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EXTRAPOLATION FROM IN VITRO MECHANISMS TO IN VIVO EFFECTS FOR DEVELOPMENTAL NEUROTOXICOLOGY.
Citation:
Barone, S, L. D. White, W R. Mundy, AND D. K. Parran. EXTRAPOLATION FROM IN VITRO MECHANISMS TO IN VIVO EFFECTS FOR DEVELOPMENTAL NEUROTOXICOLOGY. Presented at 18th Neurotoxicology Conference, Colorado Springs, CO, 9/23-26/2000.
Description:
Processes that are critical to development of the nervous system can be altered by both genetic and epigenetic factors. Developmental exposure to neurotoxicants can alter these processes and lead to perturbation of normal neural development. As numerous processes occur in tandem depending upon the region of the nervous system being examined, chemical exposure rarely affects only one process or mechanism. Thus, discrimination of the critical processes(s) and mechanism(s) that may be affected by developmental exposure to xenobiotics can be difficult to discern in vivo. In vitro model systems can be useful in defining dose response relationships and relative potency on specific processes and selected mechanisms. In order to evaluate the predictive validity of these in vitro systems, we have used a known developmental neurotoxicant, methyl mercury, to examine the dose- response relationship for indices of differentiation, apoptosis, and cytotoxicity. Examination of the EC50 dose-response profiles for these effects in a rat pheochromocytoma (PC12) cell line suggest that neurotrophic factor-induced differentiation is the process most sensitive to methyl mercury toxicity. Examination of the neonatal rat brain following developmental exposure to methyl mercury also demonstrates that neurotrophic factor receptor expression is altered in dose-related fashion. This alteration in neurotrophic factor receptor expression and subsequent neurotrophic factor signaling precedes altered regional differentiation of the brain. Subsequent work will focus on characterization of the steps that are the most critical in this neurotrophic factor-induced signaling pathway in vitro and whether exposure to other chemicals may affect these same pathways and processes. (This abstract does not reflect USEPA policy).