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 potential neurotoxic agents that may have played an important role in the development of illnesses in some veterans of the Persian Gulf War. To determine the effect of subchronic dermal application of these chemicals on the adult brain, we evaluated histopathological alterations in the brain of adult male rats following a daily dermal dose of DEET (40 mg/kg in 70% ethanol) or permethrin (0.13 mg/kg in 70% ethanol) or a combination of the two for 60 days. Control rats received a daily dermal dose of 70% ethanol for 60 days. Animals were perfused and brains were processed for morphological and histopathological analyses following the above regimen. Quantification of the density of healthy (or surviving) neurons in the motor cerebral cortex, the dentate gyrus, the CA1 and CA3 subfields of the hippocampus, and the cerebellum revealed significant reductions in all three treated groups compared with the control group. Further, animals receiving either DEET or permethrin exhibited a significant number of degenerating (eosinophilic) neurons in the above brain regions. However, degenerating neurons were infrequent in animals receiving both DEET and permethrin, suggesting that neuronal cell death occurs earlier in animals receiving combined DEET and permethrin than in animals receiving either DEET or permethrin alone. The extent of neuron loss in different brain regions was similar among the three treatment groups except the dentate gyrus, where neurodegeneration was significantly greater with exposure to DEET alone. The neuron loss in the motor cerebral cortex and the CA1 subfield of all treated groups was also corroborated by a significant 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 permethrin exhibited wavy and beaded dendrites. Analysis of glial fibrillary acidic protein immunoreactivity revealed significant hypertrophy of astrocytes in the hippocampus and the cerebellum of all treated groups (24-106% increase). Thus, subchronic dermal application of DEET and permethrin to adult rats, alone or in combination, leads to a diffuse neuronal cell death in the cerebral cortex, the hippocampal formation, and the cerebellum. Collectively, the above alterations can lead to many physiological, pharmacological, and behavioral abnormalities, particularly motor deficits and learning and memory dysfunction.
Abdel-Rahman
A
A
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Shetty
A K
AK
Abou-Donia
M B
MB
D000279:Administration, Cutaneous; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D003599:Cytoskeleton / Q000187:drug effects / Q000473:pathology; D003671:DEET / Q000008:administration & dosage / Q000633:toxicity*; D003712:Dendrites / Q000187:drug effects / Q000473:pathology; D004334:Drug Administration Schedule; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007302:Insect Repellents / Q000008:administration & dosage / Q000633:toxicity*; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009044:Motor Cortex / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D026023:Permethrin / Q000008:administration & dosage / Q000633:toxicity*; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D005904:Glial Fibrillary Acidic Protein; D007302:Insect Repellents; D007306:Insecticides; D008869:Microtubule-Associated Proteins; D003671:DEET; D026023:Permethrin