Fundamental Mechanisms Underlying the Ill Health and Chronic Fatigue Syndrome Suffered by Atomic and Gulf War Veterans: A Unifying Hypothesis

  • Carmel MothersillEmail author
  • Colin Seymour


Atomic and Gulf War veterans often complain of an ill assorted collection of symptoms which are very like those experienced by those suffering from CFIDS (chronic fatigue and immune dysfunction syndrome) or ME (Myalgic Encephalomyelitis). There are two major hypotheses concerning the aetiology of Atomic and Gulf War Veterans ill health and CFIDS. The first suggests that CFIDS results from activation of a chronic stress response, which can be triggered by exposure to a variety of stress-inducing chemical or physical agents. These include radioisotopes and chemical pollutants and natural toxins. This pathway is thought to involve ion-gated channels, which lead to activation of H-Ras and MAPK pathways in affected individuals. The downstream consequences are mitochondrial dysfunction leading to the fatigue and chronic ill health. The other major idea is that the immune system is a major target leading to chronic ill health and other symptoms. Our suggestion is that both hypotheses are correct and that chronic exposure to stressors leads to genomic instability (GI), which is driven by stress signalling pathways. The GI particularly affects stem cells such as those in the bone marrow, brain and gastrointestinal tract, leading to the characteristic CFIDS symptoms, which result from compromise of immune system, digestive system and neural system function. Our key recommendation for new research in this area is to determine the mechanism by which stressed cells activate stress signalling and consequent GI. The key therapeutic emphasis should be to determine early intervention points in the pathway, which could prevent or reverse the stress signalling leading to alleviation of signal driven symptoms of CFIDS


Chronic fatigue and immune dysfunction syndrome Atomic and gulf war veterans syndrome Genomic instability Stress signalling pathways Immune system Low doses of ionizing radiation 



We thank the Canadian National Science and Engineering Research Council and the Canada Research Chairs Programme for financial support. We are especially grateful to Alan Cocchetto of the National CFIDS Foundation Inc. for financial support and inspiration.


  1. Abriel H (2010) Cardiac sodium channel Na v 1.5 and interacting proteins: physiology and pathophysiology. J Mol Cell Cardiol 48(1):2–11CrossRefPubMedGoogle Scholar
  2. Ahmad SB, McNeill FE, Byun SH, Prestwich WV, Mothersill C, Seymour C, Armstrong A, Fernandez C (2013) Ultra-violet light emission from HPV-G cells irradiated with low let radiation from (90)Y; consequences for radiation induced bystander effects. Dose Response 11:498–516CrossRefPubMedGoogle Scholar
  3. Ballesteros-Zebadúa P, Chavarria A, Celis MA, Paz C, Franco-Pérez J (2012) Radiation-induced neuroinflammation and radiation somnolence syndrome. CNS Neurol Disord: Drug Targets 11(7):937–949CrossRefGoogle Scholar
  4. Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B (2012) Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immun 26(1):24–31CrossRefPubMedGoogle Scholar
  5. Beyder A, Rae JL, Bernard C, Strege PR, Sachs F, Farrugia G (2010) Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel. J Physiol 588(Pt 24):4969–4985CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chaudhuri A, Watson WS, Pearn J, Behan PO (2000) The symptoms of chronic fatigue syndrome are related to abnormal ion channel function. Med Hypotheses 54(1):59–63CrossRefPubMedGoogle Scholar
  7. Coughlin SS, McNeil RB, Provenzale DT, Dursa EK, Thomas CM (2013) Method issues in epidemiological studies of medically unexplained symptom-based conditions in veterans. J Mil Veterans Health 21(2):4–10PubMedPubMedCentralGoogle Scholar
  8. Cucinotta FA, Kim MH, Chappell LJ, Huff JL (2013) How safe is safe enough? Radiation risk for a human mission to Mars. PLoS One 8(10):e74988CrossRefPubMedPubMedCentralGoogle Scholar
  9. Curtis DJ, Sood A, Phillips TJ, Leinster VH, Nishiguchi A, Coyle C, Lacharme-Lora L, Beaumont O, Kemp H, Goodall R, Cornes L, Giugliano M, Barone RA, Matsusaki M, Akashi M, Tanaka HY, Kano M, McGarvey J, Halemani ND, Simon K, Keehan R, Ind W, Masters T, Grant S, Athwal S, Collett G, Tannetta D, Sargent IL, Scull-Brown E, Liu X, Aquilina K, Cohen N, Lane JD, Thoresen M, Hanley J, Randall A, Case CP (2014) Secretions from placenta, after hypoxia/reoxygenation, can damage developing neurones of brain under experimental conditions. Exp Neurol pii: S0014–4886(14)00137-X. doi: 10.1016/j.expneurol.2014.05.003 (Epub ahead of print)
  10. Etienne O, Roque T, Haton C, Boussin FD (2012) Variation of radiation-sensitivity of neural stem and progenitor cell populations within the developing mouse brain. Int J Radiat Biol 88(10):694–702CrossRefPubMedGoogle Scholar
  11. Fazzari J, Mersov A, Smith R, Seymour C, Mothersill C (2012) Effect of 5-hydroxytryptamine (serotonin) receptor inhibitors on the radiation-induced bystander effect. Int J Radiat Biol 88(10):786–790CrossRefPubMedGoogle Scholar
  12. Ferguson E, Cassaday HJ (2001–2002) Theoretical accounts of gulf war syndrome: from environmental toxins to psychoneuroimmunology and neurodegeneration. Behav Neurol 13(3–4):133–147Google Scholar
  13. Festjens N, Vanden Berghe T, Vandenabeele P (2006) Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim Biophys Acta 1757(9–10):1371–1387CrossRefPubMedGoogle Scholar
  14. Formigari A, Gregianin E, Irato P (2013) The effect of zinc and the role of p53 in copper-induced cellular stress responses. J Appl Toxicol 33(7):527–536CrossRefPubMedGoogle Scholar
  15. Frank M, Duvezin-Caubet S, Koob S, Occhipinti A, Jagasia R, Petcherski A, Ruonala MO, Priault M, Salin B, Reichert AS (2012) Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochimica et Biophys Acta (BBA)—Mol Cell Res 1823(12):2297–2310Google Scholar
  16. Fulle S, Belia S, Vecchiet J, Morabito C, Vecchiet L, Fanò G (2003) Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome. Neuromuscul Disord 13(6):479–484CrossRefPubMedGoogle Scholar
  17. Garcia B (1994) Social-psychological dilemmas and coping of atomic veterans. Am J Orthopsychiatry 64(4):651–655CrossRefPubMedGoogle Scholar
  18. Glaser R, Kiecolt-Glaser JK (1998) Stress-associated immune modulation: relevance to viral infections and chronic fatigue syndrome. Am J Med 105(3A):35S–42SCrossRefPubMedGoogle Scholar
  19. Hall EJ (2011) Radiobiology for the radiologist, 7th edn.Google Scholar
  20. Hanley NR, Van de Kar LD (2003) Serotonin and the neuroendocrine regulation of the hypothalamic–pituitary-adrenal axis in health and disease. Vitam Horm 66:189–255CrossRefPubMedGoogle Scholar
  21. Hansen D, Schriner C (2005) Unanswered questions: the legacy of atomic veterans. Health Phys 89(2):155–163CrossRefPubMedGoogle Scholar
  22. Hilgers A, Frank J (1994) Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes. Wien Med Wochenschr 144(16):399–406PubMedGoogle Scholar
  23. Huang TT (2012) Redox balance- and radiation-mediated alteration in hippocampal neurogenesis. Free Radic Res 46(8):951–958CrossRefPubMedGoogle Scholar
  24. Israeli E (2012) Gulf war syndrome as a part of the autoimmune (autoinflammatory) syndrome induced by adjuvant (ASIA). Lupus 21(2):190–194CrossRefPubMedGoogle Scholar
  25. Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ, Wright EG (1992) Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature 355(6362):738–740CrossRefPubMedGoogle Scholar
  26. Kass RS (2005) The channelopathies: novel insights into molecular and genetic mechanisms of human disease. J Clin Invest 115(8):1986–1989CrossRefPubMedPubMedCentralGoogle Scholar
  27. Katz BZ, Jason LA (2013) Chronic fatigue syndrome following infections in adolescents. Curr Opin Pediatr 25(1):95–102CrossRefPubMedGoogle Scholar
  28. Kim JS, Yang M, Kim SH, Shin T, Moon C (2013) Neurobiological toxicity of radiation in hippocampal cells. Histol Histopathol 28(3):301–310PubMedGoogle Scholar
  29. Landmark-Høyvik H, Reinertsen KV, Loge JH, Kristensen VN, Dumeaux V, Fosså SD, Børresen-Dale AL, Edvardsen H (2010) The genetics and epigenetics of fatigue. PM R 2(5):456–465CrossRefPubMedGoogle Scholar
  30. Le M, McNeill F, Seymour C, Rainbow A, Mothersill C An observed effect of ultraviolet-A radiation emitted from β-irradiated HaCaT cells upon non-β-irradiated bystander cells. Rad Res (in press)Google Scholar
  31. Lorusso L, Mikhaylova S, Capelli E, Ferrari D, Ngonga GK, Ricevuti G (2009) Immunological aspects of chronic fatigue syndrome. Autoimmun Rev 8(4):287–291CrossRefPubMedGoogle Scholar
  32. Maes M, Twisk FN (2009) Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett 30(6):677–693PubMedGoogle Scholar
  33. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E (2009) Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett 30(4):470–476PubMedGoogle Scholar
  34. Maloney CD, Jensen S, Gil-Rivas V, Goolkasian P (2013) Latent viral immune inflammatory response model for chronic multisymptom illness. Med Hypotheses 80(3):220–229CrossRefPubMedGoogle Scholar
  35. Marazziti D, Baroni S, Catena-Dell’Osso M, Schiavi E, Ceresoli D, Conversano C, Dell’Osso L, Picano E (2012) Cognitive, psychological and psychiatric effects of ionizing radiation exposure. Curr Med Chem 19(12):1864–1869CrossRefPubMedGoogle Scholar
  36. McCauley LA, Joos SK, Barkhuizen A, Shuell T, Tyree WA, Bourdette DN (2002) Chronic fatigue in a population-based study of gulf war veterans. Arch Environ Health 57(4):340–348CrossRefPubMedGoogle Scholar
  37. Meeus M, Nijs J, Hermans L, Goubert D, Calders P (2013) The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets? Expert Opin Ther Targets 17(9):1081–1089CrossRefPubMedGoogle Scholar
  38. Morgan WF, Sowa MB (2013) Non-targeted effects induced by ionizing radiation: mechanisms and potential impact on radiation induced health effects. Cancer Lett pii: S0304-3835(13)00662-9. doi:  10.1016/j.canlet.2013.09.009 Google Scholar
  39. Morris G, Maes M (2013) A neuro-immune model of myalgic encephalomyelitis/chronic fatigue syndrome. Metab Brain Dis 28(4):523–540CrossRefPubMedGoogle Scholar
  40. Morris G, Maes M (2014) Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress. Metabolic brain disease. Springer, BerlinGoogle Scholar
  41. Moss-Morris R, Deary V, Castell B (2013) Chronic fatigue syndrome. Handb Clin Neurol 110:303–314CrossRefPubMedGoogle Scholar
  42. Mothersill C, Seymour C (2012) Changing paradigms in radiobiology. Mutat Res 750(2):85–95CrossRefPubMedGoogle Scholar
  43. Mothersill C, Seymour C (2013) Uncomfortable issues in radiation protection posed by low-dose radiobiology. Radiat Environ Biophys 52(3):293–298CrossRefPubMedGoogle Scholar
  44. Mothersill C, Heffron JJ, McLoughlin JV (1976) Inhibition of actomyosin ATPase by high concentrations of 5-hydroxytryptamine. Possible basis of lesion in 5HT-induced experimental myopathy. Enzyme 21(6):481–487PubMedGoogle Scholar
  45. Mothersill C, Saroya R, Smith RW, Singh H, Seymour CB (2010) Serum serotonin levels determine the magnitude and type of bystander effects in medium transfer experiments. Radiat Res 174(1):119–123CrossRefPubMedGoogle Scholar
  46. Mothersill C, Smith RW, Fazzari J, McNeill F, Prestwich W, Seymour CB (2012) Evidence for a physical component to the radiation-induced bystander effect? Int J Radiat Biol 88(8):583–591CrossRefPubMedGoogle Scholar
  47. Murphy BC, Ellis P, Greenberg S (1990) Atomic veterans and their families: responses to radiation exposure. Am J Orthopsychiatry 60(3):418–427CrossRefPubMedGoogle Scholar
  48. Nagasawa H, Little JB (1992) Induction of sister chromatid exchanges by extremely low doses of alpha-particles. Cancer Res 52(22):6394–6396PubMedGoogle Scholar
  49. Nicolson GL (2007) Metabolic syndrome and mitochondrial function: molecular replacement and antioxidant supplements to prevent membrane peroxidation and restore mitochondrial function. J Cell Biochem 100(6):1352–1369CrossRefPubMedGoogle Scholar
  50. Ojo-Amaize EA, Conley EJ, Peter JB (1994) Decreased natural killer cell activity is associated with severity of chronic fatigue immune dysfunction syndrome. Clin Infect Dis 18(Suppl 1):S157–S159CrossRefPubMedGoogle Scholar
  51. Poon RC, Agnihotri N, Seymour C, Mothersill C (2007) Bystander effects of ionizing radiation can be modulated by signaling amines. Environ Res 105(2):200–211CrossRefPubMedGoogle Scholar
  52. Saroya R, Smith R, Seymour C, Mothersill C (2009) Injection of resperpine into zebrafish, prevents fish to fish communication of radiation-induced bystander signals: confirmation in vivo of a role for serotonin in the mechanism. Dose Response 8(3):317–330PubMedPubMedCentralGoogle Scholar
  53. Seymour CB, Mothersill C, Alper T (1986) High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol Relat Stud Phys Chem Med 50(1):167–179CrossRefPubMedGoogle Scholar
  54. Smith AK, Dimulescu I, Falkenberg VR, Narasimhan S, Heim C, Vernon SD, Rajeevan MS (2008) Genetic evaluation of the serotonergic system in chronic fatigue syndrome. Psychoneuroendocrinology 33(2):188–197CrossRefPubMedGoogle Scholar
  55. Szumiel I (2014) Ionising radiation-induced oxidative stress, epigenetic changes and genomic instability: the pivotal role of mitochondria. Int J Radiat Biol 17:1–55Google Scholar
  56. Ushakov IB, Petrov VM, Shafirkin AV, Shtemberg AS (2011) Problems of ensuring human radiation safety during interplanetary flights. Radiats Biol Radioecol 51(5):595–610PubMedGoogle Scholar
  57. Voloboueva LA, Giffard RG (2011) Inflammation, mitochondria, and the inhibition of adult neurogenesis. J Neurosci Res 89(12):1989–1995CrossRefPubMedPubMedCentralGoogle Scholar
  58. Waxman SG, Ptacek LJ (2000) Chronic fatigue syndrome and channelopathies. Med Hypotheses 55(5):457CrossRefPubMedGoogle Scholar
  59. Witthöft M, Hiller W, Loch N, Jasper F (2013) The latent structure of medically unexplained symptoms and its relation to functional somatic syndromes. Int J Behav Med 20(2):172–183CrossRefPubMedGoogle Scholar
  60. Wu Q, Wang X (2012) Neuronal stem cells in the central nervous system and in human diseases. Protein Cell 3(4):262–270CrossRefPubMedPubMedCentralGoogle Scholar
  61. Yancey JR, Thomas SM (2012) Chronic fatigue syndrome: diagnosis and treatment. Am Fam Physician 86(8):741–746PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  1. 1.Department of Medical Physics and Applied Radiation SciencesMcMaster UniversityHamiltonCanada

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