Morphological assessment of ethyl choline mustard aziridinium-induced neurotoxicity in rat brain reaggregate cultures.
Foetal rat brain reaggregate cultures have been employed to investigate the morphological changes associated with the neurotoxic action of ethylcholine mustard aziridinium (ECMA). In a companion study we provided evidence for apparent selective cholinergic neurotoxicity. Exposure of 9-day-old cultures to 12.5 microM ECMA for 3 days produced dilatation of selected axon preterminals and terminals in the outer core tissue layer. Axoplasm in these dilated terminals was electron lucent and contained a flocculent, plasma-like material with remnants of the smooth endoplasmic reticulum. Their synaptic vesicle content was much reduced or, absent. Microglial cells were engaged in phagocytosis of these effete structures and a few necrotic neurons were enveloped by glial processes. Exposure to 50 microM ECMA produced widespread necrosis with some surviving neurons, surrounded by the still-persisting capsular layer. Treatment with 100 microM ECMA generated a greater extent of tissue necrosis, with only a few surviving neurons and glial cells being contained within the necrotic tissue mass. Reaggregates frequently disintegrated following capsule loss. Our results indicate that the initial morphological manifestation of ECMA-induced toxicity is dilatation of axon terminals, that are probably of cholinergic origin and are targeted due to their possession of the high-affinity choline transport system which is unique to these neurons.
Jones
H B
HB
Toxicology and Pathology Group, Smith Kline and French, Welwyn, Hertfordshire, UK.
Pillar
A M
AM
Prince
A K
AK
D000818:Animals; D001388:Aziridines / Q000633:toxicity*; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D002794:Choline / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D008854:Microscopy, Electron; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000648:ultrastructure; D009466:Neuromuscular Blocking Agents / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D011247:Pregnancy; D017729:Presynaptic Terminals / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D013572:Synaptic Vesicles / Q000187:drug effects / Q000648:ultrastructure
D001388:Aziridines; D009466:Neuromuscular Blocking Agents; C044894:ethylcholine aziridinium; D002794:Choline