Sex-specific acute and chronic neurotoxicity of acute diisopropylfluorophosphate (DFP)-intoxication in juvenile Sprague-Dawley rats
| Autor: | Danielle J Harvey, Peter Andrew, Jonas J. Calsbeek, Eduardo A. González, Suangsuda Supasai, Naomi H. Saito, Mei Yun Tang, Yi Hua Tsai, Elizabeth L. Berg, Joan Vu, Jill L. Silverman, Pamela J. Lein, Gene G. Gurkoff |
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| Rok vydání: | 2021 |
| Předmět: |
DFP
Health Toxicology and Mutagenesis ROI region of interest Physiology Hippocampal formation intraperitoneal Neurodegenerative Toxicology Applied Microbiology and Biotechnology chemistry.chemical_compound Neuroinflammation AChE acetylcholinesterase RA1190-1270 EEG PBS intramuscular Pediatric 2-PAM pralidoxime Cognitive deficits Organophosphate Neurogenesis ROI SE status epilepticus acetylcholinesterase atropine-sulfate i.p. intraperitoneal Acetylcholinesterase Astrogliosis CT computed tomography OP butyrylcholinesterase Neurological OP organophosphate subcutaneous s.c. subcutaneous 2-PAM medicine.drug CT Pralidoxime cholinesterase organophosphate PBS phosphate-buffered saline s.c pralidoxime phosphate-buffered saline DFP diisopropylfluorophosphate i.m Article EEG electroencephalogram Vaccine Related ChE Seizures T2w Biodefense BChE Sex differences T2-weighted Behavioral and Social Science medicine T2w T2-weighted FJC Fluoro-Jade C AS atropine-sulfate Neurodegeneration SE ComputingMethodologies_COMPUTERGRAPHICS Fluoro-Jade C status epilepticus Epilepsy business.industry Prevention Neurotoxicity Neurosciences computed tomography electroencephalogram medicine.disease i.p Brain Disorders VEH vehicle FJC chemistry i.m. intramuscular ChE cholinesterase VEH Toxicology. Poisons vehicle AChE diisopropylfluorophosphate region of interest business BChE butyrylcholinesterase AS |
| Zdroj: | Current Research in Toxicology, Vol 2, Iss, Pp 341-356 (2021) Current Research in Toxicology |
| Popis: | Graphical abstract Highlights • DFP-induced seizures and neuroinflammation were more severe in males than females. • Acute DFP intoxication caused persistent sex-specific brain damage in juvenile rats. • Both sexes experienced cognitive deficits at 1 month post-DFP intoxication. • Acute DFP intoxication increased hippocampal neurogenesis in males but not females. • Microglial activation may be a critical driver of OP-induced cognitive deficits. Preclinical efforts to improve medical countermeasures against organophosphate (OP) chemical threat agents have largely focused on adult male models. However, age and sex have been shown to influence the neurotoxicity of repeated low-level OP exposure. Therefore, to determine the influence of sex and age on outcomes associated with acute OP intoxication, postnatal day 28 Sprague-Dawley male and female rats were exposed to the OP diisopropylfluorophosphate (DFP; 3.4 mg/kg, s.c.) or an equal volume of vehicle (∼80 µL saline, s.c.) followed by atropine sulfate (0.1 mg/kg, i.m.) and pralidoxime (2-PAM; 25 mg/kg, i.m.). Seizure activity was assessed during the first 4 h post-exposure using behavioral criteria and electroencephalographic (EEG) recordings. At 1 d post-exposure, acetylcholinesterase (AChE) activity was measured in cortical tissue, and at 1, 7, and 28 d post-exposure, brains were collected for neuropathologic analyses. At 1 month post-DFP, animals were analyzed for motor ability, learning and memory, and hippocampal neurogenesis. Acute DFP intoxication triggered more severe seizure behavior in males than females, which was supported by EEG recordings. DFP caused significant neurodegeneration and persistent microglial activation in numerous brain regions of both sexes, but astrogliosis occurred earlier and was more severe in males compared to females. DFP males and females exhibited pronounced memory deficits relative to sex-matched controls. In contrast, acute DFP intoxication altered hippocampal neurogenesis in males, but not females. These findings demonstrate that acute DFP intoxication triggers seizures in juvenile rats of both sexes, but the seizure severity varies by sex. Some, but not all, chronic neurotoxic outcomes also varied by sex. The spatiotemporal patterns of neurological damage suggest that microglial activation may be a more important factor than astrogliosis or altered neurogenesis in the pathogenesis of cognitive deficits in juvenile rats acutely intoxicated with OPs. |
| Databáze: | OpenAIRE |
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