期刊
TOXICOLOGICAL SCIENCES
卷 162, 期 2, 页码 688-701出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfx294
关键词
Pb; neurite outgrowth; H3K9 acetylation; TSA; HDAC1; HDAC2
类别
资金
- National Key Basic Research Program of China (973 Program) [2012CB525003]
- National Science Foundation of China [81773475, 21477031, 31401671]
- Program for New Century Excellent Talents in University [NCET-12-0835]
- Key Laboratory of Xin'an Medicine Ministry of Education, Anhui University of Chinese Medicine [2015sbgj005]
Lead (Pb) prevails among the environmental hazards against human health. Although increasing evidence highlights the epigenetic roles underlying the Pb-induced neurotoxicity, the exact mechanisms concerning histone acetylation and its causative agents are still at its infancy. In the present study, the roles of histone deacetylases 1 and 2 (HDAC1/2), as well as acetylation of Lys9 on histone H3 (Ac-H3K9), in Pb-induced neurotoxicity were investigated. Pb was administered to PC12 cells at 10 lM for 24 h. And Sprague Dawley rats were chronically exposed to Pb through drinking water containing 250ppm Pb for 2 months. Owing to Pb exposure, it indicated that HDAC2 was up-regulated accompanied by Ac-H3K9 downregulation. Meanwhile, chromatin immunoprecipitation assay revealed that the changes in HDAC2 were attributed to histone H3 Lys27 trimethylation occupancy on its promoter. Blockade of HDAC2 with either Trichostatin A or HDAC2knocking down construct (shHDAC2) resulted in amelioration of neurite outgrowth deficits via increasing Ac-H3K9 levels. It implied that HDAC2 plays essential regulatory roles in Pb-induced neurotoxicity. And, coimmunoprecipitation trials revealed that HDAC2 colocalized with HDAC1, forming a so-called HDAC1/2 complex. Subsequently, it was shown that HDAC1/2 repression could markedly prevent neurite outgrowth impairment and rescue the spatial memory deficits caused by Pb exposure, unequivocally implicating this complex in the studied toxicological process. Furthermore, Notch2 maybe the functional target of the HDAC1/2 and Ac-H3K9 alterations. Our study provided insight into the precise roles of HDAC1/2 in Pb-induced neurotoxicity, and thereby provided a promising molecular target for medical intervention of neurological disorders with environmental etiology.
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