Quantitative Structure-Toxicity Relationships Using Tops-Mode. 2. Neurotoxicity of a Non-Congeneric Series of Solvents

Abstract

Neurotoxicities of a series of solvents in rats and mice have been modeled by means of the TOPS-MODE approach. Two quantitative structure-toxicity relationship (QSTR) models were obtained explaining more than 80% of the variance in the experimental values of neurotoxicity of 45 solvents. Only one compound was detected as statistical outlier for these models. In contrast, previous models explained less than 60% of the variance in this property for 44 solvents. Finally, the contributions to neurotoxicity in rats and mice for a series of structural fragments were found. Structural characteristics of chlorinated fragments responsible for their different neurotoxicities were analyzed. The differences in neurotoxic behavior of some fragments in rats and mice were also analyzed, which could give insights on the toxicological mechanism of action of solvents studied.     

Direct Quantification of Nanoplastics Neurotoxicity by Single-Vesicle Electrochemistry

Nanoplastics are recently recognized as neurotoxic factors for the nervous systems. However, whether and how they affect vesicle chemistry (i.e., vesicular catecholamine content and exocytosis) remains unclear. This study offers the first direct evidence for the nanoplastics-induced neurotoxicity by single-vesicle electrochemistry. We observe the cellular uptake of polystyrene (PS) nanoplastics into model neuronal cells and mouse primary neurons, leading to cell viability loss depending on nanoplastics exposure time and concentration. By using single-vesicle electrochemistry, we find the reductions in the vesicular catecholamine content, the frequency of stimulated exocytotic spikes, the neurotransmitter release amount of single exocytotic event, and the membrane-vesicle fusion pore opening-closing speed. Mechanistic investigations suggest that PS nanoplastics can cause disruption of filamentous actin (F-actin) assemblies at cytomembrane zones and change the kinetic patterns of vesicle exocytosis. Our finding shapes the first quantitative picture of neurotoxicity induced by high-concentration nanoplastics exposure at a single-cell level.     

Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice

Olfactory tract has been demonstrated to be an important portal for inhaled solid nanoparticle transportation into the central nervous system (CNS). We have previously demonstrated that intranasally instilled Fe₂O₃ nanoparticles could transport into the CNS via olfactory pathway. In this study, we investigated the neurotoxicity and size effect of repeatedly low-dose (130 μg) intranasal exposure of nano- and submicron-sized Fe₂O₃ particles (21 nm and 280 nm) to mice. The biomarkers of oxidative stress, activity of nitric oxide synthases and release of monoamine neurotransmitter in the brain were studied. Our results showed that significant oxidative stress was induced by the two sizes of Fe₂O₃ particles. The activities of GSH-Px, Cu,Zn-SOD, and cNOS significantly elevated and the total GSH and GSH/GSSG ratio significantly decreased in the olfactory bulb and hippocampus after the nano- and submicron-sized Fe₂O₃ particle treatment (p < 0.05). The nano-sized Fe₂O₃ generally induced greater alteration and more significant dose–effect response than the submicron-sized particle did. Some slight perturbation of monoamine neurotransmitters were found in the hippocampus after exposure to the two sizes of Fe₂O₃ particle. The TEM image showed that some ultrastructural alterations in nerve cells, including neurodendron degeneration, membranous structure disruption and lysosome increase in the olfactory bulb, slight dilation in the rough endoplasmic reticulum and lysosome increase in the hippocampus were induced by the nano-sized Fe₂O₃ treatment. In contrast, in the submicron-sized Fe₂O₃ treated mice, slightly swollen mitochondria and some vacuoles were observed in the olfactory bulb and hippocampus, respectively. These results indicate that intranasal exposure of Fe₂O₃ nanoparticles could induce more severe oxidative stress and nerve cell damage in the brain than the larger particle did. This is the first study to compare the neurotoxicity of nano- and submicron-sized Fe₂O₃ particles in the central nervous system after long-term and low-dose intranasal exposure.     

金属锰暴露致神经毒性的多组学研究进展

锰是环境重金属污染物之一,长期暴露于金属锰或其无机化合物主要引发锰中毒或亚临床神经功能缺陷。锰暴露诱导的神经毒性对遗传易感性、基因表达调控、代谢稳态的影响机制复杂,涉及多靶点,然而常规机制研究往往只能局限于单一通路。鉴于工作场所和环境中重金属锰的分布日益广泛,需要更明确地界定锰的神经毒性作用网络,实现多靶点预防和治疗。多组学技术及其相关分析可在不同的功能水平上对疾病发生发展进程中的差异化进行描述。综述了基因组学、表观遗传学、转录组学、代谢组学在金属锰暴露致神经毒性中的研究结果,探讨潜在的代表性生物标志物,支持多组学方法的整合应用,构建锰的神经毒性作用网络,并对未来研究方向提出展望。