The effects of Nrf2 knockout on regulation of benzene-induced mouse hematotoxicity

被引：18

作者：

Li, Huiyao ^{[1
]}

Li, Daochuan ^{[1
]}

He, Zhini ^{[1
]}

Fan, Junling ^{[1
]}

Li, Qingye ^{[1
]}

Liu, Xiaoling ^{[1
]}

Guo, Ping ^{[1
]}

Zhang, Haiyan ^{[1
]}

Chen, Shen ^{[1
]}

Li, Qiong ^{[1
]}

Zhang, Rui ^{[1
]}

Xing, Xiumei ^{[1
]}

Zeng, Xiaowen ^{[1
]}

Zhang, Aihua ^{[2
]}

Tang, Huanwen ^{[3
]}

Dong, Guanghui ^{[1
]}

Wang, Qing ^{[1
]}

Xiao, Yongmei ^{[1
]}

Chen, Liping ^{[1
]}

Chen, Wen ^{[1
]}

机构：

[1] Sun Yat Sen Univ, Sch Publ Hlth, Dept Toxicol, Guangdong Prov Key Lab Food Nutr & Hlth, Guangzhou, Guangdong, Peoples R China

[2] Guizhou Med Univ, Key Lab Environm Pollut Monitoring & Dis Control, Minist Educ, Dept Toxicol,Sch Publ Hlth, Guiyang, Guizhou, Peoples R China

[3] Guangdong Med Univ, Dongguan Key Lab Environm Med, Sch Publ Hlth, Dongguan, Peoples R China

来源：

TOXICOLOGY AND APPLIED PHARMACOLOGY | 2018年 / 358卷

基金：

中国国家自然科学基金;

关键词：

Nrf2; Benzene-caused hematotoxicity; Hematopoietic stem/progenitor cells; Proliferation; Differentiation; HEMATOPOIETIC STEM-CELLS; OXIDATIVE STRESS; MALIGNANT-TRANSFORMATION; EPITHELIAL-CELLS; SELF-RENEWAL; DNA-DAMAGE; WORKERS; ACTIVATION; PATHWAY; GENES;

D O I：

10.1016/j.taap.2018.09.002

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：56 / 67

页数：12

共 51 条

[41] Regulation of Notch1 Signaling by Nrf2: Implications for Tissue Regeneration [J].