Concurrent Session III

1
Concurrent Session III

• Fish
• Moderator Robert Tanguay
• Rapporteur Stephanie Padilla

2

• High-Throughput Assessment of Small Molecule
  Bioactivity in the Zebrafish
• Randall T. Peterson
• Zebrafish as Model for ECOTOX Testing-
• How Can It Be Applied to DNT?
• Uwe Strähle
• 3. Discussion

3
Advantages of Using Zebrafish for Testing

• Zebrafish are a well-developed embryological
  system.
• Small transparent embryos
• Development outside of mother
• Transgenics and mutants available

4
Zebrafish bradycardia is a predictor of human QT
prolongation (Randall Peterson)
22/23 QT prolonging drugs cause bradycardia in
zebrafish
David Milan, Travis Peterson
5
Specific toxicogenomic profiles at 5 days
post-fertilisation
Specific toxicogenomic profiles at 5 days
post-fertilisation
Acrylamide
Valproic acid
PCB
4-chloraniline
As2O3
PbCl2
Me-mercury
CdCl2
tBHQ
DDT
TCDD
BDE47
(Uwe Strähle)
6
Summaries from Both Presentations

• Zebrafish enable facile screening of tens of
  thousands of small molecules.
• Morphological and physiological effects can be
  identified.
• Effects in zebrafish correlate well with known
  effects in humans, including drug-drug
  interactions.

• Zebrafish enable facile screening of tens of
  thousands of small molecules.
• Morphological and physiological effects can be
  identified.
• Effects in zebrafish correlate well with known
  effects in humans, including drug-drug
  interactions.

• Toxins induce specific patterns of gene
  expression.
• Changes in gene expression can be detected at
  low toxin concentration.
• Gene responses are similar to those seen in
  mammals

• Toxins induce specific patterns of gene
  expression.
• Changes in gene expression can be detected at
  low toxin concentration.
• Gene responses are similar to those seen in
  mammals

7
Strategy for integrating fish models into
developmental neurotoxicity testing

• ?What are potential advantages of using fish
  models relative to mammalian test systems?
  Discussed already Molecular tools can be easier
  to use in zebrafish than in mammals. Can assess
  the same embryo throughout development.
• ?What are the potential advantages of using fish
  models systems relative to in vitro models?
  Integrated nervous system, behavioral assessment,
  transgenics and mutants available.
• ?Are the fish models adaptable to high-throughput
  screening? To non-invasive imaging techniques?
  To integration of omics? Yes, and specific
  examples were given in the presentations. Still
  working out aspects of endpoint assessment of
  the fish using high-throughput techniques.
• ?How can these fish models be used to refine,
  reduce and replace the use of animals in toxicity
  testing? Lots of discussion. General agreement
  that fish models can definitely be used to
  explore mechanisms of developmental neurotoxicity.

8
How predictive are fish models of human
developmental neurotoxicity?

• ?Which endpoints of interest in human
  neurodevelopment or human developmental
  neurotoxicity are conserved in fish model
  systems? Generally, almost all Behaviors,
  Endpoints, and cellular targets.
• ?What are the caveats or limitations of using
  fish models? Are there endpoints of interest in
  human developmental neurotoxicity that cannot be
  assessed in fish models? See belowwe worried a
  bit about pharmacokinetic differences.
• ?Are interspecies toxicokinetic differences a
  significant issue? Maybe. Data presented by
  Randall Peterson on pharmaceuticals lessened the
  concern of the group.