A Biologically Based Doseresponse Model for Ethanolinduced Developmental neurotoxicity

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EVALUATION OF INTERSPECIES VARIABILITY DURING
NEOCORTICAL NEUROGENESIS USING BIOLOGICALLY BASED
COMPUTATIONAL MODELS

• J.M. Gohlke, W.C. Griffith, E.M. Faustman
• Institute for Risk Analysis and Risk
  Communication and Department of Environmental
  Health, University of Washington, Seattle,
  Washington, USA

• OBJECTIVE
• Quantitate interspecies toxicodynamic
  differences during neocortical development of the
  rat and primate brain.
• BACKGROUND
• Ethanol is a particularly harmful developmental
  neurotoxicant and is the leading known cause of
  mental retardation in the Western world (1).
• Extensive research on ethanol-induced
  developmental neurotoxicity provides a rich data
  set for application and subsequent assessment of
  our biologically based computational models for
  developmental toxicology.
• Numerous human, non-human primate and rat
  behavioral, histological, and stereological
  studies suggest the neocortex may be particularly
  sensitive to prenatal ethanol exposure.
• The present computational model is a application
  of the model developed by Leroux (1996) which
  uses a stochastic approach to describe the
  branching process of cell kinetics during
  development (Figure 1)(2).

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Figure 1. The anatomy of neocortical
neuronogenesis and how it relates to model
building. a. A mammalian nervous system at the
5 vesicle stage in lateral view showing
progenitor cells (orange)are generated in the
pseudostratefied ventricular epithelium (PVE).
During G1 newly generated cells either stay in
the proliferative population (P fraction) or
become postmitotic (Q fraction-blue cells) and
begin migration through the intermediate zone
(IZ) to the cortical plate (CP). In the mouse,
the neuronogenesis period is six days long and
traverses eleven cell cycles (CC1-CC11) whereas
in the rhesus monkey it is 60 days long
transversing at least 28 cell cycles b. Basic
model framework from Leroux (1996) which was
modified as a model for neocortical
neuronogenesis where Type X cells represent
neuronal progenitor cells in the PVE (orange
circles) and Type Y cells represent postmitotic
neurons leaving the PVE (blue circles).
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• I. KEY DIFFERENCES BETWEEN RODENT AND PRIMATE
  NEOCORTICAL NEUROGENESIS

Figure 2. Cell cycle length changes over time in
the mouse, rat and monkey. During rodent
neurogenesis the cell cycle lengthens over time,
whereas in the rhesus monkey the cell cycle
length peaks at E60 and thereafter shortens.
Data was derived from references 3-5.

• Key Points
• The length of neocortical neurogenesis is
  increased in the primate (6 days in the mosue
  compared with 60 days in the rhesus monkey).
• The cell cycle length is longer during primate
  neurogenesis (between 2 to 4 times on average).
• The time dependent change in the cell cycle is
  different in rodents and the rhesus monkey (See
  Fig. 2).
• The founder cell population is larger in the
  primate (approximately 4 times larger than the
  mouse founder cell population).

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• II. APPLICATION OF MODEL TO MOUSE, RAT AND
  PRIMATE CONTROL DATASETS

Figure 3. Comparison of mouse and rat
neocortical neuronal output predictions. This
figure shows a plot of our model predictions for
the normal mouse (?), rat (?), and rhesus monkey
(?) neuronal output (total Y cells). For
comparison we plotted stereological estimates of
total neurons in the neocortex of the adult mouse
and rat adjusted for a 35-50 reduction in
postnatal cells due to normal processes of cell
death ( ? ). The length of the vertical line
represents the variation due to differences in
the mean estimates from different stereological
studies (9-11) (12-16) and variation due to
35-50 reduction (17) of population in the cell
death period.

• Key Point
• Our model predictions closely match
  stereologically determined neuronal counts in the
  mouse, rat, and monkey.

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• APPLICATION OF RAT ETHANOL NEUROTOXICITY DATA TO
  PRIMATE MODEL
• Ethanol exposure (maternal BEC 150 mg/dl)
  during neocortical neurogenesis lengthens the
  cell cycle prematurely in the rat (4).
• The time-dependent effect of dose on the
  neocortical progenitor division rate is based on
  an in vitro study of cell cycle inhibition (18)
  and is modeled using the equation
• rate untreated baseline e
  (drpdose)
• where drp is the time-dependent dose-response
  parameter

• Key Points
• At human blood ethanol concentrations (BEC)
  that occur after 3-5 drinks (150 mg/dl), our
  model predicts a 30-35 neocortical cellular
  deficit by the end of neurogenesis in the rat
  model, which match independent stereological
  studies on ethanol-induced cellular loss (19).
• At BECs ranging from 15 to 50 mg/dl (occuring
  after .5 to 1.5 drinks) the model predicts a gain
  in neurons over normal.
• Application of rat toxicity data to the primate
  neurogenesis model indicates primates may be more
  sensitive to ethanol induced neocortical neuronal
  loss during neurogenesis at BECs above 75 mg/dl.

Figure 4. Prediced ethanol dose-response curve
for necortical cell loss in the rat and monkey
model. Rat toxicity data showing a lengthening
of the cell cycle what applied to our monkey
model. The differences in the dose response
curves highlight toxicodynamic differences across
species may cause differences in susceptibility.
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• CONCLUSIONS
• We have developed stochastic models for mouse,
  rat and primate neocortical neurogenesis allowing
  for cross species comparisons of toxicodynamic
  processes.
• We have applied rodent toxicity data to the new
  primate model to compare the neurodevelopmental
  impacts of ethanol on neocortical development
  across species.
• Our model predictions indicate dynamic
  differences in normal neocortical neurogenesis
  may enhance the suseptibility of the primate
  brain to neuron loss after exposure to ethanol
  during neocortical neurogenesis.

Acknowledgements This study was supported by the
Center for Child Environmental health Risks
research through EPA grant R826886 and NIEHS
1PO1ES09601.