Subchronic dermal application of N,N-diethyl m-toluamide (DEET) and permethrin to adult rats, alone or in combination, causes diffuse neuronal cell death and cytoskeletal abnormalities in the cerebral cortex and the hippocampus, and purkinje neuron loss in the cerebellum

N,N-Diethyl m-toluamide (DEET) and permethrin have been implicated as poten tial neurotoxic agents that may have played an important role in the develo pment of illnesses in some veterans of the Persian Gulf War. To determine t he effect of subchronic dermal application of these chemicals on the adult brain, we evaluated histopathological alterations in the brain of adult mal e rats following a daily dermal dose of DEET (40 mg/kg in 70% ethanol) or p ermethrin (0.13 mg/kg in 70% ethanol) or a combination of the two for 60 da ys. Control rats received a daily dermal dose of 70% ethanol for 60 days. A nimals were perfused and brains were processed for morphological and histop athological analyses following the above regimen. Quantification of the den sity of healthy (or surviving) neurons in the motor cerebral cortex, the de ntate gyrus, the CA1 and CA3 subfields of the hippocampus, and the cerebell um revealed significant reductions in all three treated groups compared wit h the control group. Further, animals receiving either DEET or permethrin e xhibited a significant number of degenerating (eosinophilic) neurons in the above brain regions. However, degenerating neurons were infrequent in anim als receiving both DEET and permethrin, suggesting that neuronal cell death occurs earlier in animals receiving combined DEET and permethrin than in a nimals receiving either DEET or permethrin alone. The extent of neuron loss in different brain regions was similar among the three treatment groups ex cept the dentate gyrus, where neurodegeneration was significantly greater w ith exposure to DEET alone. The neuron loss in the motor cerebral cortex an d the CA1 subfield of all treated groups was also corroborated by a signifi cant decrease in microtubule associated protein 2-immunoreactive elements ( 15-52% reduction), with maximal reductions occurring in rats receiving DEET alone; further, the surviving neurons in animals receiving both DEET and p ermethrin exhibited wavy and beaded dendrites. Analysis of glial fibrillary acidic protein immunoreactivity revealed significant hypertrophy of astroc ytes in the hippocampus and the cerebellum of all treated groups (24-106% i ncrease). Thus, subchronic dermal application of DEET and permethrin to adu lt rats, alone or in combination, leads to a diffuse neuronal cell death in the cerebral cortex, the hippocampal formation, and the cerebellum. Collec tively, the above alterations can lead to many physiological, pharmacologic al, and behavioral abnormalities, particularly motor deficits and learning and memory dysfunction. (C) 2001 Academic Press.