Soman-induced toxicity, cholinesterase inhibition and neuropathology in adult male Göttingen minipigs
| Autor: | Katie Walker, Linnzi K.M. Wright, Tsung-Ming Shih, Fu Du, Michael F. Stone, Zora-Maya Keith, Caroline R. Schultz, Lucille A. Lumley, Brenda Marrero-Rosado, Kimberly A. Whitten, Cindy Acon-Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Health
Toxicology and Mutagenesis Neuropathology 010501 environmental sciences Pharmacology Toxicology 01 natural sciences Median lethal dose 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine RA1190-1270 Soman medicine Göttingen minipig Neuroinflammation ComputingMethodologies_COMPUTERGRAPHICS 0105 earth and related environmental sciences Nerve agent Cholinesterase biology business.industry Chemical warfare nerve agent Regular Article Seizure chemistry Toxicity Toxicology. Poisons biology.protein Visual system business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Toxicology Reports, Vol 8, Iss, Pp 896-907 (2021) Toxicology Reports |
| ISSN: | 2214-7500 |
| Popis: | Graphical abstract Highlights • The median lethal dose of soman (GD) was estimated in adult male Göttingen minipigs. • GD exposure induces cholinesterase inhibition and behavioral seizure in minipigs. • GD induces neurodegeneration in visual cortex and lateral geniculate nucleus. • Prolonged seizure is associated with widespread microglial activation and cell death. • The minipig may be a useful alternative large animal model to the non-human primate. Animal models are essential for evaluating the toxicity of chemical warfare nerve agents (CWNAs) to extrapolate to human risk and are necessary to evaluate the efficacy of medical countermeasures. The Göttingen minipig is increasingly used for toxicological studies because it has anatomical and physiological characteristics that are similar to those of humans. Our objective was to determine whether the minipig would be a useful large animal model to evaluate the toxic effects of soman (GD). We determined the intramuscular (IM) median lethal dose (LD50) of GD in adult male Göttingen minipigs using an up-and-down dosing method. In addition to lethality estimates, we characterized the observable signs of toxicity, blood and tissue cholinesterase (ChE) activity and brain pathology following GD exposure. The 24 h LD50 of GD was estimated to be 4.7 μg/kg, with 95 % confidence limits of 3.6 and 6.3 μg/kg. As anticipated, GD inhibited ChE activity in blood and several tissues. Neurohistopathological analysis showed neurodegeneration and neuroinflammation in survivors exposed to 4.7 μg/kg of GD, including in the primary visual cortex and various thalamic nuclei. These findings suggest that the minipig will be a useful large animal model for assessing drugs to mitigate neuropathological effects of exposure to CWNAs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|