Can chemicals cause autism? Michael Li Anne Lor Richard Li Brian Tang

What is Autism Autism is a neurodevelopmental disorder that results in: ●Deficit in social skills from infancy ●lack of communicative ability ●Repetitive interests Autism is a biological genetic disorder: ●Monozygotic twins share 90% concordance ●Dizygotic twins share 10% concordance

Autism Neuropathology The brains of autistic individuals develop abnormally. ●Overdevelopment of regions of the brain responsible for social behavior o Frontal Cortex o Temporal Cortex o Amygdala ●Abnormalities in the white matter of an autistic brain o Increased amounts of short-range connections  Savants o Decreased amounts of long-range connections

Causes of Autism ●No concrete evidence linking a chemical agent to autism. ●Some possible environmental chemical causative agents include: o Lead o Mercury o Valproic Acid o Paracetamol

Valproic Acid ●anticonvulsant ●treat seizures, prevent migraine headaches, and the treatment of epilepsy

Studies of Valproic Acid and ASD ●Fetal Valproate Syndrome ●Linked to increased risk of ASD ●11 year study on cognitive development of children born to mothers with epilepsy

Rodent Model ●Mice were injected with valproic acid ●In utero exposure of VPA resulted in physical malformations ○ also showed signs of ASD

Epigenetics in ASD? ●VPA can inhibit histone deacetylases ●genetic material: ○negatively-charged DNA ○positively-charged histones ●access to genes decreases with increasing strength of DNA/histone interactions ●acetylation removes positive charge from histones ○DNA/histone interactions broken, leading to increased gene expression ●deacetylation reintroduces positive charge ○DNA/histone interactions restored, leading to decreased gene expression

A Possible Mechanism ●VPA prevents deacetylation → increased gene expression ●ASD caused by brain tissue overgrowth in areas controlling social/emotional functioning(?) ●increased gene expression leads to increased growth of neural tissue(?)

Other Possible Chemical Agents Paracetamol (acetaminophen) ●Study found that children who had pre-natal exposure to paracetamol for more than 28 days had neurodevelopmental outcomes ●Suggested correlation between prenatal paracetamol use and autism prevalence ●However, no definitive evidence to suggest correlation = causation

Other Possible Chemical Agents Lead ●Autistic children tend to have significantly higher lead blood levels in comparison to children who do not have autism ●Suggests that lead is a possible causative agent for autism, but no definitive evidence yet ●Again, no evidence to suggest correlation = causation

Summary Slide ●ASD is a neurodevelopmental disorder that impairs communicative ability ●Individuals with autism show abnormal brain development characterized by the overdevelopment of the frontal cortex, temporal cortex and amygdala. ●Studies conducted of children exposed to valproic acid prenatally showed a higher risk of neurodevelopmental disorders ●Rodent model is used to further investigate the link between prenatal valproic acid exposure and ASD ●Valproic acid inhibits histone deacetylation, thus leading to increased gene expression and tissue overgrowth in areas of the brain involved in emotional and social functioning ●Correlation between pre-natal paracetamol use and prevalence of autism exists. However, there is a lack of evidence to suggest that paracetamol causes autism. ●Autistic children tend to have higher lead blood levels than healthy children. Although a correlation exists, no mechanism is established on how lead may cause autism.

References American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders: 4th ed. Washington, DC: American Psychiatric Association V. Bambini-Junior, L. Rodrigues, G.A. Behr, J.C. Moreira, R. Riesgo, C. Gottfried Animal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters Brain Res., 1408 (2011), pp. 8–16 Takuma, K., Ago, Y., Matsuda, T., Hashimoto, H., Hayata-Takano, A., Takano, E., et al. (2014). Chronic treatment with valproic acid or sodium butyrate attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism. Pharmacology Biochemistry and Behavior, 126C, Chomiak T, Turner N, Hu B What we have learned about autism spectrum disorder from valproic acid. Pathology Research International, 2013: Brandlistuen, RE., Ystrom, E., Nulman, I., Koren, G., and Nordeng, H Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol. 42(6):1702. El-Ansary AK., Bacha, AB., and Ayahdi, LY Relationship between chronic lead toxicity and plasma neurotransmitters in autistic patients from Saudi Arabia. Clin Biochem. 44(13):