Wang Xiaoyan, Wang Lixin, Liu Sijin
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.
Chem Res Toxicol. 2015 Mar 16;28(3):460-9. doi: 10.1021/tx500422q. Epub 2014 Dec 1.
Lead (Pb) is a heavy metal with considerable environmental contamination. It is toxic to diverse cells and has been reported to cause a wide array of detrimental health problems including neurological disorders and anemia. In light of the mechanisms underlying Pb-induced anemia, the current understanding is still limited, in spite of efforts for years. Our previous studies recognized a protective role for the heme-regulated eIF2α kinase (Hri) in erythroid cells against oxidative stress exerted by arsenic and cadmium. Whether Hri is involved in Pb-induced hemolytic stress has not been scrutinized. In the current study, to more stringently address this question, we looked into erythropoiesis upon Pb(NO3)2 exposure by using an in vivo mouse model and ex vivo cultured E14.5 fetal liver cells. Diagnoses of hemolytic anemia, decreased red cell count, reduced hemoglobin concentration, and elevated bilirubin level were observed in Hri knockout (Ko) mice only, upon low-dose Pb administration. Significantly different from Ko mice, wild type (Wt) mice did not develop hemolytic anemia. Enforced extramedullary and medullary erythropoieses were found in Ko mice with Pb exposure. However, anemia was not compensated in Hri-deficient mice, as in vivo and ex vivo results manifested that expanded Hri-null erythroid precursors experienced blocked differentiation and enhanced apoptosis, leading to ineffective erythropoiesis under Pb exposure. Additionally, Pb treatment also promoted hepcidin expression and consequentially increased splenic iron storage, resulting in restrained iron availability for erythropoiesis. All considered, Hri-null erythroid precursors were prone to Pb-induced hemolytic stress. Hri deficiency gave rise to ineffective erythropoiesis and reduced iron availability for erythropoiesis under Pb stimulation, and these events together exacerbated Pb-induced hemolytic anemia. It is thus conceivable that this study delineated an indispensable function of Hri in maintaining red cell membrane integrity and guiding erythroid cell differentiation under Pb exposure. Our findings therefore deciphered a crucial role for Hri in protecting erythroid cells against Pb-induced toxicity.
铅（Pb）是一种造成严重环境污染的重金属。它对多种细胞具有毒性，据报道会引发一系列有害的健康问题，包括神经紊乱和贫血。尽管多年来一直在努力，但鉴于铅诱导贫血的潜在机制，目前的了解仍然有限。我们之前的研究认识到血红素调节的真核起始因子2α激酶（Hri）在红系细胞中对砷和镉施加的氧化应激具有保护作用。Hri是否参与铅诱导的溶血应激尚未得到仔细研究。在本研究中，为了更严格地解决这个问题，我们通过使用体内小鼠模型和体外培养的E14.5胎肝细胞来研究硝酸铅（Pb(NO3)2）暴露后的红细胞生成。仅在低剂量铅给药后，在Hri基因敲除（Ko）小鼠中观察到溶血性贫血的诊断、红细胞计数减少、血红蛋白浓度降低和胆红素水平升高。与Ko小鼠显著不同的是，野生型（Wt）小鼠未发生溶血性贫血。在暴露于铅的Ko小鼠中发现了髓外和髓内红细胞生成增强。然而，Hri缺陷小鼠的贫血并未得到代偿，因为体内和体外结果表明，扩增的Hri缺失红系前体细胞经历了分化受阻和凋亡增强，导致铅暴露下红细胞生成无效。此外，铅处理还促进了铁调素的表达，进而增加了脾脏铁储存，导致红细胞生成的铁可用性受限。综合考虑，Hri缺失的红系前体细胞容易受到铅诱导的溶血应激。Hri缺陷导致铅刺激下红细胞生成无效和红细胞生成的铁可用性降低，这些事件共同加剧了铅诱导的溶血性贫血。因此可以想象，本研究描述了Hri在铅暴露下维持红细胞膜完整性和指导红系细胞分化中不可或缺的功能。因此，我们的研究结果揭示了Hri在保护红系细胞免受铅诱导的毒性方面的关键作用。
