Toluene‐induced alterations in rat synaptosomal membrane composition and function

Abstract

Toluene is a widely used organic solvent that can produce acute central nervous system (CNS) effects. Since toluene reaches relatively high concentrations in the CNS and is extremely lipophilic, we investigated its effects on rat brain membrane composition and function. Toluene (1 g/kg, lh) did not alter total brain microsomal phospholipid (PL) or cholesterol (CL) content. However, synaptosomal PL was decreased (24%), while synaptosomal CL was unaltered. The PL/CL ratio, an indirect index of membrane fluidity, did not change, suggesting that toluene did not affect membrane fluidity. Fluorescence polarization studies employing 1,6-diphenyl-1,3,5-hexatriene (DPH) showed that toluene did not alter synaptosomal membrane fluidity after administration in vivo (1 g/kg) or in vitro (0.5 to 5.0 mM). Dose-response and time-course studies showed that toluene maximally decreased synaptosomal PL after 1 g/kg, 1 h. The dose-response and time-course studies also showed that the toluene-induced decreases in PL were a result of specific decreases in phosphatidylethanolamine (PE). Since PE was decreased, we assessed whether toluene altered synaptosomal membrane function by investigating phospholipid methylation, a reaction which uses PE as its initial substrate. Toluene decreased the incorporation of methyl groups into lipid when [3H]-methionine was used as the methyl donor, but did not affect methylation when [3H]-adenosylmethionine was the methyl donor. These data suggest that toluene-induced specific decreases in synaptosomal PE and inhibition of phospholipid methylation may alter normal synaptic function and play a critical role in the mechanism(s) of action of toluene's CNS effects.

Toluene-induced oxidative stress in several brain regions and other organs

“…All tissues examined showed an increase in ROS generation at the time of peak toluene blood levels (2 h after dosing). The blood toluene values reached in the current study, parallel those previously reported following a similar dosing regimen (LeBel and Schatz, 1988). This prior report also showed that brain levels of toluene are very similar to concurrent blood levels suggesting very rapid diffusion into the CNS.…”

Subacute exposure to low concentrations of toluene affects dopamine-mediated locomotor activity in the rat

“…The presently used low-dose toluene exposure did not affect membrane fluidity in the frontoparietal cortex, neostriatum, and subcortical limbic region, in agreement with the lack of effects following 500 ppm of toluene for 1 day up to 78 weeks [22) and of intraperitoneal injections (I g/kg) of toluene [46), but in contrast with the increase in membrane fluidity seen after toluene treatment in vitro (2.5 mmol/l, 10 mmol/I) [22,23). Thus, it seems as if changes in membrane fluidity [20,47) cannot fully explain the effects of toluene exposure in vivo on D-2 receptor binding even though the affinity of D-2 agonist binding sites are similarly reduced by in vivo and in vitro treatment [20,21), as is the modulation of D-2 agonist binding sites by neurotensin in vitro [21).…”

Effects of toluene and its metabolites on cerebral reactive oxygen species generation

“…The rationale for the doses and time-course used was based on previous studies that demonstrated maximal 879 c. J. MATTIA, c. P. LEBEL ands. C. BONDY cerebral levels of toluene within the brain, concurrent with pronounced sedative effects under these conditions [8][9][10]. Metyrapone (200 mg/kg, i.p., 4 mL/kg) was also dissolved in corn oil and given 1 hr prior to toluene.…”

“…From a mechanistic viewpoint, several recent studies have centered around the ability of toluene to alter neuronal membrane fluidity [8][9][10][11], levels of intracellular Ca 2 + and Ca 2 + -regulated events [11,12], and neuronal and astrocytic culture morphology [13]. Although it is unclear which of these events is causal to the neurotoxicity of toluene, these studies provide strong evidence to suggest that membraneassociated phenomena are integral to the mechanism of action of this solvent.…”