Computational Model for Radiation Effects at Low Doses in the Developing Neocortex

W.C. Griffith; N.M. DeFrank; J.M. Gohlke; E.J. Gribble; and E.M. Faustman (Institute for Risk Analysis and Risk Communication)

Substantial evidence has demonstrated that low-dose radiation exposures during particular gestational periods can result in permanent neuronal perturbations and eventual abnormalities in behavior and mental activity. It is hypothesized that the mechanism underlying these effects includes radiation-induced cell death among neuronal precursors in the proliferative regions of the neocortex, and perturbed migration patterns of post-mitotic neurons. We developed a new computational model based on existing data sets to describe the extent and pattern of cell death in the neocortex and the altered patterns of migration. The model predicts the subsequent effects of cell death on neuron numbers at the end of neurogenesis and the improper positioning of neurons due to altered migration. Our results indicate that the induced death of a small fraction of neuronal precursors, dependent on the dose and time of exposure, leads to a significant decrease in the final neuron count. The model provides a means for comparing differences in absorbed dose, time of exposure, and duration of exposure. The model predicts about a 1% decrease of neuronal precursor cells per cGy during the most sensitive time window of neurogenesis and about a 0.5% decrease per cGy during other times of neurogenesis. Also, the model predicts that the migration of post-mitotic neuronal cells is decreased by 75% following a 25cGy exposure, leading to the improper placement of nearly four million mature neurons. This model is of utility for risk assessment as it allows for the evaluation of alterations in specific developmental dynamic processes across times and doses. It also emphasizes the importance of evaluating the long-term potential for radiation effects at low doses. This research was supported by the Center for Child Health Risk Research (R826886-01-0 and P01 ES09601) and the Low Dose program of the Department of Energy (DE-FG02-03ER63674). Low dose Neuro development

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