Superfund Research Program
Cholinesterase Inhibition as a Target of Pesticide Residues and the Effect of Cholinergic Intervention on Gene Expression
Project Leader: Palmer W. Taylor
Grant Number: P42ES010337
Funding Period: 2000-2010
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Final Progress Reports
Year: 2009 2004
The most important and novel development in Project VII is the creation of a knock out mouse in which expression of acetylcholinesterase in the central nervous system is normal, but levels are virtually non-detectable in skeletal muscle. This was accomplished by finding an upstream intron (Intron 1) in the gene through cell culture experiments that controls expression during muscle differentiation in cell culture. These mice are of interest not only from the viewpoint of comparative phenotype with the total knockout, but also in assessing the influence of organophosphate pesticide toxicity in the central and peripheral nervous sytems. Dr. Palmer’s research team now has knock out animals for all of the alternative exon permutations as well as the aforementioned one, along with their biochemically characterized phenotypes. Physiologic phenotyping is underway as is assessing sensitivity to organophosphate insecticides.
Other studies examining organophosphate toxicity and disposition in mice with constitutively activated carboxyl esterase and P450 from Ron Evans unit complement the phenotyping of the knock-out in terms of sensitivity to malathion and malaoxon. Studies involving the development of fluorescent tags for examining acetylcholinesterase structure by fluorescence and decay of fluorescence anisotropy continue to yield interesting structural data as well as a possible practical outcome for remote sensing of organophosphate insecticide exposure. The sensing studies are complemented by mass spectrometry detection and high sensitivity monitoring of the organophosphate insecticides in situ.