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|Title:||Application of nuclear magnetic resonance imaging and spectroscopy to the study of 1,3-dinitrobenzene and S-alpha-chlorohydrin induced experimental encephalopathies|
|Presented at:||University of Leicester|
|Abstract:||1,3-dinitrobenzene and S-a-chlorohydrin are compounds representative of larger classes of organic molecules of current and past industrial interest. They exhibit testicular toxicity and a profound neurotoxic potential in rodents causing ataxia in vivo following systemic administration under appropriate dosing schemes within 24 hours. Their action affects several thalamic, brainstem, cerebellar and pontine nuclei with production of oedematous lesions in their respective sites identified post mortem after 24 hours. The encephalopathies they induce are characterised by widespread astroglial death and damage of the cerebral vasculature, which leads to disruption of the blood-brain barrier and formation of petechial haemorrhages. The present study addresses specifically the application of in vivo nuclear magnetic resonance (NMR) imaging and ex vivo 'H NMR spectroscopy at different time points following full and partial intoxication regimens of the respective rat toxicological models. The results show that: 1) the full range of lesions caused by either compound can be imaged with T2-weighted NMR imaging after 24 hours; 2) the first T2-weighted signal abnormality is observed by the 4th hour post---dose for the S-a-chlorohydrin model; 3) a large number of the susceptible brain nuclei are afflicted visibly by NMR by the 9th hour post-S-a-chlorohydrin, whereas 1,3-dinitrobenzene damage is more delayed, in agreement with neuropathological findings; 4) the S-a-chlorohydrin-induced lesions are reduced in number by the 9th day due to selective loss of T2-weighted contrast occurring despite scar tissue formation at all the lesioned nuclei; 5) diffusion-weighted NMR imaging is capable of imaging ensuing pathology in the inferior colliculus, the largest structure affected by S-a-chlorohydrin, before any visible changes are seen with T2-weighted NMR imaging or conventional histopathology (8th hour); 6) Image processing of T2-weighted NMR images diversifies between graded oedema generated contrast in the inferior colliculi and the cerebellar roof nuclei; 7) intravenous injection of paramagnetic contrast agents can demonstrate in vivo the blood-brain barrier breakdown in S-a-chlorohydrin dosed rats with T1-weighted NMR imaging; 8) analysis of quantitative 'H NMR spectroscopy data from metabolically inactivated specific brain region extracts suggests a significant elevation of lactate levels due to 1,3-dinitrobenzene treatment within 4 hours (i.e. in the absence of pathology) throughout the brain rather than in the extracts from the vulnerable regions only, as well as a decrease in N-acetyl-aspartate in the containing vulnerable structures brainstem and an increase of choline containing compounds in the toxicity resistant midbrain; on the contrary no effect was found for S-a-chlorohydrin treatment at the same time point in any of the 12 metabolites quantified.|
|Rights:||Copyright © the author. All rights reserved.|
|Appears in Collections:||Theses, MRC Toxicology Unit|
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