Approach to Neonate and Juvenile Safety Studies
Developmental Neurotoxicity Assessment: Neonatal Programmed Cell Death
The assessment of permanent damage in neonates and juveniles is made difficult due to the normal occurrence of programmed cell death in the developing brain and the fact that the timelines for disintegration (and the corresponding windows to view these) are shortened from days to hours. Patterns of degeneration must be compared to a baseline level to determine changes in cell death activity. Architecting a study design to account for the earlier and shorter observable opportunity of cell death becomes a critical consideration.
The disruption of the chronology of programmed cell death (apoptosis) in the developing brain is an increasing issue of concern. As an example, the Disintegrative Degeneration stains have been used to show how alcohol causes extensive cell death in neonate rats (Ikonomidou et al. Science 257: 1056, 2000).
The distinct pattern of degenerated cells in the ventral border of the anterior ventral thalamus is shown below.
Adjacent sections from neonate rat brain stained with thionine and the Cupric Silver method.
Upper panels are low-power views of the left anterior thalamus in a postnatal day 3 rat. Higher-power views of the ventral-medial tip of the anterior ventral (AV) thalamus are in the lower panels. High densities of condensed (pyknotic) nuclei (dark blue dots) are visible in the thionine-stained section (lower left), while in the same locations, with the Cupric Silver degeneration stain, abundant silver-impregnated, disintegrative debris (fine black dots and linear arrays of dendrites) is conspicuous even at low magnifications.
The temporal histogram below illustrates peak times of cell death in the ventral septum of rat brain. The tabulation of all neuronal populations will identify critical periods during which brain development might be perturbed.
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