Aluminum and Autism Spectrum Disorders: A working hypothesis

June 25, 2014

Sneha ShethExperimental 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 impairment

s

Language & communicat

ion difficulties

Repetitive behavior

Two-Hit hypothesis for ASDGenes 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

Human Body

VaccineAdjuvant

Breastmilk, Baby

formula, salads

Canned Foods,

Utensils, Tin foil

Antacids, pill-coatings

Cosmetics, Dyes,

Deodrants

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?

AluminumAl is a known BBB

toxin8

Al impairs mitochondrial

function6 Al induces activation of glial cells and

excessive production of proinflammatory

cytokines7

AutismCNS-related

autoimmunity in autistic patients is

partially due to disruption of the BBB3More than 1/3 of those with ASD have

mitochondrial dysfunction9Neuroglial 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 vaccin

es.

Does aluminum from vaccines contribute to ASD?Ecologi

cal 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.

SOCIAL INTERACTION TEST

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.

Study DesignBreeding

Pups randomized into control/ treated groups

Pups injected with saline/ aluminum over 2

weeks

Social Interaction test in week 7, 14, 21

Cohorts

Control

N = 11 (males)

N = 12 (females)

Treated

N = 16 (males)

N = 12 (females)

Preliminary data

*

Males

Females

Overall Limitations & proposed solutions• IHC• WB• DTI

Behavior alone is not enough

• Do a human mouse life span calculation based on different stages of physiological development

Aluminum injection schedule in mice may not be representative

of humans

• Recruit multiple observers to run the same test

Behavior test is heavily observer dependent

• Run an olfactory test

Sniffing differences indeed due to lack of interest or because of a sensory dysfunction

in the olfactory system?

• Conduct other behavior testsSocial interaction alone

may not suffice to make a claim about

ASD

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

References1. 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

2. 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.

3. 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 

4. 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.

5. 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.

6. 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.

7. 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

8. W. Zheng, Journal of Toxicology. Clinical Toxicology 39 (2001) 711–719.9. 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. 

10. Tomljenovic, Lucija;  Shaw, Christopher A(2011) Journal of inorganic biochemistry vol. 105 (11) p. 1489-9911. C.J. Newschaffer, M.D. Falb, J.G. Gurney, Pediatrics 115 (2005) e277–e282.

Thank you for listening!

Questions?