Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity
Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity
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DOI：
10.1016/j.taap.2007.01.001
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发表时间：
2007-04-15
影响因子：
3.8
通讯作者：
Menegola, Elena
中科院分区：
文献类型：
--
作者：
Di Renzo, Francesca;Cappelletti, Graziella;Menegola, Elena
组蛋白去乙酰化酶（HDAC）通过改变组织蛋白和非组织蛋白的构象来控制基因表达。HDAC抑制剂（HDAC inhibitors, HDACi）被认为是表观遗传治疗癌症最有前途的药物之一。最近，暴露于两种HDACi（丙戊酸和曲古斯汀a）的小鼠胚胎特定组织中的组蛋白超乙酰化与特定轴向骨骼畸形之间的密切关系已经得到证实。本研究的目的是验证硼酸（BA）是否通过类似于丙戊酸和trichostatin a相关的HDAC抑制和历史性超乙酰化的机制来诱导啮齿动物畸形。妊娠小鼠腹腔注射致畸剂量BA （1000 mg/kg，妊娠第8天）。对处理后1、3、4号胚外植体进行免疫印迹分析和抗高乙酰化历史4 （H4）抗体免疫染色，结果显示H4在体体水平高乙酰化。对胚核提取物进行HDAC酶测定。BA具有明显的HDAC抑制活性（符合混合型部分抑制机制）。动力学分析表明，BA对底物亲和力的影响因子为α =0.51，对最大速度的影响因子为β =0.70。这项工作提供了BA抑制HDAC的第一个证据，并提出了BA相关畸形诱导的分子机制。(c) 2007爱思唯尔公司版权所有。
Histone deacetylases (HDAC) control gene expression by changing histonic as well as non histonic protein conformation. HDAC inhibitors (HDACi) are considered to be among the most promising drugs for epigenetic treatment for cancer. Recently a strict relationship between histone hyperacetylation in specific tissues of mouse embryos exposed to two HDACi (valproic acid and trichostatin A) and specific axial skeleton malformations has been demonstrated. The aim of this study is to verify if boric acid (BA), that induces in rodents malformations similar to those valproic acid and trichostatin A-related, acts through similar mechanisms: HDAC inhibition and historic hyperacetylation.Pregnant mice were treated intraperitoneally with a teratogenic dose of BA (1000 mg/kg, day 8 of gestation). Western blot analysis and immunostaining were performed with anti hyperacetylated historic 4 (H4) antibody on embryos explanted 1, 3 or 4 It after treatment and revealed H4 hyperacetylation at the level of somites. HDAC enzyme assay was performed on embryonic nuclear extracts. A significant HDAC inhibition activity (compatible with a mixed type partial inhibition mechanism) was evident with BA. Kinetic analyses indicate that BA modifies substrate affinity by a factor alpha=0.51 and maximum velocity by a factor beta=0.70. This work provides the first evidence for HDAC inhibition by BA and suggests such a molecular mechanism for the induction of BA-related malformations. (c) 2007 Elsevier Inc. All rights reserved.