Our working hypothesis is that there is a hierarchy of effects of organophosphate embryonic organophosphate exposure but selective targets and developmental windows are responsible for adult effects. We plan to use zebrafish to screen organophosphate pesticides to examine embryonic and larval effects upon exposure and in collaboration with the Levin laboratory, to investigate and compare effects of these exposures upon learning. Our intention is to screen at least 3 additional esterase inhibitors (along with chlorpyrifos: parathion, diazinon from the superfund list, and the non-superfund list but commonly used malathion). The four specific aims are: 1) to perform dosage studies with selected transgenic lines for the first 5 days post-fertilization and to score for a)inhibition of acetylcholine esterase and b)morphological effects?preliminary behavioral differences will be noted for potential analysis of adults by E. Levin 2) to perform 5 day time courses with selected exposures and to perform microarray analyses to identify genes, clusters of genes and time course of gene expression effects 3) through analysis of expression work to a) identify potential unique genes(per chemical) that are markedly up-regulated(as candidate genes for isolating their promoters to create inhibitor-specific transgenic biosensor) and b) to identify potential genes and their time-course that are positively or negatively affected by the exposure to differentiate effects of different inhibitors and potentially identify pathways affected?this could include in situ localization of the genes affected by the exposure 4) from specific aim 3) the generation of organophosphate- specific biosensor transgenic fish based upon unique genes up-regulated by each inhibitor, evaluate transgenics with inhibitor exposures and determine whether battery of transgenic fish can be used to assay mixtures of inhibitors.
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