| Potentiation of OPIDN is an important mechanistic problem in neurotoxicology that has significant implications in the risk assessment of pesticides that may be encountered as mixtures. This thesis characterizes the pathology of PMSF-potentiated OPIDN in chickens and tests the hypothesis that potentiation involves the inhibition of a secondary target esterase/protease other than the putative OPIDN initiation target, NTE.; This thesis presents the first histopathology report of OPIDN potentiation in adult chickens. Chickens with severe DFP-induced and PMSF-potentiated OPIDN had axonal lesions of the same type, severity and localization. This similar histopathology supports the conclusion that PMSF potentiates DFP-induced OPIDN, extending the clinical reports of potentiation. The other major histopathological finding was that DFP-induced OPIDN in chickens is mainly a sensory axonopathy, producing lesions in the fasciculus gracilis, spinocerebellar tracts, and inferior cerebellar peduncles. Priming doses of DFP alone that produced no clinical ataxia caused substantial lesions in these same sensory tracts, indicating an important subclinical effect of OPIDN.; Dose-response studies of PMSF failed to separate potentiation from NTE inhibition. Likewise, Di-n-butyl dichlorovinylphosphinate potentiated OPIDN at doses that inhibited NTE in vivo. However, two serine protease inhibitors, AEBSF and TPCK, selectively potentiated perching deficits of DFP-initiated OPIDN. Neither of these compounds inhibited sciatic nerve or brain NTE in vivo, indicating that this partial potentiation effect was independent of NTE inhibition. This is the first report of OPIDN potentiation by non-NTE inhibitors, and supports the hypothesis that there is a potentiation target separate from NTE.; Finally, a new class of carbamates were characterized extensively in vitro with respect to inhibition of NTE, BuChE and AChE. Structure-activity relationships were developed for NTE inhibition and candidate compounds identified for future studies of OPIDN potentiation. The role of carbamates in potentiation is especially important in view of the joint use of carbamate and OP insecticides. Moreover, because the particular carbamates studied have structural features that may enable them to initiate OPIDN, these compounds hold considerable promise as novel probes in mechanistic studies of the role of NTE in OPIDN. |
