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Drug and Chemical Exposures in Animal Models Related to ASD Theodore Slotkin, Ph.D. Department of Pharmacology & Cancer Biology Integrated Toxicology & Environmental Health Program Duke University Support: NIH ES10356. Main Points.

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slide1

Drug and Chemical Exposures in Animal Models Related to ASD

Theodore Slotkin, Ph.D.

Department of Pharmacology & Cancer Biology

Integrated Toxicology & Environmental Health Program

Duke University

Support: NIH ES10356

slide2

Main Points

  • Why an increase in neurodevelopmental disorders including ASD?
  • Why do neuroactive agents produce permanent alterations with developmental exposures?
  • Why is there a critical period for these effects?
  • Why do apparently unrelated agents produce similar outcomes?
  • Example from environmental chemicals: organophosphate pesticides
  • Example from prenatal drug exposure: terbutaline
slide3

Developmental Neurotoxicity from Environmental Chemical Exposures

  • 5000 new chemicals/year
  • EPA estimate: 25% neurotoxic
  • 67% of High Production Chemicals Not Tested for Neurotoxicity
  • High vulnerability of the developing brain
  • Increases in ADHD, learning/cognitive problems?
    • 17% of US schoolchildren suffer from neurobehavioral disabilities
    • Annual cost: $80-170 billion
    • 250% increase in ADHD diagnosis between 1990-1998
    • 190% increase in children in special ed for learning disabilities between 1977-1994
    • Increase in autistic spectrum disorders from 4/10,000 (1980s) to 30-60 (1990s)
developmental neurotoxicants the silent pandemic
Developmental Neurotoxicants - The “Silent Pandemic”

LDDI Initiative, 2007

Grandjean & Landrigan, Lancet 2006

slide5

Why Neuroactive Agents Disrupt Brain Development —

Neurotransmitter Signals Control Cell Fate

Nerve

Terminal

Signaling

Cascades

Nucleus

Receptors

Gene Transcription

Replicate Differentiate Grow Die Learn

The same neurotransmitter may be used for multiple decisions

why there is a critical period
Why there is a Critical Period

Input After Critical Period

Input During Critical Period

Change in Cell Differentiation

Short-Term Response Elicited

Permanent Change in the Response to Stimulation

Short-Term, Reversible, Compensatory Adjustments

slide7
Apparently Unrelated Agents Can Produce Similar Outcomes —[maybe we shouldn’t focus on common mechanisms?]

Correct Connection

Damage or Loss of Input

Damage or Loss of Target

Miswired Connection

Mismatched Phenotypes

Corollary - exposure to multiple agents can produce additive or synergistic effects - worsened outcome

organophosphate pesticides chlorpyrifos
Organophosphate Pesticides — Chlorpyrifos
  • Widely used - ubiquitous exposure
    • - OPs = 50% of all insecticide use
  • Not an endocrine disruptor
  • Replaced organochlorines
  • Superfund Site Disposal Problem
  • OPs: nerve gases in warfare/terrorism
  • Developmental neurotoxicity unrelated to mechanisms in adults
  • Effects are subtle but widespread
  • Originally modeled in animals, neurodevelopmental deficits now confirmed in children (inner-city, agricultural populations)
  • Developmental exposure increases autism risk
chlorpyrifos multiple mechanisms disrupt neurodevelopment
Chlorpyrifos - Multiple Mechanisms Disrupt Neurodevelopment

Direct Actions on Cholinergic Receptors

Interaction with

Signaling Intermediates

Signaling

Cascades

Nerve

Terminal

Nucleus

Transcription Factor Expression, Function

Receptors

Gene Transcription

AChE Inhibition:

CPF Oxon

Replicate Differentiate Grow Die Learn

Critical period in rats: late gestation to early neonatal stage

[equivalent - 2nd trimester in human fetus]

chlorpyrifos impact on serotonin systems miswiring
Chlorpyrifos - Impact on Serotonin Systems = Miswiring

Male Female

Enhanced neuronal

impulse activity (serotonin turnover)

Increases in serotonin receptors and transporter

BUT….

impaired serotonergic function
…Impaired Serotonergic Function

aka: increased risk-taking, impulsive behavior

slide12
Chlorpyrifos - Miswiring of Acetylcholine Systems -Serotonin Replaces Acetylcholine for Hippocampal Circuits and Behaviors
slide13

Terbutaline Use in Preterm Labor

  • Stimulates BARs to inhibit uterine contraction
  • Crosses the placenta to stimulate fetal BARs
  • Effective for 48 hr max - NOT for maintenance use
  • Animal studies from our lab, 1980s-1990s
    • altered neural cell differentiation
    • receptor and signaling shifts
    • permanent changes in responsiveness
  • Hadders-Algra 1986 - impaired school performance
  • Pitzer 2001 - psychiatric, learning disorders
slide14

Cerebellum

Thinning of cerebellar lobules

Thinning of hippocampal CA3

Reactive gliosis

Somatosensory cortex - loss of pyramidal cells

Critical Period Newborn Rat - PN2-5 =

human 2nd trimester

Control

Terbutaline - 44% decrease in Purkinje cells

slide15

Neuroinflammation in cerebral cortex and cerebellum - microglial activation

  • Morphological changes almost identical to those in postmortem autism samples
  • Critical period PN2-5
  • Hyperreactive to novelty, aversive stimuli, sensory input

Decompensation of CVS responses similar to those in autism

(compare to Ming 2005)

slide16

Continuous terbutaline exposure for 2 weeks: RR=2.0

  • Male twins with no other affected siblings: RR=4.4

Further increase: BAR polymorphisms (16G, 27E) that prevent desensitization and therefore would enhance terbutaline effects

terbutaline impact on serotonin systems miswiring chlorpyrifos
Terbutaline - Impact on Serotonin Systems = Miswiring ≈ Chlorpyrifos

Increases in serotonin receptors and transporter

Enhanced neuronal

impulse activity (serotonin turnover)

terbutaline followed by chlorpyrifos
Terbutaline Followed by Chlorpyrifos

Enhanced Effect on Serotonin Turnover

slide19

CONCLUSIONS

  • Developmental neurotoxicants likely to play an important role in the increased incidence of childhood behavioral disorders including ASD
  • Disparate mechanisms and effects converge on common final pathways
    • different agents may produce similar outcomes
    • different agents may produce additive/synergistic outcomes
  • Lasting effects only when exposure occurs in critical periods
  • Specific examples with relevance to ASD:
    • organophosphate pesticides (ubiquitous exposure)
    • terbutaline (use in preterm labor ≈10% US pregnancies)

Neurodevelopmental disorders - CAUSES, not a single ‘cause’

Origins of autism and ASD may not be so distinct from other neurodevelopmental disorders