. Int J Radiat Oncol Biol Phys 2008; 70:554-62; PMID:18207032; https://doi.org/10.1016/j.ijrobp.2007.09.039
   PubMed Web of Science ®Google Scholar
• Koturbash I, Zemp FJ, Kutanzi K, Luzhna L, Loree J, Kolb B, Kovalchuk O. Sex-specific microRNAome deregulation in the shielded bystander spleen of cranially exposed mice. Cell Cycle 2008; 7:1658-67; PMID:18560276; https://doi.org/10.4161/cc.7.11.5981
   PubMed Web of Science ®Google Scholar
• Koturbash I, Kutanzi K, Hendrickson K, Rodriguez-Juarez R, Kogosov D, Kovalchuk O. Radiation-induced bystander effects in vivo are sex specific. Mutat Res 2008; 642:28-36; PMID:18508093; https://doi.org/10.1016/j.mrfmmm.2008.04.002
   PubMed Web of Science ®Google Scholar
• Koturbash I. Molecular mechanisms of radiation-induced bystander efefcts in vivo. (Unpublished PhD thesis). Department of Biological Sciences. Lethbridge, AB, Canada: University of Lethbridge 2008
   Google Scholar
• Marin A, Martin M, Linan O, Alvarenga F, Lopez M, Fernandez L, Buchser D, Cerezo L. Bystander effects and radiotherapy. Rep Pract Oncol Radiother 2015; 20:12-21; PMID:25535579; https://doi.org/10.1016/j.rpor.2014.08.004
   PubMedGoogle Scholar
• Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, Formenti SC. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004; 58:862-70; PMID:14967443; https://doi.org/10.1016/j.ijrobp.2003.09.012
   PubMed Web of Science ®Google Scholar
• Mothersill C, Seymour C. Are epigenetic mechanisms involved in radiation-induced bystander effects? Frontiers in Genetics 2012; 3:74; PMID:22629281; https://doi.org/10.3389/fgene.2012.00074
   PubMedGoogle Scholar
• Ilnytskyy Y, Kovalchuk O. Non-targeted radiation effects-an epigenetic connection. Mutat Res 2011; 714:113-25; PMID:21784089; https://doi.org/10.1016/j.mrfmmm.2011.06.014
   PubMed Web of Science ®Google Scholar
• Mancuso M, Pasquali E, Leonardi S, Tanori M, Rebessi S, Di Majo V, Pazzaglia S, Toni MP, Pimpinella M, Covelli V, et al. Oncogenic bystander radiation effects in Patched heterozygous mouse cerebellum. Proc Natl Acad Sci U S A 2008; 105:12445-50; PMID:18711141; https://doi.org/10.1073/pnas.0804186105
   PubMed Web of Science ®Google Scholar
• Mancuso M, Pasquali E, Leonardi S, Rebessi S, Tanori M, Giardullo P, Borra F, Pazzaglia S, Naus CC, Di Majo V, et al. Role of connexin43 and ATP in long-range bystander radiation damage and oncogenesis in vivo. Oncogene 2011; 30:4601-8; PMID:21602884; https://doi.org/10.1038/onc.2011.176
   PubMed Web of Science ®Google Scholar
• Kovalchuk A, Mychasiuk R, Muhammad A, Hossain S, Ilnytskyy S, Ghose A, Kirkby C, Ghasroddashti E, Kovalchuk O, Kolb B. Liver irradiation causes distal bystander effects in the rat brain and affects animal behaviour. Oncotarget 2016; 7:4385-98; PMID:26678032
   PubMed Web of Science ®Google Scholar
• Kovalchuk A, Mychasiuk R, Muhammad A, Hossain S, Ilnytskyy Y, Ghose A, Kirkby C, Ghasroddashti E, Kolb B, Kovalchuk O. Profound and Sexually Dimorphic Effects of Clinically-Relevant Low Dose Scatter Irradiation on the Brain and Behavior. Front Behav Neurosci 2016; 10:84; PMID:27375442; https://doi.org/10.3389/fnbeh.2016.00084
   PubMed Web of Science ®Google Scholar
• Monje ML, Palmer T. Radiation injury and neurogenesis. Curr Opin Neurol 2003; 16:129-34; PMID:12644738; https://doi.org/10.1097/00019052-200304000-00002
   PubMed Web of Science ®Google Scholar
• Mustafa S, Walker A, Bennett G, Wigmore PM. 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 2008; 28:323-30; PMID:18702703; https://doi.org/10.1111/j.1460-9568.2008.06325.x
   PubMed Web of Science ®Google Scholar
• Briones TL, Woods J. Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications. BMC Neurosci 2011; 12:124; PMID:22152030; https://doi.org/10.1186/1471-2202-12-124
   PubMed Web of Science ®Google Scholar
• Christie LA, Acharya MM, Parihar VK, Nguyen A, Martirosian V, Limoli CL. Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clin Cancer Res 2012; 18:1954-65; PMID:22338017; https://doi.org/10.1158/1078-0432.CCR-11-2000
   PubMed Web of Science ®Google Scholar
• Faw B. Pre-frontal executive committee for perception, working memory, attention, long-term memory, motor control, and thinking: a tutorial review. Conscious Cogn 2003; 12:83-139; PMID:12617864; https://doi.org/10.1016/S1053-8100(02)00030-2
   PubMed Web of Science ®Google Scholar
• Joshi G, Aluise CD, Cole MP, Sultana R, Pierce WM, Vore M, St Clair DK, Butterfield DA. Alterations in brain antioxidant enzymes and redox proteomic identification of oxidized brain proteins induced by the anti-cancer drug adriamycin: implications for oxidative stress-mediated chemobrain. Neuroscience 2010; 166:796-807; PMID:20096337; https://doi.org/10.1016/j.neuroscience.2010.01.021
   PubMed Web of Science ®Google Scholar
• Lyons L, Elbeltagy M, Bennett G, Wigmore P. The effects of cyclophosphamide on hippocampal cell proliferation and spatial working memory in rat. PloS One 2011; 6:e21445; PMID:21731752; https://doi.org/10.1371/journal.pone.0021445
   PubMed Web of Science ®Google Scholar
• Lyons L, ElBeltagy M, Umka J, Markwick R, Startin C, Bennett G, Wigmore P. Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy. Psychopharmacology 2011; 215:105-15; PMID:21181126; https://doi.org/10.1007/s00213-010-2122-2
   PubMed Web of Science ®Google Scholar
• Parihar VK, Limoli CL. Cranial irradiation compromises neuronal architecture in the hippocampus. Proc Natl Acad Sci U S A 2013; 110:12822-7; PMID:23858442; https://doi.org/10.1073/pnas.1307301110
   PubMed Web of Science ®Google Scholar
• Acharya MM, Patel NH, Craver BM, Tran KK, Giedzinski E, Tseng BP, Parihar VK, Limoli CL. Consequences of low dose ionizing radiation exposure on the hippocampal microenvironment. PloS One 2015; 10:e0128316; PMID:26042591; https://doi.org/10.1371/journal.pone.0128316
   PubMed Web of Science ®Google Scholar
• Ngun TC, Ghahramani N, Sanchez FJ, Bocklandt S, Vilain E. The genetics of sex differences in brain and behavior. Frontiers Neuroendocrinol 2011; 32:227-46; PMID:20951723; https://doi.org/10.1016/j.yfrne.2010.10.001
   PubMed Web of Science ®Google Scholar
• Hu VW, Sarachana T, Sherrard RM, Kocher KM. Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism. Mol Autism 2015; 6:7; PMID:26056561; https://doi.org/10.1186/2040-2392-6-7
   PubMed Web of Science ®Google Scholar
• Mottron L, Duret P, Mueller S, Moore RD, Forgeot d'Arc B, Jacquemont S, Xiong L. Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism. Mol Autism 2015; 6:33; PMID:26052415; https://doi.org/10.1186/s13229-015-0024-1
   PubMed Web of Science ®Google Scholar
• Kuhn C. Emergence of sex differences in the development of substance use and abuse during adolescence. Pharmacol Therapeutics 2015; 153:55-78
   PubMed Web of Science ®Google Scholar
• Acaz-Fonseca E, Duran JC, Carrero P, Garcia-Segura LM, Arevalo MA. Sex differences in glia reactivity after cortical brain injury. Glia 2015; [Epub ahead of print]; https://doi.org/10.1002/glia.22867
   PubMed Web of Science ®Google Scholar
• Pyter LM, Kelly SD, Harrell CS, Neigh GN. Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats. Brain Behavior Immunity 2013; 30:88-94; PMID:23348027; https://doi.org/10.1016/j.bbi.2013.01.075
   PubMed Web of Science ®Google Scholar
• Shi Y, Zhang X, Tang X, Wang P, Wang H, Wang Y. MiR-21 is continually elevated long-term in the brain after exposure to ionizing radiation. Radiat Res 2012; 177:124-8; PMID:22034847; https://doi.org/10.1667/RR2764.1
   PubMed Web of Science ®Google Scholar
• Weber M, Hellmann I, Stadler MB, Ramos L, Paabo S, Rebhan M, Schubeler D. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nature Genetics 2007; 39:457-66; PMID:17334365; https://doi.org/10.1038/ng1990
   PubMed Web of Science ®Google Scholar
• Wen L, Tang F. Genomic distribution and possible functions of DNA hydroxymethylation in the brain. Genomics 2014; 104:341-6; PMID:25205307; https://doi.org/10.1016/j.ygeno.2014.08.020
   PubMed Web of Science ®Google Scholar
• Acharya MM, Martirosian V, Christie LA, Riparip L, Strnadel J, Parihar VK, Limoli CL. Defining the optimal window for cranial transplantation of human induced pluripotent stem cell-derived cells to ameliorate radiation-induced cognitive impairment. Stem Cells Transl Med 2015; 4:74-83; PMID:25391646; https://doi.org/10.5966/sctm.2014-0063
   PubMed Web of Science ®Google Scholar
• Acharya MM, Rosi S, Jopson T, Limoli CL. Human neural stem cell transplantation provides long-term restoration of neuronal plasticity in the irradiated hippocampus. Cell Transplant 2015; 24:691-702; PMID:25289634; https://doi.org/10.3727/096368914X684600
   PubMed Web of Science ®Google Scholar
• Baulch JE, Acharya MM, Allen BD, Ru N, Chmielewski NN, Martirosian V, Giedzinski E, Syage A, Park AL, Benke SN, et al. Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain. Proc Natl Acad Sci U S A 2016; 113:4836-41; PMID:27044087; https://doi.org/10.1073/pnas.1521668113
   PubMed Web of Science ®Google Scholar
• Acharya MM, Baulch JE, Lusardi TA, Allen BD, Chmielewski NN, Baddour AA, Limoli CL, Boison D. Adenosine Kinase Inhibition Protects against Cranial Radiation-Induced Cognitive Dysfunction. Front Mol Neurosci 2016; 9:42; PMID:27375429; https://doi.org/10.3389/fnmol.2016.00042
   PubMed Web of Science ®Google Scholar
• Acharya MM, Green KN, Allen BD, Najafi AR, Syage A, Minasyan H, Le MT, Kawashita T, Giedzinski E, Parihar VK, et al. Elimination of microglia improves cognitive function following cranial irradiation. Sci Rep 2016; 6:31545; PMID:27516055; https://doi.org/10.1038/srep31545
   PubMed Web of Science ®Google Scholar
• Hirase H, Shinohara Y. Transformation of cortical and hippocampal neural circuit by environmental enrichment. Neuroscience 2014; 280:282-98; PMID:25242640; https://doi.org/10.1016/j.neuroscience.2014.09.031
   PubMed Web of Science ®Google Scholar
• Pang TY, Hannan AJ. Enhancement of cognitive function in models of brain disease through environmental enrichment and physical activity. Neuropharmacology 2013; 64:515-28; PMID:22766390; https://doi.org/10.1016/j.neuropharm.2012.06.029
   PubMed Web of Science ®Google Scholar
• Fan Y, Liu Z, Weinstein PR, Fike JR, Liu J. Environmental enrichment enhances neurogenesis and improves functional outcome after cranial irradiation. Eur J Neurosci 2007; 25:38-46; PMID:17241265; https://doi.org/10.1111/j.1460-9568.2006.05269.x
   PubMed Web of Science ®Google Scholar
• Ji JF, Ji SJ, Sun R, Li K, Zhang Y, Zhang LY, Tian Y. Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway. Biochem Biophys Res Communications 2014; 443:646-51; PMID:24333433; https://doi.org/10.1016/j.bbrc.2013.12.031
   PubMed Web of Science ®Google Scholar