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The neurotoxicology and pathology of organomercury, organolead, and organotin.

The toxicities of many metals, such as mercury and lead, are known to man since the dawn of civilization. Organic compounds of some heavy metals are known to have a particular toxic impact on the central nervous system. Organomercury, particularly alkyl-mercuric compounds (e.g. methylmercury), has a selective effect on the granule cells of the cerebellum, the nerve cells of the calcarine cortex, and the sensory neurons in the dorsal root ganglia. The well known Minamata Bay disease is the result of a massive epidemic episode of human exposure to alkylmercury contaminated food sources. Mental retardation and other developmental defects are also known to be a consequence of exposure to this toxic metal. Organic lead compounds have been employed as gasoline additives and in other industrial purposes. Unlike its inorganic counterpart, organolead compounds have a more prominent impact on the central nervous system. Pathological changes of the brain stem neurons have been described. Organotin compounds have been used in plastic industries and as agricultural chemicals. Both trimethyl and triethyl tin compounds are found to be extremely neurotoxic. Despite the similarity of their chemical structures, trimethyl and triethyl tins have a diversely different toxic property and effects. While triethyl tin is myelinotoxic, producing edematous and vacuolar changes in the central myelin, trimethyl tin is neurotoxic, producing prominent toxic changes in the neurons of the limbic system (hippocampus, entorhinal cortex, etc.). The factors which determine the specificity and selectivity of the neurotoxic impacts by various organometals are still unknown. In view that most of the organometals are still widely employed by many countries for industrial and for agricultural purposes, caution must be made for their proper handling and disposure to avoid undesirable exposures to workers and environmental contamination of water sources and food-chain for the common public. Since organometals are difficult to eliminate from the central nervous system, injuries usually lead to permanent neurological deficits, such tragedies are frequently long lasting and create not only a medical problem, but also a social economical problem for the society.

Animals↗

The effects of triethyltin bromide on red cell and brain cyclic AMP-dependent protein kinases.

Triethyltin bromide activates the cyclic AMP-dependent protein kinases of human red cell membranes and of bovine brain. Additions of 25-500 microM triethyltin to red cell ghosts resulted in enhanced phosphorylation of ghost proteins. When added to partially purified cyclic AMP-dependent protein kinases from red cell ghosts or bovine brain, stimulation of the phosphorylation of calf thymus histone was observed. The enhancement of kinase activity was due to release of catalytic subunits from the intact protein kinase. Brief exposure of the partially purified enzymes to triethyltin, followed by DE52 chromatography, resulted in elution profiles for regulatory and catalytic subunits that were similar to the profile resulting after cyclic AMP activation. Triethyltin interacts with both regulatory and catalytic subunits. When it was added to the partially purified cyclic AMP-dependent protein kinases from human red cell ghosts or bovine brain, noncompetitive inhibition of cyclic AMP binding to the regulatory subunit of the enzyme was observed. It interacted with the catalytic subunit to produce slow inhibition of catalytic activity. The inhibition was non-competitive with respect to both histone and ATP. When intact red cells were subjected to brief exposure with triethyltin, enhanced phosphorylation of certain membrane proteins occurred, suggesting that the activation of the cyclic AMP protein kinases by triethyltin may be physiologically significant.

Animals↗

Inactivation of yeast hexokinase B by triethyltin bromide.

Triethyltin bromide was found to demonstrate temperature-dependent inactivation of yeast hexokinase B. At temperatures of 20 degrees C or lower, little or no inactivation of the enzyme was detected after 2 h of reaction with 50-300 microM concentrations of the reagent. However, incubation at 25 degrees C or higher resulted in an increased rate and extent of loss of the enzyme activity with increasing incubation temperatures. The Arrhenius plot for the inactivation process showed a sharp break at approximately 30 degrees C, with a heat of activation (delta H*) above this temperature of 55.2 kcal, indicating that a triethyltin-induced conformational change occurred at the elevated temperatures. Sugar substrates provided protection against the inactivating effect by reducing the binding of triethyltin to the enzyme. In the absence of glucose, two sites of different affinity for triethyltin exist in the hexokinase monomer. Binding of triethyltin to the enzyme shifted its monomer-dimer equilibrium toward the monomeric form in an early stage of the interaction. Inactivation of the enzyme was associated with a slower subsequent event. Comparative effects of various organotin compounds on the activity of the enzyme indicated that inhibitory potency was associated with increasing hydrophobicity of the alkyl groups attached to the tin.

Adenosine Triphosphatases↗

[Implication of lipid peroxidation in triethyltin poisoning in the rat].

Triethyltin intoxication induces, in vivo, a significant increase of malondialdehyde concentration in rat brain. After treatment with a Ginkgo biloba extract, an extract known to possess antiedematous and radical scavenging properties, the malondialdehyde level in the brain is significantly decreased. This suggests that a lipid peroxidation process is associated with cerebral oedema induced by triethyltin.

Animals↗

Triethyltin-produced decrease and recovery of wheel running and food-reinforced lever pressing in rats.

Behavioral effects of triethyltin were studied in rats living in Wahmann activity cages. Wheel running activity and food-reinforced lever pressing were recorded 23 hr/day from 4 rats. Triethyltin injections (4 mg/kg IP) produced large transient decreases in running, lever pressing, and daily water consumption, without affecting body weight. These measures recovered to pre-treatment levels within 1-2 days. After 4 weekly injections, wheel running was reduced in 2 rats, and increased in 1 rat, while lever pressing remained at baseline levels. Good correlation was noted between the extent of reductions in wheel running and lever pressing, and the extent of characteristic triethyltin-induced morphological lesions in the central and peripheral nervous system. Over the course of repeated treatments, several critical behaviors known to be sensitive to neurotoxicants can be continually monitored using automated testing apparatus. While further validation with more compounds is required, these results suggest that monitoring wheel running, food-reinforced lever pressing, and water consumption may be an inexpensive way to test for behavioral neurotoxicity using small numbers of animals.

Animals↗