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Environmental Exposures in Autism Etiology

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Environmental Exposures in Autism Etiology. Irva Hertz-Picciotto. University of California Davis, ... Effects on genes that regulate CNS development ... – PowerPoint PPT presentation

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Title: Environmental Exposures in Autism Etiology


1
Environmental Exposures in Autism Etiology
Irva Hertz-Picciotto University of California
Davis, M.I.N.D. Institute Center for Childrens
Environmental Health Department of Public
Health Sciences
2
Mechanisms for Environmental Chemicals to Affect
Autism Risk
  • Direct action on neural tissue during
  • Differentiation
  • Migration
  • Dendritic branching/pruning
  • Synaptogenesis
  • Effects on genes that regulate CNS development
  • Perturbation of immune signaling/inflammation via
    neurotransmitters /or cytokines
  • Endocrine disruption sex steroids/thyroid
    hormones

3
Causes Unknown but Numerous
  • Autism is multifactorial, meaning
  • multiple causes across the population and within
    an individual

A
B
B
D
E
F
C
Most rare one cause
Most common 3 or more causes
Possible 2 causes
4
Genes Environment in Autism?
  • Genetics 60-90 (twin studies)
  • Environment 10-40 minimum
  • Sum not 100
  • Risk Ratios of 10
  • Congenital rubella
  • Thalidomide
  • Risk Ratios 4 to 5
  • Maternal age
  • Male sex

B
A
D
C
E
B
F
G
D
H
5
Center for Childrens Environmental Health (CCEH)
  • NIEHS call in 2000
  • State of the epidemiologic literature on risk
    factors
  • Descriptive malefemale
  • Obstetric suboptimality
  • Twin studies familial aggregation
  • Reported trend towards increasing prevalence
  • Environmental causes viral, pharmacologic
  • Need for multi-disciplinary approach
  • UC Davis CCEH The CHARGE Study

6
The CHARGE Study
CHildhood Autism Risk from Genetics and the
Environment
7
Goals of the CHARGE Study
  • To identify causes and contributing risk
    protective factors for childhood autism
  • Genetic susceptibility
  • Environmental exposures
  • Interactions of the two
  • To determine mechanisms of susceptibility and
    identify subsets of possible distinct etiologies
    for childhood autism
  • Immunologic
  • Genetic/Genomic
  • Metabolic/metabolomic
  • Phenotypic

8
Environmental Exposures
Biospecimens Blood (recent exposures) Childs
hair (recent - depends on length) Baby lock
(first year of life) Mothers hair (if long
enough, prenatal) Urine (recent exposure,
metabolism) Newborn blood spot (prenatal) Intervie
ws Recall? Diet Residential information Lifesty
le Consumer products Medical history Linkage to
exposure databases Air, water, pesticides, haz
waste GIS Medical records Completeness?
  • Pesticides
  • Metals
  • Organic pollutants(PCBs, PBDEs, phthalates)
  • Viruses, bacteria other infections
  • Medical procedures pharmaceuticals
  • Nutritional factors

9
DESIGN METHODS
Population-based recruitmentClinical
confirmation of dxLinkage to state-of-the-art
laboratories
10
CHARGE Study DesignCase-control - three groups
  • Children with autism
  • Children with developmental delay
  • Children drawn from general population of births,
    frequency-matched on age, gender geography

California DDS
California Birth files
All children - Eligibility 24-60 months, born in
Calif, mother English/Spanish speaking, living
with biologic parents
11
(No Transcript)
12
The CHARGE Study Clinical Protocol
  • Confirmation of diagnosis
  • ADI and ADOS (autism cases only)
  • Social Communication Questionnaire (all others)
  • Cognitive adaptive development (all children)
  • Medical Exam
  • Medical Hx
  • Parent forms
  • Medical records obtained
  • Environmental Exposure Questionnaire

13
The CHARGE Study Clinical Protocol
  • Specimens- blood - urine- hair from
    index child, parents siblings
  • Newborn blood spots from CDPH GDB

14
RESULTSImmunologic Deviations
15
Maternal Antibodies to Fetal Brain Tissue (n163)
  • Braunschweig et al., Neurotoxicology 2008
    29226-23

16
Leptin a cytokine
The CHARGE Study
Ashwood et al., J Autism Dev Disorders
200838169-175
17
RESULTSGenomics, Genetics Epigenetics
18
Early Onset Autism (A-E) vs General Population
(GP)
Gregg et al., Genomics 20089122-29
19
Differential gene expression in autism compared
to typically developing, general population
controls
Fold-change Gene Affymetrix GeneChip
Taqman p-value PAM 1.86 1.51
0.007 SPON2 1.87 1.86 0.005 IL2RB 1.56
1.35 0.046 PRF1 1.79 1.53 0.027 GZMB
2.01 1.72 0.014 CX3CR1 1.60 1.37
0.006 SH2D1B/EAT 2 2.19 1.78 0.011 EDG8
1.99 ND IGFBP7 1.70 ND ZNF145
1.99 ND KIR3DL2 1.58 ND
20
Early Onset Autism vs GP Cell Types
Genes Expression Levels
PMN
Mono
B
CD4
CD8
NK
Gregg et al., Genomics 20089122-29
21
Other Related Studies
  • Candidate genes (Tassone)
  • MAOA, 5HT-receptor, GSTM1
  • SNPs (Gregg)
  • Copy Number Variants (Selleck)
  • Epigenetics (Lasalle) - X-Chromosome Inactivation

22
Dysmorphology
  • Digital photos are taken of face frontal and
    profile views
  • Blind review by experts in genetics pediatrics
  • Identify minor physical anomalies
  • Disagreements resolved by consensus of all 3
    raters.
  • 242 children were reviewed (121 ASD, 51 DD, and
    70 TD)
  • ASD children more likely to be classified as
    dysmorphic or partially dysmorphic.
  • Those with 6 or more dysmorphic features may be a
    subgroup with a high genetic susceptibility.

Angkustsiri et al., in preparation presented at
Ped Acad Soc 2008
23
RESULTSLipids
24
Autism and Fatty Acid Profiles (n250)
Wiest et al., in submission
25
Autism and Fatty Acid Profiles
  • Docosahexanoic acid (DHA)
  • abundant in phospholipids of brain and retina
  • contributes to membrane structure and
    functioneicosanoid signalinggene expression
    modulation
  • Other Functions
  • Inhibition of neuronal apoptosis and
  • Regulating neuronal excitability through GABA
    receptors
  • Developing brains obtain DHA from circulation

Wiest et al., in submission
26
RESULTSEnvironmental Chemicals
27
Hg and Autism
  • Great interest known neurotoxin
  • Most research focused on thimerosal in vaccines
  • Multiple sources
  • Fish
  • Dental amalgams
  • Broken thermometers, light bulbs
  • Nasal sprays, contact lens solution
  • CHARGE Study approach
  • Current blood
  • Baby locks (first haircuts)
  • Newborn blood spots
  • Questionnaire about use of products

28
The CHARGE Study
29
Prediction of log(Blood Hg)
Multivariate analysis to adjust for
confounding Subjects weighted to adjust for
differential participation by SES
30
Interpretation/Conclusion
  • No difference in current blood levels of Hg
  • Does not confirm previous report of higher blood
    Hg in children with autism
  • Does not address early life exposures as
    potential causal factors
  • Possible sequestering of ethyl as opposed to
    methyl Hg not addressed in this study
  • Only 5 of Hg body burden is in circulation

31
PBDEsPolybrominated diphenyl ethers
  • Flame retardants
  • Sweden (1998) and then EU has banned penta and
    octa-PBDEs
  • Rodents lack of ability to habituate to a novel
    situation.

All US women's milk samples were contaminated
with PBDEs from 6 to 419 ng/g, lipid, orders of
magnitude higher than levels reported in
European studies, and are the highest reported
worldwide. Mol Nutr
Food Res 2008
32
Pilot Study Results Autism PBDEs
  • Children with ASD do not have higher levels of
    PBDEs
  • Contrary to our hypothesis, their levels of PBDEs
    are lower than in typically developing children
  • Possibility of reverse causation behaviors
    changed?
  • High SES more air flow in home?
  • Association with head growth?
  • Used a post-dx measurement -- need to measure
    PBDE exposures during critical windows of
    development

33
Household items that may contain deca-PBDEs
  • Televisions?Cell phones?Fax machines?Audio
    and video equipment?Computers?Printers?Scanners?Ph
    otocopiers?Remote controls?Lamp
    sockets?Hairdryers?Fans?Upholstered
    sofas?Upholstered chairs?Polyurethane
    foam?Mattresses?Curtains?Drapes?Carpet
    padding?Ovens and stoves?Stove hoods?Refrigerators
    ?Dishwashers?Washing machines?Clothes
    dryer?Microwaves?Toasters?Coffee makers?Water
    heaters?Wires and cables?Circuit
    breakers?Electrical outlets

34
Pesticides Autism
  • Roberts et al EHP 2007
  • Organochlorines applied commercially within 1/2
    mile of mothers residence at delivery associated
    with greater risk of autism.
  • Strongest association in weeks 1-8 of gestation
  • Eskenazi et al, Basic Clin Pharm Toxicol 2008
  • Organophosphate metabolites (DAPs) in urine
    collected during pregnancy and 1st year of life
    associated with autism spectrum disorder
    symptoms.
  • These compounds cross the placenta and
    bioaccumulate.

35
Pesticides Autism n531
  • CHARGE Study self-reported use of household
    products (about 2 dozen)
  • Use of pet flea or tick soaps/shampoos by mother
    doubled the risk that the child developed autism.
  • Associations from 3 months prior to conception
    through first year of childs life
  • These shampoos are formulated primarily with
    pyrethrins

36
Pet flea/tick shampoos
Mode of Action Pyrethrins affect the nervous
system of insects and result in repeated and
extended firings of the nerves. They do this by
affecting the flow of sodium out of nerve cells
through voltage-sensitive sodium channels.
Bio-Groom Flea Tick Pyrethrin Spray 16 fl oz.
EctoKyl CA Pyrethrin Flea Shampoo - 12 oz.
Hartz 2 in 1 Rid Flea Dog Shampoo with Pyrethrin
- 18 oz.
37
Toxicities of pyrethroids
  • Neuronal cell death in hippocampus
  • Mechanisms may involve not only sodium but also
    calcium channels
  • Wide variation in age sensitivity
  • Piperonyl butoxide enhances toxicity

Early life exposure to pyrethrins has been shown
to compromise the blood-brain barrier in rodents
38
Labor Induction /or Augmentation
  • Drugs increasingly used to alter the course of
    labor
  • Oxytocin receptors throughout the brain
  • Prostaglandins are potent pro-inflammatory
    compounds.

Walker et al., in preparation (to be presented at
IMFAR 2008)
39
Critical Window(s) for Susceptibility?
Conception
Delivery
1 year
1st
2nd
3rd
LMP
Brain Development
40
Limitations of CHARGE
  • Numbers large for this type of study (n1000),
    but small for studying rare exposures, or rare
    polymorphisms.
  • Data on non-medical exposures by retrospective
    self-report possible reporting bias
  • Unclear whether differences (e.g., immune) are
    - part of causal pathway - a result of
    neuropathology - a concommitant parallel effect
  • Limited specimens that predate the diagnosis

Newest epidemiologic study from the UC Davis
Center for Childrens Environmental Health
MARBLES
41
Markers of Autism Risk in BabiesLearning Early
Signs
A study of pregnant moms, who already have a
child with autism, following their pregnancies
and new child
42
Eligibility Criteria for MARBLES
  • Be the biological mother or father of a child
    diagnosed with autism
  • Be pregnant or planning a pregnancy in the near
    future
  • Live within 2-hours drive of the Sacramento/Davis
    area
  • Be over the age of 18

43
Critical Window(s) for Susceptibility?
Conception
Delivery
1 year
1st
2nd
3rd
LMP
Brain Development
44
MARBLES Participants
  • Answer questionnaires and telephone interviews
    about family medical history, illnesses and
    medications, lifestyle, diet, home product use,
    and other factors that may influence their babys
    development
  • Complete weekly symptom diaries during pregnancy
    and monthly diaries during the first year of
    childs life
  • Donate biological specimens
  • Permit collection of environmental samples

45
Investigators
  • UC Davis CCEH
  • Isaac Pessah
  • Robin Hansen
  • Cheryl Walker
  • Judy Van de Water
  • Paul Ashwood
  • Jeffrey Gregg
  • Frank Sharp
  • Bruce German
  • Bruce Hammock
  • Peter Green
  • Robert Berman
  • Danh Nguyen
  • UC Davis
  • Flora Tassone
  • Lihong Qi
  • Janine Lasalle
  • Sally Ozonoff
  • Univ Minnessota
  • Scott Selleck
  • Vanderbilt
  • Pat Levitt
  • USC (Southern Calif)
  • Rob McConnell
  • Johns Hopkins
  • Li-Ching Lee

46
Be in CHARGE !
  • http//beincharge.ucdavis.edu/

47
Grateful thanks to
Paula Krakowiak, Lora Delwiche, Lesley Deprey,
Carrie Jones, Beth Goodlin-Jones, Susan Bacalman
Nicole Tartaglia, Steve Nowicki, Jean Sakamura,
Kathleen Angkuststiri Melissa RoseAmy Harley,
Angelica Guzon, Eva Long, Danielle Greenfield,
Carola Gutierrez de King, Susana Gonzales,
Caroline Grantz, Cynthia Contreras, Devon Baird,
Matthew Parro,Alice Baker
48
Special Thanks to our Funders
  • NIEHS P01 ES11269
  • NIEHS 1R01 ES015359
  • NIEHS 1R01 ES 015171
  • Environmental Protection Agency (EPA), Science to
    Achieve Results (STAR) program, R829388
  • The M.I.N.D. Institute/UC Davis Matching Funds
  • Autism Speaks
  • Cure Autism Now
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