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-induced delayed neurotoxicity (OPIDN). Animals received either three subcutaneous injections of TPP (1184 mg/kg body wt each dose) administered at 3-day intervals or a single subcutaneous injection of DFP (4 mg/kg body wt). TPP-induced clinical signs were initially observed 2 to 18 days after the last injection and included ataxia, flaccid paresis, stereotyped alternating side-to-side movements, and circling behavior. Axonal and terminal degeneration were present in the cerebellum, vestibular nuclear complex, cochlear nuclei, and superior and inferior colliculi. The subthalamic nucleus, substantia nigra, septal region, hypothalamus, thalamus, hippocampus, and cerebral cortex also contained degenerating axons and terminals. Degeneration was particularly evident in the sensorimotor cerebral cortex, mediodorsal, ventromedial, and medial geniculate thalamic nuclei and in the magnocellular preoptic and medial mammillary nuclei of the hypothalamus. Very light degeneration was present in the gracile fasciculus and nucleus. In contrast, rats injected with DFP showed moderate degeneration in the gracile fasciculus and nucleus but did not display degeneration in any other brain region. Injections of DFP did not produce delayed onset clinical signs. The results indicate that in the rat, different central nervous system cell groups are affected by these two organophosphorus compounds and that TPP affects nuclei and tracts at all levels of the neuraxis, including those associated with higher-order processing and cognitive functions. In addition, the distinct degeneration patterns produced by these two compounds support the view that TPP-induced neurotoxicity should not be considered as a type of OPIDN, but rather as a separate category of organophosphorus-induced neurotoxicity.