Neurotoxic changes in cat neurohypophysis after single and multiple exposures to diisopropylfluorophosphate and soman*1

Department of Physiology and Pharmacology, College of Veterinary Medicine, Iowa State University, Ames, Iowa 50011 USA
Fundamental and Applied Toxicology 12/1985; 5(6):1087-1096. DOI: 10.1016/0272-0590(85)90144-7


Fine structural changes in cat neurohypophysis have been studied after single and multiple parenteral sub-LD50 doses of the organophosphates diisopropylfluorophosphate (DFP) and pinacolyl methylphosphonofluoridate (soman). While a single sub-LD50 dose of DFP does not alter fine structure, multiple exposures result in degeneration of axons. Single as well as multiple sub-LD50 doses of soman cause dilation of axons with an accumulation of neurosecretory granulated vesicles (NGVs). Increased metabolic activity is suggested by the presence of well-developed Golgi complexes and increased amounts of endoplasmic reticulum in the pituicytes of treated animals. Direct and indirect actions of DFP and soman on neurohypophysial hormone release are discussed as putative mechanisms responsible for the morphological changes in the neurohypophysis.

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    ABSTRACT: Fine structural changes in neurons of the dorsal hippocampus, caudate nucleus, supraoptic nucleus (SON), and ventral horn of the spinal cord of adult male or spayed female cats were studied after single and multiple doses (dose range 1.0-20.0 μg/kg sc) of the organophosphonate, pinacolyl methylphosphonofluoridate (soman). Increases in amounts of rough endoplasmic reticulum (rER) and polyribosomes, proliferation of Golgi complexes, as well as indentations of nuclear membranes occur after single and multiple exposures. The degree of change is dependent on dose, duration of exposure, and time of survival after exposure. The cell organelles affected are essential for protein synthesis and changes in their quantities are morphological indicators for changes in protein synthesis. The data presented in this study suggest an initial increase in protein synthesis after soman exposure, followed by early signs of degeneration. Soman (10 μg/kg iv) inhibition of cholinesterases of whole blood, spinal cord, and caudate nucleus of control and cats from which electrophysiological recordings of Renshaw cell field potentials were taken show significant differences. Moreover, while blood values are unmeasurable, spinal cord and caudate nucleus values are 42.21 and 53.6% those of controls at 30 min after injection and 63.41 and 50.75% those of controls after 240 min, respectively. No differences are noted between Renshaw cell field potentials after treatment and controls. Similarly, no changes in gross behavior are noted after 10 μg/kg sc. Yet, morphological signs of increases in protein synthesis are present. It is concluded that soman induces increased protein synthesis in many areas studied and that this increase is not dependent on inhibition of cholinesterase to a degree that affects gross behavior of evoked potentials from a CNS cholinergic-transmitting synapse-the motoneuron axon collateral and Renshaw cell (J. C. Eccles, P. Fatt, and K. Koketsu (1954), J. Physiol.126, 524-562).
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    ABSTRACT: Intrastriatal injection of soman (14.85 nmol) inhibits cholinesterase (ChE) activity in the striatum with much smaller decreases in ChE activity in other brain areas of the rat. As would be expected, there is a substantial increase in striatal acetylcholine (ACh) content shortly after soman injection. However, this increase is no longer significant 1 h following intrastriatal injection. There is no change in striatal KACh 20 min, 1 h or 24 h following soman injection. ACh content is not affected in the parietal cortex, hippocampus, or medulla/pons following intrastriatal soman injection. However, KACh and/or ACh turnover are reduced in these brain areas following soman injection. There is no consistent effect on dopamine (DA) metabolism in any of the brain areas studied. However, serotonin (5-HT) metabolism appears to be affected in the cortex, hippocampus and medulla/pons following intrastriatal injection of soman. Possible mechanisms of the actions of local injection of soman on brain Ach and 5-HT metabolism are discussed, as well as the differences observed between the effects of local and peripheral administration of soman on DA metabolism in the striatum.
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    No preview · Article · Dec 2005 · Toxicology