Aluminum adjuvant linked to gulf war illness induces motor neuron death in mice

Abstract

Gulf War illness (GWI) affects a significant percentage of veterans of the 1991 conflict, but its origin remains unknown. Associated with some cases of GWI are increased incidences of amyotrophic lateral sclerosis and other neurological disorders. Whereas many environmental factors have been linked to GWI, the role of the anthrax vaccine has come under increasing scrutiny. Among the vaccine’s potentially toxic components are the adjuvants aluminum hydroxide and squalene. To examine whether these compounds might contribute to neuronal deficits associated with GWI, an animal model for examining the potential neurological impact of aluminum hydroxide, squalene, or aluminum hydroxide combined with squalene was developed. Young, male colony CD-1 mice were injected with the adjuvants at doses equivalent to those given to US military service personnel. All mice were subjected to a battery of motor and cognitive-behavioral tests over a 6-mo period postinjections. Following sacrifice, central nervous system tissues were examined using immunohistochemistry for evidence of inflammation and cell death. Behavioral testing showed motor deficits in the aluminum treatment group that expressed as a progressive decrease in strength measured by the wire-mesh hang test (final deficit at 24 wk; about 50%). Significant cognitive deficits in water-maze learning were observed in the combined aluminum and squalene group (4.3 errors per trial) compared with the controls (0.2 errors per trial) after 20 wk. Apoptotic neurons were identified in aluminum-injected animals that showed significantly increased activated caspase-3 labeling in lumbar spinal cord (255%) and primary motor cortex (192%) compared with the controls. Aluminum-treated groups also showed significant motor neuron loss (35%) and increased numbers of astrocytes (350%) in the lumbar spinal cord. The findings suggest a possible role for the aluminum adjuvant in some neurological features associated with GWI and possibly an additional role for the combination of adjuvants.

References

  1. Abou-Donia M. B., Wilmarth K. R., Jensen K. F., Oehme F. W., and Kurt T. L. (1996) Neurotoxicity resulting from coexposure to pyridostigmine bromide, deet, and permethrin: implications of Gulf War chemical exposures. J. Toxicol. Environ. Health 48, 35–56.

    PubMed  Article  CAS  Google Scholar 

  2. Asa P. B., Cao, Y., and Garry R. F. (2000) Antibodies to squalene in Gulf War syndrome. Exp. Mol. Pathol. 68, 55–64.

    PubMed  Article  CAS  Google Scholar 

  3. Asa P. B., Wilson R. B., and Garry R. F. (2002) Antibodies to squalene in recipients of anthrax vacine. Exp. Mol. Pathol. 73, 19–27.

    PubMed  Article  CAS  Google Scholar 

  4. Banks W. A. and Kastin A. J. (1989) Aluminum-induced neurotoxicity: alterations in membrane function at the blood-brain barrier. Neurosci. Biobehav. Rev. 13, 47–53.

    PubMed  Article  CAS  Google Scholar 

  5. Barbeito L. H., Pehar M., Cassina P., et al. (2004) A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res. Brain Res. Rev. 47, 263–274.

    PubMed  Article  CAS  Google Scholar 

  6. Baylor N. W., Egan W., and Richman P. (2002) Aluminum salts in vaccines—US perspective. Vaccine 20(Suppl 3), S18-S23.

    PubMed  Article  CAS  Google Scholar 

  7. Benisek Z., Suli, J., Elias D., et al. (2004) Experimental squalene adjuvant. II. Harmlessness and local reactogenity. Vaccine 22, 3470–3474.

    PubMed  Article  CAS  Google Scholar 

  8. Bilkei-Gorzo A. (1993) Neurotoxic effect of enteral aluminium. Food Chem. Toxicol. 31, 357–361.

    PubMed  Article  CAS  Google Scholar 

  9. Brewer J. M., Conacher M., Hunter C. A., Mohrs M., Brombacher F., and Alexander J. (1999) Aluminium hydroxide adjuvant initiates strong antigen-specific Th2 responses in the absence of IL-4-or IL-13-mediated signaling. J. Immunol. 163, 6448–6454.

    PubMed  CAS  Google Scholar 

  10. Bromberg M. B. (2002) Diagnostic criteria and outcome measurement of amyotrophic lateral sclerosis. Adv. Neurol. 88, 53–62.

    PubMed  Google Scholar 

  11. Carlson B. C., Jansson A. M., Larsson A., Bucht A., and Lorentzen J. C. (2000) The endogenous adjuvant squalene can induce a chronic T-cell-mediated arthritis in rats. Am. J. Pathol. 156, 2057–2065.

    PubMed  CAS  Google Scholar 

  12. Charatan F. (2002) US links motor neurone disease with Gulf war service. BMJ 324, 65.

    PubMed  Article  Google Scholar 

  13. Crapper D. R., Krishnan S. S., and Dalton A. J. (1973) Brain aluminum distribution in Alzheimer’s disease and experimental neurofibrillary degeneration. Science 180, 511–513.

    PubMed  Article  CAS  Google Scholar 

  14. Crawley J. N. (2000) What’s Wrong With My Mouse? Behavioral Phenotyping of Trangenic and Knockout Mice. 65–69.

  15. Crawley J. N., Belknap J. K., Collins A., et al. (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology (Berl.) 132, 107–124.

    Article  CAS  Google Scholar 

  16. DeFries, J. C., Hegmann, J. P., and Halcomb, R. A. (1974) Response to 20 generations of selection for open-field activity in mice. Behav. Biol. 11, 481–495.

    PubMed  Article  CAS  Google Scholar 

  17. Duan W. R., Garner D. S., Williams, S. D., Funckes-Shippy C. L., Spath I. S., and Blomme E. A. (2003) Comparison of immunohistochemistry for activated caspase-3 and cleaved cytokeratin 18 with the TUNEL method for quantification of apoptosis in histological sections of PC-3 subcutaneous xenografts. J. Pathol. 199, 221–228.

    PubMed  Article  CAS  Google Scholar 

  18. Dyer O. (2004) Inquiry finds that Gulf war veterans face extra burden of disease. BMJ 329, 1257.

    PubMed  Article  Google Scholar 

  19. Eisen A. and Weber M. (2001) The motor cortex and amyotrophic lateral sclerosis. Muscle Nerve 24, 564–573.

    PubMed  Article  CAS  Google Scholar 

  20. Everts H. G. and Koolhaas J. M. (1999) Differential modulation of lateral septal vasopressin receptor blockade in spatial learning, social recognition, and anxiety-related behaviors in rats. Behav. Brain Res. 99, 7–16.

    PubMed  Article  CAS  Google Scholar 

  21. Fellows P. F., Linscott M. K., Ivins B. E., et al. (2001) Efficacy of a human anthrax vaccine in guinea pigs, rabbits, and rhesus macaques against challenge by Bacillus anthracis isolates of diverse geographical origin. Vaccine 19, 3241–3247.

    PubMed  Article  CAS  Google Scholar 

  22. Ferguson E. and Cassaday H. J. (2001 and 2002) Theoretical accounts of Gulf War Syndrome: from environmental toxins to psychoneuroimmunology and neurodegeneration. Behav. Neurol. 13, 133–147.

    PubMed  Google Scholar 

  23. Lick-Smith H. C., Waters E. L., Walker N. J., et al. (2005) Mouse model characterisation for anthrax vaccine development: comparison of one inbred and one outbred mouse strain. Microb. Pathol. 38, 33–40.

    Article  CAS  Google Scholar 

  24. Fukuda K., Nisenbaum R., Stewart G., et al. (1998) Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA 280, 981–988.

    PubMed  Article  CAS  Google Scholar 

  25. Fulco C. E., Liverman C. T., and Sox H. C. (2000) Gulf War and Health: Volume 1. Depleted Uranium, Pyridostigmine, Bromide, Sarin, and Vaccines. Institute of Medicine. National Academy Press, pp. 89–168.

  26. Gabutti G., Guido M., Durando P., et al. (2005) Safety and immunogenicity of conventional subunit and MF59-adjuvanted influenza vaccines in human immunodeficiency virus-1-seropositive patients. J. Int. Med. Res. 33, 406–416.

    PubMed  CAS  Google Scholar 

  27. Gajkowska B., Smialek M., Ostrowski R. P., Piotrowski P., and Frontczak-Baniewicz M. (1999) The experimental squalence encephaloneuropathy in the rat. Exp. Toxicol. Pathol. 51, 75–80.

    PubMed  CAS  Google Scholar 

  28. Garruto R. M., Shankar S. K., Yanagihara R., Salazar A. M., Amyx H. L., and Gajdusek D. C. (1989) Low-calcium, high-aluminum diet-induced motor neuron pathology in cynomolgus monkeys. Acta Neuropathol. (Berl) 78, 210–219.

    Article  CAS  Google Scholar 

  29. Haley R. W. (2003) Excess incidence of ALS in young Gulf War veterans. Neurology 61, 750–756.

    PubMed  Google Scholar 

  30. Haley R. W., Kurt T. L., and Hom J. (1997) Is there a Gulf War Syndrome? Searching for syndromes by factor analysis of symptoms. JAMA. 277, 215–222.

    PubMed  Article  CAS  Google Scholar 

  31. Hom J., Haley R. W., and Kurt T. L. (1997) Neuropsychological correlates of Gulf War syndrome. Arch Clin. Neuropsychol. 12, 531–544.

    PubMed  Article  CAS  Google Scholar 

  32. Horner R. D., Kamins K. G., Feussner J. R., et al. (2003) Occurrence of amyotrophic lateral sclerosis among Gulf War Veterans. Neurology 61, 742–749.

    PubMed  CAS  Google Scholar 

  33. Hotopf M., David A., Hull, L., Ismail K., Unwin C., and Wessely S. (2000) Role of vaccinations as risk factors for ill health in veterans of the Gulf war: cross sectional study. BMJ 320, 1363–1367.

    PubMed  Article  CAS  Google Scholar 

  34. Hunter D., Zoutman D., Whitehead J., Hutchings J., and MacDonald K. (2004) Health effects of anthrax vaccination in the Canadian forces. Mil Med. 169, 833–838.

    PubMed  Google Scholar 

  35. Ivins B., Fellows P., Pitt L., et al. (1995) Experimental anthrax vaccines: efficacy of adjuvants combined with protective antigen against an aerosol Bacillus anthracis spore challenge in guinea pigs. Vaccine 13, 1779–1784.

    PubMed  Article  CAS  Google Scholar 

  36. Jefferson T., Rudin M., and Di Pietrantonj C. (2004) Adverse events after immunisation with aluminium-containing DTP vaccines: systematic review of the evidence. Lancet Infect Dis 4, 84–90.

    PubMed  Article  CAS  Google Scholar 

  37. Joshi J. G. (1990) Aluminum, a neurotoxin which affects diverse metabolic reactions. Biofactors 2, 163–169.

    PubMed  CAS  Google Scholar 

  38. Kalra R., Singh S. P., Razani-Boroujerdi S., et al. (2002) Subclinical doses of the nerve gas sarin impair T cell responses through the autonomic nervous system. Toxicol. Appl. Pharmacol. 184, 82–87.

    PubMed  Article  CAS  Google Scholar 

  39. Kang H. K., Mahan C. M. Lee K. Y., et al. (2002) Evidence for a deployment-related GulfWar syndrome by factor analysis. Arch. Environ. Health 57, 61–68.

    PubMed  Article  Google Scholar 

  40. Kanra G., Viviani S., Yurdakok K., et al. (2003) Effect of aluminum adjuvants on safety and immunogenicity of Haemophilus influenzae typeb-CRM197 conjugate vaccine. Pediatr. Int. 45, 314–318.

    PubMed  Article  CAS  Google Scholar 

  41. Kawahara M., Kato M., and Kuroda Y. (2001) Effects of aluminum on the neurotoxicity of primary cultured neurons and on the aggregation of betaamyloid protein. Brain Res. Bull. 55, 211–217.

    PubMed  Article  CAS  Google Scholar 

  42. Kurland L. T. (1988) Amyotrophic lateral sclerosis and Parkinson’s disease complex on Guam linked to an environmental neurotoxin. Trends Neurosci. 11, 51–54.

    PubMed  Article  CAS  Google Scholar 

  43. Kurt T. L. (1998) Epidemiological association in US veterans between Gulf War illness and exposures to anticholinesterases. Toxicol. Lett. 102–103, 523–536.

    PubMed  Article  Google Scholar 

  44. Lee V. M., Page C. D., Wu H. L., and Schlaepfer W. W. (1984) Monoclonalantibodies to gel-excised glial filament protein and their reactivities with other intermediate filament proteins. J. Neurochem. 42, 25–32.

    PubMed  Article  CAS  Google Scholar 

  45. Levine, J. B., Kong J., Nadler M., and Xu Z. (1999) Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS). Glia 28, 215–224.

    PubMed  Article  CAS  Google Scholar 

  46. Maatkamp A., Vlug A., Haasdijk E., Troost D., French P. J., and Jaarsma D. (2004) Decrease of Hsp25 protein expression precedes degeneration of motoneurons in ALS-SOD1 mice. Eur. J. Neurosci. 20, 14–28.

    PubMed  Article  Google Scholar 

  47. Matyas G. R., Rao M., Pittman P. R., et al. (2004) Detection of antibodies to squalene: III. Naturally occurring antibodies to squalene in humans and mice. J. Immunol. Methods 286, 47–67.

    PubMed  Article  CAS  Google Scholar 

  48. Morris R. (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47–60.

    PubMed  Article  CAS  Google Scholar 

  49. Mullen R. J., Buck C. R., and Smith A. M. (1992) Neu N, a neuronal specific nuclear protein in vertebrates. Development 116, 201–211.

    PubMed  CAS  Google Scholar 

  50. Murakami N. (1999) Parkinsonism-dementia complex on Guam—overview of clinical aspects. J. Neurol. 246(Suppl. 2), II16-II18.

    PubMed  Article  Google Scholar 

  51. Nagy D., Kato T., and Kushner P. D. (1994) Reactive astrocytes are widespread in the cortical gray matter of amyotrophic lateral sclerosis. J. Neurosci. Res. 38, 336–347.

    PubMed  Article  CAS  Google Scholar 

  52. Nass M. (1999) Anthrax vaccine. Model of a response to the biologic warfare threat. Infect Dis. Clin. North Am. 13, VIII187-VIII208.

    Article  Google Scholar 

  53. Nass M. (2002) The Anthrax Vaccine Program: an analysis of the CDC’s recommendations for vaccine use. Am. J. Public Health 92, 715–721.

    PubMed  Google Scholar 

  54. Nass M., Fisher B. L., and Robinson S. (2005) Comments and Questions regarding FDA’s proposed rule and order to licnese Anthrax Vaccine Absorbed. FDA Anthrax vaccine docket submission. Proposed rule and proposed order. 29 Fed. Reg. 78, 281–78, 293. December 29, 2004.

    Google Scholar 

  55. Nicolson G. L., Nasralla M. Y., Haier J., and Pomfret J. (2002) High frequency of systemic mycoplasmal infections in Gulf War veterans and civilians with Amyotrophic Lateral Sclerosis (ALS). J. Clin. Neurosci. 9, 525–529.

    PubMed  Article  CAS  Google Scholar 

  56. O’Reilly S. A., Roedica J., Nagy D., et al. (1995) Motor neuron-astrocyte interactions and levels of Cu, Zn superoxide dismutase in sporadic amyotrophic lateral sclerosis. Exp. Neurol. 131, 203–210.

    PubMed  Article  CAS  Google Scholar 

  57. Paxinos G. and Franklin K. B. J. (2001) The Mouse Brain in Stereotoxic Coordinates 2nd ed. Academic Press. Sydney.

    Google Scholar 

  58. Perl D. P., Gajdusek D. C., Garruto R. M., Yanagihara R. T., and Gibbs C. J. (1982) Intraneuronal aluminum accumulation in amyotrophic lateral sclerosis and Parkinsonism-dementia of Guam. Science, 217, 1053–1055.

    PubMed  Article  CAS  Google Scholar 

  59. Perl D. P. and Pendlebury W. W. (1986) Aluminum neurotoxicity—potential role in the pathogenesis of neurofibrillary tangle formation. Can. J. Neurol. Sci. 13, 441–445.

    PubMed  CAS  Google Scholar 

  60. Plaisier M. (2000) Letter dated March 20, 2000 from Department of Health and Human Services to former US member of Congress, Rep. Jack Metcalf, admitting to squalene, in anthrax vaccine while denying that it was in the licencsed formulation.

  61. Platt B., Fiddler G., Riedel G., and Henderson Z. (2001) Aluminium toxicity in the rat brain: histochemical and immunocytochemical evidence. Brain Res. Bull. 55, 257–267.

    PubMed  Article  CAS  Google Scholar 

  62. Rao J. K., Katsetos C. D., Herman M. M., and Savory J. (1998) Experimental aluminum ecephalomyelopathy. Relationship to human neurodegenerative disease. Clin. Lab. Med. 18, VIII687-VIII698.

    Google Scholar 

  63. Redhead K., Quinlan G. J., Das R. G., and Gutteridge J. M. (1992) Aluminium-adjuvanted vaccines transiently increase aluminium levels in murine brain tissue. Pharmacol. Toxicol. 70, 278–280.

    PubMed  CAS  Google Scholar 

  64. Rook G. A. and Zumla A. (1997) Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile?. Lancet 349, 1831–1833.

    PubMed  Article  CAS  Google Scholar 

  65. Rook G. A. and Zumla A. (1998) Is the Gulf War syndrome an immunologically mediated phenomenon? Hosp. Med. 59, 10–11.

    PubMed  CAS  Google Scholar 

  66. Sahin G., Varol I., Temizer A., Benli K., Demirdamar R., and Duru S. (1994) Determination of aluminum levels in the kidney, liver, and brain of mice treated with aluminum hydroxide. Biol. Trace Elem. Res. 41, 129–135.

    PubMed  CAS  Article  Google Scholar 

  67. Salamon R., Verret C., Jutand M. A., et al. (2006) Health consequences of the first Persian Gulf War on French troops. Int J Epidemiol. 35, 479–487.

    PubMed  Article  CAS  Google Scholar 

  68. Samson K. (2002) VA study finds ALS spike in Gulf War vets. Neurol. Today 2(1), 13–14.

    Article  Google Scholar 

  69. Sartin J. S. (2000) Gulf War illnesses: causes and controversies. Mayo Clin. Proc. 75, 811–819.

    PubMed  CAS  Article  Google Scholar 

  70. Sasaki S., Tsutsumi Y., Yamane K., Sakuma H., and Maruyama S. (1992) Sporadic amyotrophic lateral sclerosis with extensive neurological involvement. Acta Neuropathol. (Berl.) 84, 211–215.

    Article  CAS  Google Scholar 

  71. Satoh M., Kuroda Y., Yoshida H., et al. (2003) Induction of lupus autoantibodies by adjuvants. J. Autoimmun, 21, 1–9.

    PubMed  Article  CAS  Google Scholar 

  72. Savory J. and Garruto R. M. (1998) Aluminum, tau protein, and Alzheimer’s disease: an important link? Nutrition 14, 313–314.

    PubMed  Article  CAS  Google Scholar 

  73. Schumm W. R., Webb F. J., Jurich A. P., and Bollman S. R. (2002a) Comments on the Institute of Medicine’s 2002 report on the safety of anthrax vaccine. Psychol. Rep. 91, 187–191.

    PubMed  Article  Google Scholar 

  74. Schumm W. R., Reppert E. J., Jurich A. P., et al. (2002b) Self-reported changes in subjective health and anthrax vaccination as reported by over 900 Persian Gulf War era veterans. Psychol. Rep. 90, 639–653.

    PubMed  Article  Google Scholar 

  75. Schumm W. R., Jurich A. P., Bollman S. R., Webb F. J., and Castelo C. S. (2005) The long term safety of anthrax vaccine, pyridostigmine bromide (PB) tablets, and other risk factors among Reserve Component Veterans of the First Persian Gulf War. Medical Veritas 2, 348–362.

    Article  Google Scholar 

  76. Shaw C. A. and Wilson J. M. (2003) Analysis of neurological disease in four dimensions: insight from ALS-PDC epidemiology and animal models. Neurosci. Biobehav. Rev. 27, 493–505.

    PubMed  Article  CAS  Google Scholar 

  77. Shawky S. (2002) Depleted uranium: an overview of its properties and health effects. East Mediterr. Health J. 8, 432–439.

    PubMed  CAS  Google Scholar 

  78. Sidman R. L., Angevine J. B. Jr., and Pierce E. T. (1971) Atlas of the Mouse Brain and Spinal Cord.

  79. Skowera A., Hotopf M., Sawicka E., et al. (2004) Cellular immune activation in Gulf War veterans. J. Clin. Immunol. 24, 66–73.

    PubMed  Article  CAS  Google Scholar 

  80. Steele L. (2000) Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am. J. Epidemiol. 152, 992–1002.

    PubMed  Article  CAS  Google Scholar 

  81. Suli J., Benisek Z., Elias D., et al. (2004) Experimental squalene adjuvant. I. Preparation and testing of its effectiveness. Vaccine 22, 3464–3469.

    PubMed  Article  CAS  Google Scholar 

  82. Taylor D. N., Sanchez J. L., Smoak B. L., and DeFraites R. (1997) Helicobacter pylori infection in Desert Storm troops. Clin. Infect Dis. 25, 979–982.

    PubMed  CAS  Google Scholar 

  83. Tohyama T., Lee V. M., Rorke L. B., and Trojanowski J. Q. (1991) Molecular milestones that signal axonal maturation and the commitment of human spinal cord precursor cells to the neuronal or glial phenotype in development. J. Comp. Neurol. 310, 285–299.

    PubMed  Article  CAS  Google Scholar 

  84. Tsuchiya K., Takahashi M., Shiotsu H., et al. (2002) Sporadic amyotrophic lateral sclerosis with circumscribed temporal atrophy: a report of an autopsy case without dementia and with ubiquitinated intraneuronal inclusions. Neuropathology 22, 308–316.

    PubMed  Article  Google Scholar 

  85. Unwin C., Blatchley N., Coker W., et al. (1999) Health of UK servicemen who served in Persian Gulf War. Lancet 353, 169–178.

    PubMed  Article  CAS  Google Scholar 

  86. Valensi J. P., Carlson J. R., and Van Nest G. A. (1994) Systemic cytokine profiles in BALB/c mice immunized with trivalent influenza vaccine containing MF59 oil emulsion and other advanced adjuvants. J. Immunol. 153, 4029–4039.

    PubMed  CAS  Google Scholar 

  87. Wagner-Recio M., Toews A. D., and Morell P. (1991) Tellurium blocks cholesterol synthesis by inhibiting squalene metabolism: preferential vulnerability to this metabolic block leads to peripheral nervous system demyelination. J. Neurochem. 57, 1891–1901.

    PubMed  Article  CAS  Google Scholar 

  88. Wang D., Perides G., and Liu Y. F. (2005) Vaccination alone or in combination with pyridostigmine promotes and prolongs activation of stress-activated kinases induced by stress in the mouse brain. J. Neurochem. 93, 1010–1020.

    PubMed  Article  CAS  Google Scholar 

  89. Weisskopf M. G., O’Reilly E. J., McCullough M. L., et al. (2005) Prospective study of military service and mortality from ALS. Neurology 64, 32–37.

    PubMed  Article  CAS  Google Scholar 

  90. Wen G. Y. and Wisniewski H. M. (1985) Histochemical localization of aluminum in the rabbit CNS. Acta Neuropathol (Berl.) 68, 175–184.

    Article  CAS  Google Scholar 

  91. Wetts R. and Vaughn J. E. (1996) Differential vulnerability of two subsets of spinal motor neurons in amyotrophic lateral sclerosis. Exp. Neurol. 141, 248–255.

    PubMed  Article  CAS  Google Scholar 

  92. Williamson E. D., Hodgson I., Walker N. J., et al. (2005) Immunogenicity of recombinant protective antigen and efficacy against aerosol challenge with anthrax. Infect Immun. 73, 5978–5987

    PubMed  Article  CAS  Google Scholar 

  93. Wolf H. K., Buslei R., Schmidt-Kastner R., et al. (1996) NeuN: a useful neuronal marker for diagnostic histopathology. J. Histochem. Cytochem. 44, 1167–1171

    PubMed  CAS  Google Scholar 

  94. Wolfe J., Proctor S. P., Erickson D. J., and Hu H. (2002) Risk factors for multisymptom illness in US Army veterans of the Gulf War. J. Occup. Environ. Med. 44, 271–281.

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Michael S. Petrik.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Petrik, M.S., Wong, M.C., Tabata, R.C. et al. Aluminum adjuvant linked to gulf war illness induces motor neuron death in mice. Neuromol Med 9, 83–100 (2007). https://doi.org/10.1385/NMM:9:1:83

Download citation

Keywords

  • Amyotrophic Lateral Sclerosis
  • Motor Neuron
  • Squalene
  • Aluminum Hydroxide
  • Lumbar Spinal Cord