triethyltin and triethyllead

Metabolically competent isolated cerebral cortical nerve terminals were used to determine the effects of triethyllead (TEL) and triethyltin (TET) on cytosolic free calcium ([Ca2+]c), on plasma and mitochondrial membrane potentials, and on oxidative metabolism. In the presence of physiological concentrations of extracellular ions, 20 microM TEL and 20 microM TET increase [Ca2+]c from 185 nM to 390 and 340 nM, respectively. A simultaneous depolarization of plasma membrane potential (delta psi p) by only 3-4 mV occurs, a drop which is insufficient to open the voltage-sensitive Ca2+ channels. In contrast, an instant and substantial depolarization of mitochondrial membrane potential (delta psi m) upon addition of TEL and TET is evident, as monitored with safranine O fluorescence. At the same concentration, TEL and TET stimulate basal respiration of synaptosomes by 45%, induce oxidation of endogenous NAD(P)H, and reduce the terminal ATP/ADP ratio by 45%. Thus, TEL and TET inhibit ATP production of intrasynaptosomal mitochondria by a mechanism consistent with uncoupling of oxidative phosphorylation. This bioenergetic effect by TEL and TET can be prevented by omitting external chloride, and a concomitant reduction of the increase in [Ca2+]c by about 60% is observed. Uncoupling of mitochondrial ATP synthesis from oxidation by TEL and TET, [corrected] a process that is dependent on external chloride, is the main mechanism by which they [corrected] increase [Ca2+]c.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Calcium; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Cerebral Cortex; Chlorides; Cytosol; Guinea Pigs; Membrane Potentials; Mitochondria; NADP; Organometallic Compounds; Oxidative Phosphorylation; Spectrometry, Fluorescence; Synaptosomes; Trialkyltin Compounds; Triethyltin Compounds

Effects of several alkylmetals on free intrasynaptosomal Ca2+ concentration, [Ca2+]i, were studied in vitro using the fluorescent Ca2+ indicator fura-2. Neurotoxic alkylmetals methylmercury (Met-Hg), triethyllead (TEL), triethyltin (TET), and trimethyltin (TMT) (at 2.5-30 microM) increased [Ca2+]i to different degrees. Met-Hg was the most potent, elevating [Ca2+]i 100-800 nM, dose dependently and significantly more than high K+ (150 nM) or veratridine (350 nM). The effect of Met-Hg could not be inhibited with a Ca2+ channel blocker, verapamil, nor with a Na+ channel blocker, tetrodotoxin. Inhibition of the mitochondrial Ca2+ uptake in situ with rotenone + oligomycin decreased the potency of Met-Hg to elevate [Ca2+]i but did not change the resting [Ca2+]i. Met-Hg also slightly decreased synaptosomal ATP. TEL and TET elevated [Ca2+]i by 100-200 nM. The effect of TEL, but not that of TET, could be blocked with verapamil (36%) and veratridine (67%). TEL was less efficient in the presence of ouabain. Neither TEL nor TET had significant mitochondrial effects in situ contributing to [Ca2+]i. TMT increased [Ca2+]i less than TET while dimethyltin and methyltin were inactive. These results indicate that neurotoxic derivatives of alkylmetals studied increase [Ca2+]i. This occurs mainly either by nonspecific increase (Met-Hg, TET) of Ca2+ leakage through the plasma membrane and/or specific interference with the mechanisms regulating Ca2+ fluxes through the plasma membrane (TEL).

Topics: Adenosine Triphosphate; Animals; Calcium; Dose-Response Relationship, Drug; Ion Channels; Male; Mathematics; Methylmercury Compounds; Mitochondria; Oligomycins; Organometallic Compounds; Ouabain; Rats; Rats, Inbred F344; Rotenone; Synaptosomes; Tetrodotoxin; Trialkyltin Compounds; Triethyltin Compounds; Trimethyltin Compounds; Veratridine

The effect of organic lead and tin compounds upon the integrity of cerebral neurotubules has been studies in vitro and in vivo, using 3H-colchicine binding as an index of tubulin aggregation. Triethyl tin, trimethyl lead and triethyl lead chlorides at concentrations above 5 X 10(-5)M, all prevented the polymerization of tubulin. Inorganic lead had a similar effect. Trimethyl tin had a much lesser capacity to prevent such polymerization. Rats received a single dose of each organometal, by subcutaneous injection and the capacity of hippocampal soluble protein to bind 3H colchicine was assessed. At organometal doses sufficient to cause morphological damage and behavioral change, no significant differences of colchicine binding capacity were apparent.

Topics: Animals; Brain; Lead; Male; Microtubules; Organometallic Compounds; Rats; Rats, Inbred F344; Tetraethyl Lead; Triethyltin Compounds; Trimethyltin Compounds; Tubulin

Recent reports have demonstrated that organolead and -tin compounds can alter behavioral reactivity to noxious stimuli. To further define the dose response and temporal characteristics of these neurobehavioral effects, male Fischer 344 rats were injected sc with either one-fourth, one-half, or three-fourths the acute LD50 of triethyl lead (TEL), triethyl tin (TET), trimethyl lead (TML), trimethyl tin (TMT), or distilled water and tested on a 57.5 degrees C hot plate 1, 7, 14, 21, and 28 days after dosing. All four organometals altered hot plate latencies, but the magnitude and time course of these effects differed among the compounds. TEL produced a dose-related increase in latencies which was maximal 1 and 7 days postdosing and had dissipated by 28 days. In contrast, the group administered TML (3/4 LD50) exhibited a late developing antinocioception which became evident 14 days after dosing and persisted throughout the period of testing. The intermediate dose of TMT (1/2 LD50) also produced a delayed increase in response times which was observed 21 and 28 days post-treatment. The 3/4 LD50 dose of TMT produced increased hot plate latencies on all post-treatment test days except Day 14. TET (1/2 LD50) produced increased hot plate latencies 1, 7, 14, and 21 days postdosing and also induced a reversible ataxia and akinesia. Higher doses of TET proved lethal to 80% of the animals and lower doses failed to alter response times in the hot plate. These data demonstrate that trialkyl lead and tin compounds can produce time- and dose-related increases in hot plate latencies.

Topics: Animals; Central Nervous System Diseases; Dose-Response Relationship, Drug; Lead; Lead Poisoning; Lethal Dose 50; Male; Organometallic Compounds; Organotin Compounds; Pain; Rats; Rats, Inbred F344; Reaction Time; Tetraethyl Lead; Time Factors; Triethyltin Compounds; Trimethyltin Compounds