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.
Hendry J, DeVito T, Gelman N, Densmore M, Rajakumar N, Pavlosky W, Williamson PC, Thompson PM, Drost
DJ, Nicolson R.White matter abnormalities in autism detected through transverse relaxation time
imaging. Neuroimage 2006; 29: 1049–57
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in
the brain of patients with autism. Ann Neurol. 2005;57(1):67-81.
Vojdani A, Campbell AW, Anyanwu E, et al. Antibodies to neuron-specific antigens in children with autism: possible
cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J
Neuroimmunol2002;129(1-2):168-77
Dietert RR, Dietert JM. Potential for early-life immune insult including developmental immunotoxicity in autism and
autism spectrum disorders: focus on critical windows of immune vulnerability. J Toxicol Environ Health B Crit Rev.
2008;11(8):660-80.
Tomljenovic L. 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?