Li Zhen, Wang Chunhong, Zhu Jie, Bai YuE, Wang Wei, Zhou Yanfeng, Zhang Shaozun, Liu Xiangxiang, Zhou Sheng, Huang Wenting, Bi Yongyi, Wang Hong
Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, Hubei, People's Republic of China.
Hubei Key Laboratory of Allergy and Immune-Related Diseases, Wuhan, Hubei, People's Republic of China.
Environ Toxicol. 2016 Jul;31(7):830-41. doi: 10.1002/tox.22094. Epub 2014 Dec 23.
Epidemiological studies suggest that the increasing incidence of childhood leukemia may be due to maternal exposure to benzene, which is a known human carcinogen; however, the mechanisms involved remain unknown. Liver Kinase B1 (LKB1) acts as a regulator of cellular energy metabolism and functions to regulate hematopoietic stem cell (HSC) homeostasis. We hypothesize that LKB1 contributes to the deregulation of fetal or bone hematopoiesis caused by the benzene metabolite hydroquinone (HQ). To evaluate this hypothesis, we compared the effects of HQ on murine fetal liver hematopoietic stem cells (FL-HSCs) and bone marrow hematopoietic stem cells (BM-HSCs). FL-HSCs and BM-HSCs were isolated and enriched by a magnetic cell sorting system and exposed to various concentrations of HQ (0, 1.25, 2.5, 5, 10, 20, and 40 μM) for 24 h. We found that the inhibition of differentiation and growth, as well as the apoptosis rate of FL-HSCs, induced by HQ were consistent with the changes in BM-HSCs. Furthermore, G1 cell cycle arrest was observed in BM-HSCs and FL-HSCs in response to HQ. Importantly, FL-HSCs were more sensitive than BM-HSCs after exposure to HQ. The highest induction of LKB1 and adenosine monophosphate-activated protein kinase (AMPK) was observed with a much lower concentration of HQ in FL-HSCs than in BM-HSCs. LKB1 may play a critical role in apoptosis and cell cycle arrest of HQ-treated HSCs. This research has developed innovative ideas concerning benzene-induced hematopoietic toxicity or embryotoxicity, which can provide a new experimental evidence for preventing childhood leukemia. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 830-841, 2016.
流行病学研究表明，儿童白血病发病率的上升可能是由于母亲接触苯所致，苯是一种已知的人类致癌物；然而，其中涉及的机制仍不清楚。肝脏激酶B1（LKB1）作为细胞能量代谢的调节因子，对造血干细胞（HSC）的稳态起调节作用。我们假设LKB1促成了由苯代谢物对苯二酚（HQ）引起的胎儿或骨髓造血功能失调。为了验证这一假设，我们比较了HQ对小鼠胎儿肝脏造血干细胞（FL-HSCs）和骨髓造血干细胞（BM-HSCs）的影响。通过磁性细胞分选系统分离并富集FL-HSCs和BM-HSCs，然后将其暴露于不同浓度的HQ（0、1.25、2.5、5、10、20和40μM）中24小时。我们发现，HQ诱导的FL-HSCs的分化和生长抑制以及凋亡率与BM-HSCs的变化一致。此外，响应HQ，在BM-HSCs和FL-HSCs中均观察到G1期细胞周期阻滞。重要的是，暴露于HQ后，FL-HSCs比BM-HSCs更敏感。在FL-HSCs中，观察到LKB1和单磷酸腺苷激活蛋白激酶（AMPK）的最高诱导所需的HQ浓度远低于BM-HSCs。LKB1可能在HQ处理的HSCs的凋亡和细胞周期阻滞中起关键作用。本研究为苯诱导的造血毒性或胚胎毒性提出了创新思路，可为预防儿童白血病提供新的实验证据。©2014威利期刊公司。《环境毒理学》31:830 - 841，2016年。
