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Transcript of 1 Welcome to the CLU-IN Internet Seminar Early-life Exposures - Long-term Health Consequences:...
1
Welcome to the CLU-IN Internet Seminar
Early-life Exposures - Long-term Health Consequences: Session 2, Metals and Metal Mixtures
Sponsored by: NIEHS Superfund Research Program Delivered: March 28, 2012, 1:00 PM - 3:00 PM, EDT (17:00-19:00
GMT)
Instructors:Robert Wright, Associate Professor of Pediatrics & Environmental Health, Director, Superfund
Research Program, Harvard Medical School and School of Public Health ([email protected])
Rebecca Fry, Assistant Professor, Environmental Sciences & Engineering, University of North Carolina Gillings School of Global Public Health ([email protected])
Moderator:Bill Hagel, U.S. EPA, Region 3 ([email protected]) Visit the Clean Up Information Network online at www.cluin.org
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Chemical Mixtures and NeurodevelopmentRobert O. Wright MD MPH
Director, Harvard SRP
Associate Professor of Pediatrics
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Why should we study Mixtures?
Real life exposure scenario Most Superfund sites are mixtures
Can guide which chemicals to assess
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Why should we study Mixtures?
Mixed Exposures can be thought of as an extension of the “2-hit” hypothesis1st hit leaves brain in vulnerable state2nd hit needed to produce toxicity
Fits with developmental theories of plasticity
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Mixtures may be most relevant to the general population High vs low doses of chemicals Mixtures may be irrelevant at “high” doses
If blood lead is >100 ug/dL, can a low dose of Mn make any difference?
If blood Pb is 10 ug/dL perhaps a second hit by Mn then becomes relevant
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Chemical Mixtures and Brain Development Metals
Pb, Mn, As, Hg, methyl Hg, Organic chemicals
PCBs, DDT, Solvents
Pesticides Organophosphates, Carbamates, pyrethroids
Drugs of abuse GHB, cocaine, benzodiazepine, ketamine
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Neurodevelopment-Review
How do chemicals produce neurotoxicity in the developing brain?High dose
Neurodegeneration, damage, cell death
Low dose May be no signs of damage Interferes with network formation
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Developmental Neurotoxicology
Vulnerable periods Childhood
Neurodevelopment Elderly
Neurodegeneration
Critical Developmental Windows Developmental life stages at which processes
occur (i.e. gene expression) which may not occur at other life stages.
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Neuronal Cells
Axon
Myelin (Schwann cell)
Synapse
Dendrite
Cell Body
Nucleus
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Biological Vulnerability-Neurodevelopment Construction of the central nervous system
(CNS) begins in utero, Continues throughout childhood and
involves the production of 100 billion nerve cells and 1 trillion glial cells.
Cell migrate, differentiate, and form synapses
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Synapses Transmit signals between neurons
Environmental stimuli will cause neurons to fireNeuronal/synaptic firing is a signaling process to
mold the synaptic architecture of the brain
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How does the Brain Build this Network? Some of it is stochastic
Synapses are made by the billions, and in some respects randomly, between neurons.
We make a net gain in synapses from fetal life till about age 2 years
Then the number of synapses in our brain starts to decrease
Why?
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Synaptic Network
Environmental Stimuli cause nerves to fire: When they fire, neurotransmitters are
released into synaptic junctions This releases growth factorsSignals that this is an important neuronal
connection (i.e. it gets used)
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Synaptic Pruning Environmental stimuli mold the CNS.
Synapses that produce function are repeatedly fired and kept
Synapses that are dormant are deleted In other words there is a “natural selection”
process Functional synapses release growth factors Nonfunctional synapses do not release the growth
factors
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Hebb Synapses
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Weisel and Hubel
Newborn kittens Patch one eye for one month Retinal development (specifically the development of
neuronal connections) in the patched eye would not occur.
Patch Adult cat eye for one month Compare neuronal networks between patched and
unpatched eye No difference than comparing unpatched cats
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Implication
Natural Selection is not just a process by which genetic variants are selected.
Neuronal Cells and synaptic networks may also undergo a process of natural selection
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So how do Chemicals affect Development? Lead as a “paradigm” toxicant At “low” doses (blood lead around 5-10 ug/dL)
Lead will interact with Protein Kinase C Stimulate neurotransmitter release Neurons fire in the absence of an appropriate environmental
stimuli Lead mimics calcium
Calcium is critical to nerve signal transmission Calcium enters neurons during depolarization Lead blocks calcium channels
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Lead and the Brain
Net effect Lead stimulates nerves to fire in a more stochastic
fashion Lead also inhibits neurotransmission (both
appropriate neurotransmission and inappropriate neurotransmission)
Makes it hard to think/concentrate Changes the underlying synaptic architecture, making it
less efficient
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Childhood Lead Poisoning
Lead exposure introduces noise to the process of synaptic pruning
Which synapses are chosen for survival and which regress becomes more random
Net effect if prolonged- is that the underlying neuronal networks are less efficient.
Structurally no damage is evidentFunctionally, deficits are measurable.
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Plasticity
The brain’s capacity to diminish the effects of toxic insults through structural/functional changes This occurs through the same processes as synaptic
selection In other words plasticity allows for new connections to
be made which improve function following an insult
Maladaptive vs adaptive plasticity
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Additive Effects of sequential exposure
Multiplicative Effects of sequential exposure
Child with low prenatal &High post natal exposure
Child with high prenatal &low post natal exposure
Child with high prenatal &High post natal exposure
Bay
ley
Sca
les
MD
I
0 6 12 18 24
Age in Months
90
1
00
110
Effects of Sequential Toxic Metal Exposure on Neurodevelopment
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Harvard SRP Project 1: Epidemiology of Developmental Windows, Metal Mixtures and Neurodevelopment
Uses existing infrastructure/data in 2 ongoing cohorts of neurodevelopment and metals Mexico City, Tar Creek Measure As, Mn, Pb
Use existing infrastructure on a 3rd cohort designed to assess reproductive health study in Bangladesh on Arsenic Add follow-up and neurodevelopment measures
Add Pb and Manganese measure
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Design
Prenatal exposure biomarkers in mother2nd, 3rd trimester, delivery
Post natal exposure biomarkers in child1 and 2 years of age
Bayley Scales of infant development1 and 2 years of age
Either Pooled across cohortsOr as a meta-regression
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Outline of Cohort Resource Utilization For this Program
Proposed Cohort 1000 Bangladesh Children (2 yr old)Blood Pb/Mn/As
umbilical cord1 year2 year
Bayley 6 months12 months18 months24 months
DSA 12 monthsCovariates Maternal IQ, gender education, hemoglobin,
DNA, Mother, Father, Infant
Existing Cohort1000 Mexico children (2 yr old)Blood Pb/Mn/As
umbilical cord1 year2 year
Bayley 6 months12 months18 months24 months
DSA 12 monthsCovariates Maternal IQ, gender, education, hemoglobin,
DNA, Mother, Father, Infant
Existing Cohort600 Tar Creek (2 yr old)Blood Pb/Mn/As
umbilical cord1 year2 year
Bayley 12 months24 months
Covariates Maternal IQ, gender, education, hemoglobin,
DNA- Mothers/Infants
Metal Mixtures in NeurodevelopmentProject 1
Gene-Metal interactions in NeurodevelopmentProject 2
DSA=Delayed SpatialAlternation
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40
60
80
10
01
20
MD
I_2
4/F
itte
d v
alu
es
0 5 10 15bloodpb12
MDI_24 Fitted values
40
60
80
10
01
20
MD
I_2
4/F
itte
d v
alu
es
0 5 10 15 20bloodpb12
MDI_24 Fitted values
Lowest 4 Quintiles of Blood Mn Highest Quintile of Blood Mn
Plots of MDI scores vs Blood Lead by Quintiles of Blood Mn
40
60
80
10
01
20
MD
I_2
4/F
itte
d v
alu
es
0 5 10 15bloodpb12
MDI_24 Fitted values
40
60
80
10
01
20
MD
I_2
4/F
itte
d v
alu
es
0 5 10 15 20bloodpb12
MDI_24 Fitted values
Lowest 4 Quintiles of Blood Mn Highest Quintile of Blood Mn
Plots of MDI scores vs Blood Lead by Quintiles of Blood Mn
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Current workFinishing Year 2
Pooling vs meta-regressionMeta data issues
BiomarkersAll bloodAvoids issues that come up if using biomarkers
from different matricesUrine vs blood vs hair
Different half lives
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Other complexities
Different doses in different cohortsBangladesh>Mexico>Tar Creek
Which developmental windows are important for mixtures?Repeated measures of exposure at different life
stages Interactions may occur across time
Prenatal may modify 1 year blood Metal
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Summary
Low level chemical exposures may be more relevant in children
Low level chemical mixed exposures may also be more relevant in children
Our program is designed to test 2 and 3 way interactions among Pb, Mn and As2 way Mn-Pb interactions already demonstrated
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Summary
Chemical mixtures reflect real life While complex, understanding the
variance in dose response curves requires understanding mixed exposures
Ignoring mixed exposures will lead to biased effect estimates
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Summary
Like understanding G X E interactions mixtures research requiresLarge sample sizesValidation in multiple populationsComplex analytical approaches
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