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.
Chem Biol Interact. 2022 Mar 1;355:109845. doi: 10.1016/j.cbi.2022.109845. Epub 2022 Feb 4.
Although it has been well recognized that benzene exposure can cause hematopoietic disorders such as aplastic anemia and leukemia, the underlying molecular mechanism remains to be fully understood. Emerging evidence indicated that aryl hydrocarbon receptor (AhR) plays important roles in hematopoietic and immune systems. This study investigated the activation of aryl hydrocarbon receptor (AhR) by hydroquinone (HQ) and its role in HQ-induced DNA damage and apoptosis in cultured human lymphocytes (JHP cells). We also investigated the effect of ROS on AhR activation and functions in JHP cells exposed to HQ with and without regulator including N-acetyl-l-cysteine (NAC), a potent antioxidant, and tert-butylhydroquinone (TBHQ), a Nrf2 activator. Results showed that HQ can cause oxidative stress, DNA damage and apoptosis. Pretreatment of an AhR antagonist (CH223191) can significantly increase the cell survival and mitigate HQ-induced toxicities such as DNA damage and apoptosis. We found that HQ can obviously increase expressions of total protein of AhR and prompt nuclear translocation compared to the control group. Interestingly, NAC can block HQ-induced AhR activation and DNA damage and apoptosis. Conclusively, our results indicated that HQ toxicity is mediated by AhR which is in turn regulated by ROS generated by HQ. The interaction between AhR and ROS drive and amplify the hematopoietic toxicity of HQ. This study provided new insights of mechanism and potential targets for the prevention and treatment to benzene-induced hematopoietic toxicity.
虽然苯暴露会导致再生障碍性贫血和白血病等血液系统疾病已得到广泛认可，但其中的分子机制仍未完全阐明。新出现的证据表明，芳香烃受体（AhR）在造血和免疫系统中发挥着重要作用。本研究旨在探讨对苯二酚（HQ）对人淋巴细胞（JHP 细胞）中芳烃受体（AhR）的激活作用及其在 HQ 诱导的 DNA 损伤和细胞凋亡中的作用。还研究了 ROS 在 HQ 处理的 JHP 细胞中对 AhR 激活和功能的影响，以及包括 N-乙酰-L-半胱氨酸（NAC）在内的调节剂对 AhR 激活和功能的影响，NAC 是一种有效的抗氧化剂，叔丁基对苯二酚（TBHQ）是 Nrf2 激活剂。结果表明，HQ 可引起氧化应激、DNA 损伤和细胞凋亡。AhR 拮抗剂（CH223191）预处理可显著提高细胞存活率，并减轻 HQ 诱导的毒性，如 DNA 损伤和细胞凋亡。结果发现，与对照组相比，HQ 明显增加了 AhR 的总蛋白表达，并促使其核转位。有趣的是，NAC 可阻断 HQ 诱导的 AhR 激活、DNA 损伤和细胞凋亡。综上，本研究表明 HQ 毒性是通过 AhR 介导的，而 AhR 又受 HQ 产生的 ROS 调节。AhR 与 ROS 之间的相互作用驱动并放大了 HQ 的血液毒性。本研究为预防和治疗苯诱导的血液毒性提供了新的机制和潜在靶点。
