Transcript Existing Cohort - CLU-IN

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
Neurodevelopment
Robert 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” hypothesis
 1st
hit leaves brain in vulnerable state
 2nd 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
Myelin (Schwann cell)
Synapse
Axon
Dendrite
Nucleus
Cell Body
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Biological VulnerabilityNeurodevelopment
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 fire
 Neuronal/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 factors
 Signals 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 evident
Functionally, 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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110
Child with low prenatal &
High post natal exposure
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Child with high prenatal &
low post natal exposure
Child with high prenatal &
High post natal exposure
Additive Effects of sequential exposure
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Bayley Scales MDI
Effects of Sequential Toxic Metal Exposure on
Neurodevelopment
Multiplicative Effects of sequential exposure
0
6
12
18
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Age in Months
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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 mother
 2nd,

Post natal exposure biomarkers in child
1

and 2 years of age
Bayley Scales of infant development
1

3rd trimester, delivery
and 2 years of age
Either Pooled across cohorts
 Or
as a meta-regression
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Outline of Cohort Resource Utilization For this Program
Metal Mixtures in
Neurodevelopment
Project 1
Gene-Metal interactions in
Neurodevelopment
Project 2
DSA=Delayed Spatial
Alternation
Proposed Cohort
1000 Bangladesh Children (2 yr old)
BloodPb/Mn/As
umbilical cord
1 year
2 year
Bayley
6 months
12 months
18 months
24 months
DSA
12 months
Covariates Maternal IQ, gender
education, hemoglobin,
Existing Cohort
600 Tar Creek (2 yr old)
BloodPb/Mn/As
umbilical cord
1 year
2 year
Bayley
12 months
24 months
Covariates Maternal IQ, gender,
education, hemoglobin,
Existing Cohort
1000 Mexico children (2 yr old)
BloodPb/Mn/As
umbilical cord
1 year
2 year
Bayley
6 months
12 months
18 months
24 months
DSA
12 months
Covariates Maternal IQ, gender,
education, hemoglobin,
DNA- Mothers/Infants
DNA, Mother, Father, Infant
DNA, Mother, Father, Infant
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Plots of MDI scores vs Blood Lead by Quintiles of Blood Mn
Highest Quintile of Blood Mn
80
60
40
40
60
80
MDI_24/Fitted values
100
100
120
120
Lowest 4 Quintiles of Blood Mn
0
5
10
bloodpb12
MDI_24
15
Fitted v alues
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0
5
10
15
bloodpb12
MDI_24
Fitted v alues
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Current work
 Finishing
Pooling
 Meta
Year 2
vs meta-regression
data issues
Biomarkers
 All
blood
 Avoids issues that come up if using
biomarkers from different matrices
Urine
vs blood vs hair
 Different half lives
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Other complexities

Different doses in different cohorts
 Bangladesh>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 As

2
way Mn-Pb interactions already
demonstrated
30
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 requires
 Large
sample sizes
 Validation in multiple populations
 Complex analytical approaches
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