Triphenyl Phosphite and Diisopropylphosphorofluoridate Produce Separate and Distinct Axonal Degeneration Patterns in the Central Nervous System of the Rat

This study compared the neurotoxic effects of triphenyl phosphite(TPP) in the rat with those seen after exposure to diisopropylphosphorofluoridate(DFP), a compound known to produce organophosphorus-induceddelayed neurotoxicity (OPIDN). Animals received either threesubcutaneous injections of TPP (1184 mg/kg body wt each dose)administered at 3-day intervals or a single subcutaneous injectionof DFP (4 mg/kg body wt). TPP-induced clinical signs were initiallyobserved 2 to 18 days after the last injection and includedataxia, flaccid paresis, stereotyped alternating side-to-sidemovements, and circling behavior. Axonal and terminal degenerationwere present in the cerebellum, vestibular nuclear complex,cochlear nuclei, and superior and inferior colliculi. The subthalamicnucleus, substantia nigra, septal region, hypothalamus, thalamus,hippocampus, and cerebral cortex also contained degeneratingaxons and terminals. Degeneration was particularly evident inthe sensorimotor cerebral cortex, mediodorsal, ventromedial,and medial geniculate thalamic nuclei and in the magnocellularpreoptic and medial mammillary nuclei of the hypothalamus. Verylight degeneration was present in the gracile fasciculus andnucleus. In contrast, rats injected with DFP showed moderatedegeneration in the gracile fasciculus and nucleus but did notdisplay degeneration in any other brain region. Injections ofDFP did not produce delayed onset clinical signs. The resultsindicate that in the rat, different central nervous system cellgroups are affected by these two organophosphorus compoundsand that TPP affects nuclei and tracts at all levels of theneuraxis, including those associated with higher-order processingand cognitive functions. In addition, the distinct degenerationpatterns produced by these two compounds support the view thatTPP-induced neurotoxicity should not be considered as a typeof OPIDN, but rather as a separate category of organophosphorus-inducedneurotoxicity.