Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.
Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, Guizhou, China.
Toxicol Appl Pharmacol. 2018 Nov 1;358:56-67. doi: 10.1016/j.taap.2018.09.002. Epub 2018 Sep 6.
Previous studies have demonstrated that oxidative stress is implicated in benzene-induced hematotoxicity. However, the low dose-response effects and the mechanism underlying perturbation of hematopoiesis remain to be defined. This study aims to address the role of Nrf2 pathway in mediating benzene-induced hematotoxicity. Nrf2 (wildtype, Nrf2-WT) and Nrf2 (knockout, Nrf2-KO) mice were administrated with benzene at doses of 0.1, 1.0, 10.0, 100.0 mg/kg by oral gavage for a consecutive 4 weeks (6 times/week). As a result, benzene exposure caused a decline of WBC and lymphocyte counts in a dose-dependent manner at a dose range from 1.0 to 100.0 mg/kg, while low dose benzene induced hormesis effects. Interestingly, Nrf2 deficiency seemed to relieve the decline of peripheral blood cell counts upon benzene exposure, indicating the involvement of Nrf2 in regulation of benzene-induced hematotoxicity. The suppression of phase II enzyme expression in Nrf2-KO mice resulted in considerable reduction in detoxification indicated by the decrease of urinary S-phenylmercapturic acid (SPMA), a metabolite of benzene. Ex vivo assay revealed enhanced cytotoxicity and oxidative stress were induced by benzene in Nrf2-KO mice. Notably, the depletion of Nrf2 triggered the proliferation and differentiation of hematopoietic cells, but induced aberrant morphological changes in periphery erythrocytes and bone marrow cells, implicating the compensatory effects carried on at the expense of induction of dysfunctional blood cells. Our findings provide a new insight into a low dose-response towards benzene-induced hematotoxicity and uncover the critical role of Nrf2 pathway in mediating abnormal hematopoiesis in response to oxidative stress.
先前的研究表明，氧化应激与苯诱导的血液毒性有关。然而，低剂量反应效应和导致造血功能紊乱的机制仍有待确定。本研究旨在探讨 Nrf2 通路在介导苯诱导的血液毒性中的作用。Nrf2（野生型，Nrf2-WT）和 Nrf2（敲除型，Nrf2-KO）小鼠通过口服灌胃连续 4 周（每周 6 次）给予 0.1、1.0、10.0、100.0mg/kg 的苯。结果显示，苯暴露以剂量依赖性方式导致白细胞和淋巴细胞计数下降，剂量范围为 1.0 至 100.0mg/kg，而低剂量苯诱导了兴奋效应。有趣的是，Nrf2 缺失似乎减轻了苯暴露引起的外周血细胞计数下降，表明 Nrf2 参与了苯诱导的血液毒性的调节。Nrf2-KO 小鼠中Ⅱ相酶表达的抑制导致苯代谢物尿 S-苯巯基尿酸（SPMA）减少，表明解毒作用明显减弱。体外实验显示，Nrf2-KO 小鼠中的苯诱导了细胞毒性和氧化应激增强。值得注意的是，Nrf2 的耗竭触发了造血细胞的增殖和分化，但在外周红细胞和骨髓细胞中诱导了异常的形态变化，表明在诱导功能失调的血细胞的同时存在代偿效应。我们的研究结果为苯诱导的血液毒性的低剂量反应提供了新的认识，并揭示了 Nrf2 通路在介导氧化应激引起的异常造血中的关键作用。
