Introduction

The extensive use of 6PPD in tire rubber has led to its increase in atmospheric tire wear particles. 6PPD reacts with ozone to form 6PPD-quinone (6PPD-Q), a respiratory toxicant enriched in tire and road wear particles.

Objectives

The aim of this study is to decipher the potential sensitive target organs and toxic actions by inhalation exposure to atmospheric 6PPD-Q.

Methods

This study employed a mouse inhalation exposure model to simulate environmental levels of 6PPD-Q at three concentrations of 0, 0.14, and 14 mg/m³. Using a 28-day exposure period followed by an equivalent recovery phase, we systematically evaluated the toxicological targets and effects of subacute exposure.

Results

The findings revealed that, compared to pulmonary, cardiovascular, and metabolic organ damage, 6PPD-Q-induced neurotoxicity was more persistent and irreversible, particularly characterized by prolonged anxiety-like behaviors. Histopathological analyses of the basolateral amygdala, using Nissl staining and markers of neuronal aging, indicated substantial neuronal degeneration linked to elevated oxidative stress, identifying this region as a critical target of 6PPD-Q neurotoxicity. Transcriptomic analysis uncovered that the expression of Egr1, a transcription factor crucial for neuronal plasticity, was markedly dysregulated. Findings of significant downregulation at the gene level and an upward trend in protein expression suggest that Egr1 expression is influenced by translational efficiency, epigenetic modifications, and post-translational regulatory mechanisms. Egr1 dysregulation disrupted downstream networks involving solute carrier proteins and calcium-binding proteins, contributing to aberrant neurobehavioral outcomes. Notably, the elevation of Egr1 protein levels in the basolateral amygdala but not in the cerebral cortex highlights the region-specific nature of 6PPD-Q’s neurotoxic effects.

Conclusion

This study provides the first insights into the neurotoxicity and irreversibility of inhaled 6PPD-Q exposure, paving the way for future research into the long-term neurological consequences and regulatory mechanisms of 6PPD-Q.

中文翻译：

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吸入轮胎橡胶颗粒源污染物 6PPD-醌，涉及雄性 ICR 小鼠基底外侧杏仁核损伤

 介绍

6PPD 在轮胎橡胶中的广泛使用导致其大气轮胎磨损颗粒的增加。6PPD 与臭氧反应形成 6PPD-醌 （6PPD-Q），这是一种富含轮胎和道路磨损颗粒的呼吸道毒物。

 目标

本研究的目的是破译吸入暴露于大气 6PPD-Q 的潜在敏感靶器官和毒性作用。

 方法

本研究采用小鼠吸入暴露模型模拟 0、0.14 和 14 mg/m³ 三种浓度下 6PPD-Q 的环境水平。使用 28 天的暴露期和等效的恢复期，我们系统地评估了亚急性暴露的毒理学靶点和影响。

 结果

研究结果显示，与肺、心血管和代谢器官损伤相比，6PPD-Q 诱导的神经毒性更持久且不可逆，特别是以长时间的焦虑样行为为特征。使用 Nissl 染色和神经元衰老标志物对基底外侧杏仁核进行组织病理学分析，表明与氧化应激升高相关的大量神经元变性，将该区域确定为 6PPD-Q 神经毒性的关键靶点。转录组学分析发现，Egr1（一种对神经元可塑性至关重要的转录因子）的表达明显失调。基因水平显着下调和蛋白质表达上升趋势的结果表明，Egr1表达受翻译效率、表观遗传修饰和翻译后调节机制的影响。Egr1失调破坏了涉及溶质载体蛋白和钙结合蛋白的下游网络，导致异常的神经行为结果。值得注意的是，基底外侧杏仁核中Egr1蛋白水平的升高，但在大脑皮层中没有升高，这突出了 6PPD-Q 神经毒性作用的区域特异性。

 结论

这项研究首次了解了吸入 6PPD-Q 暴露的神经毒性和不可逆性，为未来研究 6PPD-Q 的长期神经系统后果和调节机制铺平了道路。