Morphologic and biochemical studies of a nitrobenzene-induced encephalopathy in rats

Administration of single oral doses (550 mg/kg body wt) of nitrobenzene to male F-344 rats induced petechial hemorrhages in the brain stem and cerebellum, and bilaterally symmetric degeneration (malacia) in the cerebellum and cerebellar peduncles, within 48 hours of treatment. The malacia, which was lateral and dorsal to the fourth ventricle and involved the vestibular nuclei, was attributed to edematous swelling of a membrane bounded tissue compartment. Degenerating neurons present in, and adjacent to, areas of malacia exhibited severe watery swelling of mitochondria. Myelinated axons showed moderate to severe condensation of the axoplasm and accumulation of electron-lucent fluid between the inner myelin leaflets and less frequently in the periaxonal space. Blood vessels appeared morphologically normal, while leakage of intravascularly administered horseradish peroxidase from blood vessels in the brain accompanied the hemorrhages in a small number of animals. Extravasation of this tracer did not precede the onset of hemorrhages or malacia. Autoradiographic and analytical studies demonstrated that a very small percentage (0.02%) of the administered dose reached the brain; it was present as the parent compound and accumulated in higher concentration in grey matter than white matter. There was no preferential accumulation of nitrobenzene in the areas in which lesions occurred, which may reflect a regional susceptibility to nitrobenzene or an indirect mechanism of nitrobenzene neurotoxicity.