cyclic-gmp and 1-1-1-trichloroethane

As it is known that volatile organic compounds (VOCs) exhibit differential dispositions among anatomically discrete brain regions in rodents as well as in humans, potential toxicological consequences of this pharmacokinetic feature were evaluated using measurements of cyclic GMP (glucose monophosphate). With the knowledge of 1, 1, 1-trichloroethane (TRI) uptake and distribution in the various brain regions, cyclic GMP was evaluated due to (1) known susceptibility to the effects of organic solvents, (2) pivotal physiological role in perpetuating changes in neurochemical pathways, and (3) possible involvement with neurobehavioral functions, whose disruption is one of the primary health effects associated with solvent exposures. Male CD-1 mice and Sprague-Dawley rats inhaled 5000 ppm TRI for 40 and 100 min in dynamic inhalation exposure chambers, and the brain was procured from the animals immediately following termination by microwave irradiation. After 40 min of TRI inhalation, significant decreases in cyclic GMP levels were found in the cerebellum of both species, 55% and 58%, respectively, relative to the controls. There was a further decrease in both species after 100 min of TRI inhalation. Smaller decreases in cyclic GMP were seen in the cortex of both species at both time points of measurement. A decrease in cyclic GMP was observed in the medulla oblongata of mice but not in rats after 40 min of exposure. Due to its signal transduction functions, it might be expected that the effects of TRI on cyclic GMP levels could directly impact neurological function. Comparison of the results from this study with the regional brain distribution of TRI and its effects on behavioral performance seen in previous studies by this laboratory appeared to indicate that alterations in brain cyclic GMP levels are only involved with the neurobehavioral toxicity of TRI in an indirect fashion; consequently, behavioral effects and decreases in cyclic GMP do not appear to be directly related to regionally differential dispositions of TRI in rodent brain.

Topics: Administration, Inhalation; Animals; Cerebellum; Cerebral Cortex; Cyclic GMP; Male; Medulla Oblongata; Mice; Mice, Inbred Strains; Rats; Rats, Sprague-Dawley; Solvents; Trichloroethanes

Administration of 1,1,1-trichloroethane (TCE) to mice by inhalation or intraperitoneally reduced the cGMP contents of the brain stem, cerebral cortex, and vermis anterior, including the hemispheres. Following intraperitoneal administration the cGMP contents of the vermis posterior and hippocampus were also reduced. To investigate the mechanism underlying these changes, the effects of TCE on brain guanylate cyclase (GC) and phosphodiesterase (PDE) activities were examined after intraperitoneal administration in mice. The basal GC activities in the particulate and soluble fractions of the homogenates of the cerebellum, brain stem and cerebral cortex were not altered by TCE. In the cerebellum TCE treatment inhibited sodium azide-stimulated GC activity in the particulate and soluble fractions, while in the brain stem it enhanced the particulate GC activity induced by Ca2+. TCE treatment increased the rate of cGMP hydrolysis in the cerebral cortex and this was further accelerated by addition of Ca2+. Ca2+ also increased the rate of cGMP hydrolysis in the brain stem. However, in the cerebellum TCE enhanced the Ca2+-independent PDE activity as well as the enzyme activity in the presence of Ca2+ and exogenous calmodulin. These results indicate that the reduction of the cGMP content in the brain stem and cerebral cortex in vivo on exposure to TCE is due to changes in the rate of cGMP hydrolysis. In the cerebellum the TCE reduced cGMP content may be regulated by increased rate of cGMP hydrolysis as well as effects on the guanylate cyclase.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Brain; Cyclic GMP; Guanylate Cyclase; Hydrocarbons, Chlorinated; Injections, Intraperitoneal; Male; Mice; Nerve Tissue Proteins; Trichloroethanes