Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University & Shandong Academy of Medical Science, Ji'nan 250062, China.
Key Laboratory of Chemical Safety and Health, National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention (CDC), Beijing 100050, China.
Toxicol Lett. 2023 Mar 1;376:39-50. doi: 10.1016/j.toxlet.2023.01.005. Epub 2023 Jan 13.
Benzene is a frequent component of environmental pollution and is abundant in petrochemicals, decorative materials, motor vehicle exhaust and cigarette smoke. Benzene is a well-known carcinogen in humans and animals, but the molecular mechanism has not yet been elucidated. Our earlier research indicated that hydroquinone (HQ), one of the main reactive metabolites of benzene, could activate aryl hydrocarbon receptor (AhR), which is essential for HQ-induced toxicity, including apoptosis and DNA damage. Since AhR is an important regulator of the immune system that integrates the environmental stimulus and immune response, we examined whether and how HQ-induced AhR activity could lead to NLRP3 inflammasome-dependent pyroptosis in JHP cells. Our results showed that HQ could cause inflammation process and resultant pyroptosis. In JHP cells, HQ also induced endoplasmic reticulum stress (ERS) by releasing excessive reactive oxygen species (ROS). The activation of pyroptosis induced by HQ treatment was reversed by an antioxidant (NAC) and an ERS inhibitor (4-PBA). Interestingly, the treatment of CH223191, an AhR inhibitor, reversed HQ-induced oxidative stress, ERS and pyroptosis. These data suggested that AhR-mediated HQ-induced ERS, ROS and inflammasome activation may play vital roles in the toxic effects of benzene. This work provides insights and prospective strategies into potential mechanisms for reducing benzene-induced hematotoxicity.
苯是环境污染中常见的成分，广泛存在于石化产品、装饰材料、汽车尾气和香烟烟雾中。苯是人类和动物中一种已知的致癌物，但分子机制尚未阐明。我们之前的研究表明，苯的主要反应代谢物之一对苯二酚（HQ）可以激活芳香烃受体（AhR），这对于 HQ 诱导的毒性，包括细胞凋亡和 DNA 损伤是必不可少的。由于 AhR 是免疫系统的重要调节剂，它整合了环境刺激和免疫反应，我们研究了 HQ 诱导的 AhR 活性是否以及如何导致 JHP 细胞中 NLRP3 炎性体依赖性细胞焦亡。结果表明 HQ 可引起炎症过程和由此产生的细胞焦亡。在 JHP 细胞中，HQ 通过释放过量的活性氧（ROS）也诱导内质网应激（ERS）。抗氧化剂（NAC）和 ERS 抑制剂（4-PBA）逆转了 HQ 处理诱导的细胞焦亡的激活。有趣的是，AhR 抑制剂 CH223191 的处理逆转了 HQ 诱导的氧化应激、ERS 和细胞焦亡。这些数据表明，AhR 介导的 HQ 诱导的 ERS、ROS 和炎性体激活可能在苯的毒性作用中发挥重要作用。这项工作为减少苯诱导的血液毒性的潜在机制提供了新的见解和潜在的策略。
