Aluminum adjuvant linked to gulf war illness induces motor neuron death in mice
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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.
KeywordsAmyotrophic Lateral Sclerosis Motor Neuron Squalene Aluminum Hydroxide Lumbar Spinal Cord
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- Crawley J. N. (2000) What’s Wrong With My Mouse? Behavioral Phenotyping of Trangenic and Knockout Mice. 65–69.Google Scholar
- 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.PubMedCrossRefGoogle Scholar
- 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.Google Scholar
- 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
- Paxinos G. and Franklin K. B. J. (2001) The Mouse Brain in Stereotoxic Coordinates 2nd ed. Academic Press. Sydney.Google Scholar
- 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.Google Scholar
- 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
- Sidman R. L., Angevine J. B. Jr., and Pierce E. T. (1971) Atlas of the Mouse Brain and Spinal Cord.Google Scholar