Environmental Risks Factors in ASD: What We Know What We Need to Know

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Environmental Risks Factors in ASD What We Know
/ What We Need to Know
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Scope of the Problem

• At present, the causes of the majority of
  developmental
• defects are not understood.

• 3 of all developmental defects are
  attributable to
• exposure to toxic chemicals
• 25 of all developmental defects may be due
  to a
• combination of genetic and
  environmental factors.

• Underestimate most neurological and
  behavioral problems
• are not diagnosed until early childhood or
  young adulthood

National Res. Council Report (2000)
http//www.nap.edu/catalog.php?record_id9871toc
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What we dont know about environmental triggers
of developmental disorders
Thousands of commercially important chemicals

• industrial chemicals

• pesticides

• ingredients

• food additives

The vast majority of commercially important
chemicals lack adequate toxicity testing,
especially for developmental neurotoxicity
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In any population, there are individual
susceptible to environmental toxicants
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Are children genetically predisposed to
autisms deficits especially susceptible to
environmental toxicants
Autism
TD50
TD50
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Are children genetically predisposed to
autisms deficits especially susceptible to
environmental toxicants
100
100
Typical
Autism
with adverse effects
50
50
0
0
TD50
Log Toxicant Concentration (mg/kg)
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Autism is a Complex Disorder

• Very high heritability
• Multiple genes confer risk (estimates of
  5-100)
• Epigenetic mechanisms (DNA methylation)
• Other mechanisms (de novo copy number
  variations)

Given that autism risk is contributed by multiple
defective genes.many expressed both within and
outside the central nervous system.
Could autism represent a multi-system disorder
whose outcome is likely to be more profoundly
impacted by environment than other disorders and
diseases. What are the possible mechanisms
involved?
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Strategy for generating hypotheses, and testing
them
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A common mechanism for autism susceptibility may
stem from abnormal ratios of excitatory/inhibitory
neurons and the networks they form
From Belmont and Bourgeron (2006) Nature
Neuroscience 9(10)1221- 1225
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Framework for understanding gene-environment
interactions impacting autism risk

Many of the most heavily used pesticides alter
the balance of excitation/inhibition within the
developing nervous system

• Neonicotinoid Insecticides (e.g. imidacloprid,
  thiacloprid)
• Target nicotinic cholinergic receptors (insect
  selective?)

Neuronal nAChR subunits a2 a3 a4 a5 a6 a7 a8 a9 a
10? ?? ?? ??
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PDD association with levels of OP metabolites
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PON1 Polymorphisms associated with autism
Paraoxonase gene variants are associated with
autism in North America, but not in Italy
possible regional specificity in gene-environment
interactions. D'Agruma L, Muscarella LA,
Guarnieri V, et al (2005) Mol Psychiatry.
10(11)1006-16. Laboratory of Molecular
Psychiatry and Neurogenetics, University Campus
Bio-Medico, Rome, Italy. Assessed
linkage/association between autism and variants
of the paraoxonase gene (PON1) encoding
paraoxonase, the enzyme responsible for OP
detoxification. Three functional (less active
OP metabolizing activity) single nucleotide
polymorphisms PON1 C-108T, L55M, and
Q192R. Found significant association between
autism and PON1 variants in Caucasian-American,
but not Italian families
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PON1 Polymorphisms associated with autism
Pasca SP, Nemes B, Vlase L, Gagyi CE, Dronca
E, Miu AC, Dronca M. High levels of homocysteine
and low serum paraoxonase 1 arylesterase
activity in children with autism. Life Sci. 2006
Apr 478(19)2244-8.
OP insecticides
PON1 Activity
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Framework for understanding gene-environment
interactions impacting autism risk

Many of the most heavily used insecticides alter
the balance of excitation/inhibition within the
developing nervous system

• 4-alkyl-1-phenylpyrazole insecticides (e.g.
  Fipronil)
• Non-competitive inhibitor of GABAA receptors
  (insect selective?)

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Framework for understanding gene-environment
interactions impacting autism risk

Many of the most heavily used insecticides alter
the balance of excitation/inhibition within the
developing nervous system
GABAergic Neurotransmission

• 4-alkyl-1-phenylpyrazole insecticides (e.g.
  Fipronil)
• Non-competitive inhibitor of GABAA receptors
  (insect selective?)

six types of a subunits (GABRA1, GABRA2, GABRA3,
GABRA4, GABRA5, GABRA6) three ß's (GABRB1,
GABRB2, GABRB3) three ?'s (GABRG1, GABRG2,
GABRG3) a d (GABRD), an e (GABRE), a p (GABRP),
and a ? (GABRQ)
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Pesticides that antagonize GABAA Receptors
Schematic illustration of a GABAA receptor with
its binding sites
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4-alkyl-1-phenylpyrazoles may not be as
selective for Some GABAA receptors as we once
thought
GABA receptor antagonists and insecticides
common structural features of 4-alkyl-1-phenylpyra
zoles and 4-alkyl-1-phenyltrioxabicyclooctanes Sam
melson RE, Caboni P, Durkin KA, Casida JEBioorg
Med Chem. 2004 12(12)3345-55.
Structure-activity studies described here reveal
that fipronil retains its very high
binding potency at the human beta3 and house fly
gamma-aminobutyric acid (GABA) receptors
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1?M fipronil
Control
Stehr et al, Tox Sci 92, 270 (2006)
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Defective/deficient GABAA Receptors in Autisms

• Epigenetic mechanisms
• MeCP2-deficiency associated with down
  regulation of GABR?3
• (Samaco et al 2005, Hum Mol Genet 14(4),
  483-92)

• Complex gene-gene interactions
• Polymorphisms at GABR?4 are involved in the
  etiology of autism,
• interaction with GABR?1 increases autism risk
• (Ma et al, 2005, Am J Hum Gen 77, 377)

• Polymorphisms

GABR?1, GABR?3 genes (Vincent et al,
2006 J Med Gen 43, 429 Ashley-Koch et al, 2006
Ann Hum Gen 70, 281
Open Question
Could children with heritable deficiencies in
GABA-mediated neurotransmission be particularly
susceptible to chemicals that interfere with GABA
neurotransmission? (Chlorinated hydrocarbons,
4-alkyl-1-phenylpyrazoles, avermectins, etc)
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Defective/deficient GABAA Receptors in Autisms
Open Question
Could children with heritable deficiencies in
GABA-mediated neurotransmission be particularly
susceptible to chemicals that interfere with GABA
neurotransmission? (Organochlorine,
4-alkyl-1-phenylpyrazoles, avermectins, etc)
From Roberts et al Environ. Health Perspect.
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Aromatic Chlorinated Hydrocarbons
Non-dioxin-like
Dioxin-like
Polychlorinated dibenzo-p-dioxin (PCDD)
Polychlorinated biphenyl (non coplanar PCB)
Polychlorinated dibenzofuran (PCDF)
Polybrominated diphenylether (non coplanar PBDE)
Triclosan
Polychlorinated biphenyl (coplanar PCB)
X and Y represent the number of chlorine on the
respective rings
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Non-coplanar Triclosan - Concerns for Human Health

• Levels of Triclosan in the U.S. Population
• CDC scientists tested the urine of 2,517 people
  ages six years and older who took part in
  nationwide survey, called the National Health and
  Nutrition Examination Survey (NHANES), during
  2003-2004.
• Triclosan was detected in the urine of nearly
  75 percent of the people tested.
• Triclosan levels were greater among people in
  the highest income bracket than among those in
  either the middle or lower income brackets.

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Framework for understanding gene-environment
interactions impacting autism risk
How can autism susceptibility genes inform us
about Environmental modifiers of risk, severity,
treatment