Neurotoxicity induced by toluene: In silico and in vivo evidences of mitochondrial dysfunction and dopaminergic neurodegeneration.

Toluene is an air pollutant widely used as an organic solvent in industrial production and emitted by fossil fuel combustion, in addition to being used as a drug of abuse. Its toxic effects in the central nervous system have not been well established, and how and which neurons are affected remains unknown. Hence, this study aimed to fill this gap by investigating three central questions: 1) How does toluene induce neurotoxicity? 2) Which neurons are affected? And 3) What are the long-term effects induced by airborne exposure to toluene? To this end, a Caenorhabditis elegans model was employed, in which worms at the fourth larval stage were exposed to toluene in the air for 24 h in a vapor chamber to simulate four exposure scenarios. After the concentration-response curve analysis, we chose scenarios 3 (E3: 792 ppm) and 4 (E4: 1094 ppm) for the following experiments. The assays were performed 1, 48, or 96 h after removal from the exposure environments, and an irreversible reduction in neuron fluorescence and morphologic alterations were observed in different neurons of exposed worms, particularly in the dopaminergic neurons. Moreover, a significant impairment in a dopaminergic-dependent behavior was also associated with negative effects in healthspan endpoints, and we also noted that mitochondria may be involved in toluene-induced neurotoxicity since lower adenosine 5'-triphosphate (ATP) levels and mitochondrial viability were observed. In addition, a reduction of electron transport chain activity was evidenced using ex vivo protocols, which were reinforced by in silico and in vitro analysis, demonstrating toluene action in the mitochondrial complexes. Based on these findings model, it is plausible that toluene neurotoxicity can be initiated by complex I inhibition, triggering a mitochondrial dysfunction that may lead to irreversible dopaminergic neuronal death, thus impairing neurobehavioral signaling.

Caenorhabditis elegans as a model for studies on quinolinic acid-induced NMDAR-dependent glutamatergic disorders.

Quinolinic acid (QUIN) is an agonist of the neurotransmitter glutamate (Glu) capable of binding to N-methyl-D-aspartate receptors (NMDAR) increasing glutamatergic signaling. QUIN is known for being an endogenous neurotoxin, able to induce neurodegeneration. In Caenorhabditis elegans, the mechanism by which QUIN induces behavioral and metabolic toxicity has not been fully elucidated. The effects of QUIN on behavioral and metabolic parameters in nmr-1 and nmr-2 NMDA receptors in transgenic and wild-type (WT) worms were performed to decipher the pathway by which QUIN exerts its toxicity. QUIN increased locomotion parameters such as wavelength and movement amplitude medium, as well as speed and displacement, without modifying the number of body bends in an NMDAR-dependent-manner. QUIN increased the response time to the chemical stimulant 1-octanol, which is modulated by glutamatergic neurotransmission in the ASH neuron. Brood size increased after exposure to QUIN, dependent upon nmr-2/NMDA-receptor, with no change in lifespan. Oxygen consumption, mitochondrial membrane potential, and the flow of coupled and unbound electrons to ATP production were reduced by QUIN in wild-type animals, but did not alter citrate synthase activity, altering the functionality but the mitochondrial viability. Notably, QUIN modified fine locomotor and chemosensory behavioral parameters, as well as metabolic parameters, analogous to previously reported effects in mammals. Our results indicate that QUIN can be used as a neurotoxin to elicit glutamatergic dysfunction in C. elegans in a way analogous to other animal models.