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NEW METHODS TO SCREEN FOR DEVELOPMENTAL NEUROTOXICITY.
Citation:
MUNDY, W. R., J. COWDEN, K. M. CROFTON, S. J. PADILLA, AND T. J. SHAFER. NEW METHODS TO SCREEN FOR DEVELOPMENTAL NEUROTOXICITY. Presented at DNT TestSmart, Reston, VA, March 13 - 15, 2006.
Description:
The development of alternative methods for toxicity testing is driven by the need for scientifically valid data (i.e. predictive of a toxic effect) that can be obtained in a rapid and cost-efficient manner. These predictions will enable decisions to be made as to whether further testing is required. Our strategy for developing new methods for assessing developmental neurotoxicity is based on the fundamental principle that expression of toxicity is the result of chemical effects on molecular and cellular events that are highly conserved across biological systems. Normal brain development involves the coordinated expression of specific events including proliferation, differentiation, migration, neurite growth, synaptogenesis, myelination, and apoptosis. We will examine the effects of known developmental neurotoxicants on these cellular processes in two model systems: in vitro neural cell cultures and the developing nervous system of the Medaka fish. In vitro systems provide a model in which chemical effects on cellular events can be examined using techniques that are amenable to high-throughput analysis. A variety of neural cell cultures (cell lines, primary cultures, human neural progenitor cells) will be compared for their ability to model developmental processes. Chemical effects on these processes will be assessed using High Content Analysis with the Cellomics ArrayScan V. Medaka provide a model which allows for assessment of chemical effects on the intact developing nervous system. They are small, easy and inexpensive to maintain, and have transparent embryos that allow visual access to the developing nervous system in vivo using non-invasive techniques. Chemical effects on the fish will be assessed at three levels: (1) LD50 determination (2) teratogenic potential (e.g., kinked tail, edema, changes in heart rate, changes in gestation length) and (3) neurotoxic potential (e.g., assessment of cell proliferation, apoptosis, synaptogenesis in the Medaka nervous system). Specificity for effects on development in both models will be determined in part by comparing dose-response curves for effects on developmental endpoints with effects on overt toxicity. The ultimate goal is to provide an in vitro screening battery and Medaka embryo assay that can be used as first tier test for ranking the potential of chemicals to produce developmental neurotoxicity. This work was reviewed by the U.S. EPA and approved for publication but does not necessarily reflect Agency policy.