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IACC July 16 , 2010
Update: Center for Children’s Environmental Health and Disease Prevention
UNIVERSITY OF CALIFORNIA, DAVIS
UC Davis M.I.N.D. Institute
Isaac N. Pessah, Ph.D.
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UC Davis Center for Children’s Environmental Healthand Disease Prevention
Isaac N. Pessah, Ph.D. - Director
Irva Hertz-Picciotto, Ph.D. - Associate Director
Funded by NIEHS P01ES011269 & EPA R833292/R829388
UC Davis M.I.N.D. Institute
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Established in 2001Competitive NIH/EPA Peer review
Competitive renewal granted 2006
IACC July 16 , 2010
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Goal:
To advance scientific knowledge in the field of Autism
IACC July 16 , 2010
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evaluate environmental factors contributing to
autism risk
evaluate gene x environment factors contributing to
autism susceptibility
identify xenobiotic mechanisms of developmental neurotoxicity relevant to ASD
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Integrated multidisciplinary approach
- Epidemiology
(Project 1/COTC: CHARGE, CHARGE-BACK, MARBLES)
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Clinical and cellular immunology
(Project 2: autoanitbodies, cytokines, PBDEs)
Cellular & mechanism mouse models
(Project 3: autoanitbodies, mercury, PCBs, PBDEs
Analytical chemistry
(Core 3: Mercury, PBDEs, pesticides, oxylipids, vitamin D)
Molecular genomics
(Core 4: transcription arrays, CNV, epigenetics)
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Statistics Core
Administrative Core
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EXTRAPOLATION OF EXPOSURE RISK
RISKASSESSMENT(susceptible groups)
( 10 )
IN VITRO(molecules)
IN VIVO(animal models)
EPIDEMIOLOGY(human populations)
High throughputscreening
Identify associationsChemical exposures
vs.
Health Outcome
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UC DAVIS Center for Children’s Environmental Health and Disease Prevention
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Mechanism of thimerosal immunotoxicity
Project 3; Core 4
Uncoupling of ATP-Mediated Ca2+ Signaling and Dysregulated IL-6 Secretion in Dendritic Cells by Nanomolar Thimerosal
Samuel Goth, Ruth Chu, Jeffery Gregg, Gennady Cherednichenko, Isaac N. Pessah
Environmental Health Perspectives 114(7), 1083-91 (2006)
Oxygen tension regulates the in vitro maturation of GM-CSF expanded murine bone marrow dendritic cells by modulating class II MHC expression
Samuel Goth, Ruth Chu, Isaac N. Pessah
Journal of Immunological Methods 308, 179-191 (2006)
Project 3
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Mercury and autism susceptibility
Project 3; Cores 1,3
Low-Level Neonatal Thimerosal Exposure: Further Evaluation of Altered Neurotoxic Potential in SJL Mice
Robert F. Berman, Isaac N. Pessah, Peter R. Mouton, Deepak Mav, Jean Harry
Toxicological Sciences 101(2), 294-309 (2008)
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Mercury and autism susceptibility
Projects 1,3; Cores 1,2,3
Environmental Health Perspectives 118(1), 161-166 (2010)Blood Mercury Concentrations in CHARGE Study Children with and without AutismIrva Hertz-Picciotto, Peter G. Green, Lora Delwiche, Robin Hansen, Cheryl Walker, Isaac N. Pessah
Projects 1,2,3; Cores 1,2,3,4
Correlations of Gene Expression and Mercury Levels in Blood of Boys with Autism Compared to Typically Developing ControlsBoryana Stamova, Peter G Green, Yingfang Tian, IrvaHertz-Picciotto, Isaac N Pessah, Robin Hansen, XiaoweiYang, Jennifer Teng, Jeffrey P Gregg, Paul Ashwood, Judy Van de Water, Frank R Sharp
Neurotoxicology Research in press (2010)
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Immunological Factors and Autism Risk
Projects 1,2,3; Cores 1,2,4
Altered gene expression and function of peripheralBlood natural killer cells in children with autismAmanda Enstrome, Lisa Lit, Charity Onore, Jeff Gregg, Robin Hansen, Isaac Pessah, Irva Hertz-Picciotto, Judy Van de Water, Frank Sharp, Paul Ashwood
Brain, Behavior, and Immunity 23(1):124-33 (2009)
Projects 1,2,3; Cores 1,2Autism: Maternally derived antibodies specific for fetal brain proteinsDaniel Braunschweig, Paul Ashwood, Paula Krakowiak, IrvaHertz-Picciotto, Hansen, Lisa Croen, Isaac Pessah, Judy Van Judy Van de Water
NeuroToxicology 118(1), 161-166 (2010)
Autism: Maternal IgG from mothers at risk can affect brain development and produce behavioral syndrome in a mouse model (Projects 2,3; Cores 1,2,5)
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Non-dioxin-Like Compounds Under the regulatory radar screen?
Dioxin-like
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Non-dioxin-Like Compounds
Under the radar screen?
Project 3; Core 3
Toxicology and Applied Pharmacology 237(2):168-77 (2009).
Project 3 and new investigator (Lein)Environmental Health Perspectives 117(3):426-35 (2009)
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Common pesticide exposures could further influence already abnormal ratios of excitatory/inhibitory neurons and impact the networks they form
From Belmonte and Bourgeron (2006) Nature Neuroscience 9(10):1221- 1225
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Ca2+: A Common Currency of Cell SignalingAll cells utilize spatially and temporally discrete changes
in [Ca2+]i to regulate ongoing functions
signal transduction
metabolism
gene transcription
growth
migration
apoptosis
Pessah Lab, UnpublishedAlexa 488-phalloidin Alexa 568-shank
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Control (DMSO; 48 hr)
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PCB 95 (1000 nM; 48 hr)
Time, seconds Time, seconds
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Nanomolar non-coplanar PCB 95 enhances hippocampal excitability in vitro
Kim et al Tox Appl Pharm 237:168 (2009)
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PCBs alters activity dependent dendritic growthIn vivo
Yang, et al Env Health Persect. 117: 426-435 (2009)
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• Do PCB-like effects extend to other nondioxin-like
compounds of concern to human health?
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PCB 95
Living in a Non-Coplanar World
Bisphenol-A Triclosan BDE-47
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PBDEs and Autism susceptibility?
IACC July 16 , 2010
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PCBs, PBDEs and non-dioxin-like environmental contaminants
Role in autism risk?
Projects 2,3
IACC July 16 , 2010
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Impairments of mitochondrial bioenergetics in autism?
Scheme of the mitochondrial electron transport chain and its complexes