Aluminum and Autism Spectrum Disorders: A working hypothesis June 25, 2014 Sneha Sheth Experimental Medicine, UBC Supervisor: Dr. Chris Shaw Research Question: Do aluminum adjuvants contribute to an autism-like phenotype in young mice? Autism Spectrum Disorders (ASD) ASD is a set of neurodevelopmental disorders whose core deficits manifest as: Social impairments Language & communication difficulties Repetitive behavior Two-Hit hypothesis for ASD Genes Environment • Neuroinflammatory processes and immune dysfunction associated with ASD can result following pre or post natal exposure to various xenobiotics (i.e., bisphenol A, PCBs, Pb, Hg and Al)4 Examples of Aluminum Exposure Vaccine Adjuvant Cosmetics, Dyes, Deodrants Breastmilk, Baby formula, salads Human Body Antacids, pillcoatings Canned Foods, Utensils, Tin foil Aluminum is a neurotoxin • • • • • • • • • impairs memory, cognition and psychomotor control impairs neurotransmission and synaptic activity blood brain barrier changes pro-oxidant activates microglia and brain inflammation depresses brain glucose metabolism impairs protein transcription promotes neurite damage promotes amyloidosis (Tomljenovic, J of Alzheimers Dis 2011, 23(4): 567-598) A case for Al in the etiology of ASD? Aluminum Autism Al is a known BBB toxin8 CNS-related autoimmunity in autistic patients is partially due to disruption of the BBB3 Al impairs mitochondrial function6 More than 1/3 of those with ASD have mitochondrial dysfunction9 Al induces activation of glial cells and excessive production of proinflammatory cytokines7 Neuroglial activation and neuroinflammation may be central to abnormalities present in autism2. Are vaccines containing aluminum adjuvants safe? Aluminum is a known neurotoxin. Many adverse events reported from vaccines. Does aluminum from vaccines contribute to ASD? Ecological study shows statistically significant correlation between Al & ASD. Does aluminum from vaccines impair sociability? Social interaction is a core deficit underlying ASD. Social interaction test is a standardized test used to test for ASD in mice. Protocol: Yang, M., Silverman, J. L. and Crawley, J. N. 2011. Automated Three-Chambered Social Approach Task for Mice. Current Protocols in Neuroscience. 56:8.26.1–8.26.16. SOCIAL INTERACTION TEST Study Design Breeding Pups randomized into control/ treated groups Cohorts Control Treated Pups injected with saline/ aluminum over 2 weeks N = 11 (males) N = 16 (males) Social Interaction test in week 7, 14, 21 N = 12 (females) N = 12 (females) Preliminary data Males * Females Overall Limitations & proposed solutions Behavior alone is not enough • IHC • WB • DTI Aluminum injection schedule in mice may not be representative of humans • Do a human mouse life span calculation based on different stages of physiological development Behavior test is heavily observer dependent • Recruit multiple observers to run the same test Sniffing differences indeed due to lack of interest or because of a sensory dysfunction in the olfactory system? • Run an olfactory test Social interaction alone may not suffice to make a claim about ASD • Conduct other behavior tests Conclusion and key takeaways • Aluminum is a proven neurotoxin • Oddities in social interaction is a defining characteristic of Autism Spectrum disorders • Young male and female mice have shown deficits in social interaction as a result of aluminum exposure • More data is needed to establish a putative role of aluminum in the etiology of Autism Spectrum Disorders References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 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Aluminum and Alzheimer's Disease: After a Century of Controversy, Is there a Plausible Link? J Alzheimers Dis. 2011;23(4):567-98. Toimela T, Tahti H. Mitochondrial viability and apoptosis induced by aluminum, mercuric mercury and methylmercury in cell lines of neural origin. Arch Toxicol. 2004;78(10):565-74. Li X, Zheng H, Zhang Z, Li M, Huang Z, Schluesener HJ, et al. Glia activation induced by peripheral administration of aluminum oxide nanoparticles in rat brains. Nanomedicine. 2009;5(4):473-9 W. Zheng, Journal of Toxicology. Clinical Toxicology 39 (2001) 711–719. Oliveira, G., Diogo, L., Grazina, M., Garcia, P., Psych, A. A., Marques, C., Miguel, T., Borges, L., Vicente, A. M. and Oliveira, C. R. (2005), Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Developmental Medicine & Child Neurology, 47: 185–189. Tomljenovic, Lucija; Shaw, Christopher A(2011) Journal of inorganic biochemistry vol. 105 (11) p. 1489-99 C.J. Newschaffer, M.D. Falb, J.G. Gurney, Pediatrics 115 (2005) e277–e282. Thank you for listening! Questions?