Male germ cell apoptosis and epigenetic histone modification induced by Tripterygium wilfordii Hook F.
Male germ cell apoptosis and epigenetic histone modification induced by Tripterygium wilfordii Hook F.
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雷公藤诱导的雄性生殖细胞凋亡和表观遗传组蛋白修饰。
DOI：
10.1371/journal.pone.0020751
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Xiong J;Wang H;Guo G;Wang S;He L;Chen H;Wu J
雷公藤多苷是一种用于治疗类风湿性关节炎的中草药，被认为是一种影响哺乳动物精子的可逆抗生育药物。然而，这种效应背后的机制尚不清楚。为了研究GTW对精子发生影响的可能机制，我们给4组4周龄雄性小鼠注射了不同剂量的GTW。我们发现，GTW治疗40天后，生殖细胞数量呈剂量依赖性减少，凋亡细胞从低剂量组增加到高剂量组。在同一时期，gtw处理的睾丸生殖细胞中组蛋白H3赖氨酸9 （H3K9me2）的二甲基化水平下降。此外，从6日龄小鼠中分离精原干细胞（SSCs），以评估GTW或雷公藤甲素对SSCs发育的可能影响。我们发现，与对照组相比，GTW或雷公藤甲素处理的SSCs中凋亡发生率显著升高，H3K9me2二甲基化水平显著降低。因此，这些数据提示gtw诱导的细胞凋亡可能是导致小鼠生育能力受损的原因。这种损害可以追溯到精子形成的早期阶段。GTW还影响精子发生过程中H3K9的表观遗传修饰。分子动力学模拟表明，雷公藤甲素和二甲基化或三甲基化的H3K9可能与EED（胚胎外胚层发育）有相似的相互作用机制。这些候选的激活机制为gtw诱导性腺毒性的途径提供了初步的了解，这对进一步的研究和临床应用至关重要。
Multiglycosides of Tripterygium wilfordii Hook f (GTW), a Chinese herb-derived medicine used as a remedy for rheumatoid arthritis, are considered to be a reversible anti-fertility drug affecting the mammalian spermatids. However, the mechanism behind this effect is still unknown. To study the possible mechanism behind the impact of GTW on spermatogenesis, we administered 4 groups of 4-week-old male mice with different doses of GTW. We found a dose-dependent decrease in the number of germ cells after 40 days of GTW treatment, and an increase in apoptotic cells from the low-dose to the high-dose group. During this same period the dimethylated level of histone H3 lysine 9 (H3K9me2) in GTW-treated testes germ cells declined. Additionally, spermatogonial stem cells (SSCs) from 6-day-old mice were isolated to evaluate the possible effect of GTW or triptolide on development of SSCs. We found a significantly higher incidence of apoptosis and lower dimethylation level of H3K9me2 in the SSCs of GTW or triptolide treatment than in controls. Thus, these data suggest that the GTW-induced apoptosis might be responsible for the fertility impairment in mice. This damage could be traced back to the early stages of spermatogenesis. GTW also affected the epigenetic modification of H3K9 in spermatogenesis. Molecular dynamics simulation suggested that triptolide and dimethylated or trimethylated H3K9 might have similar interaction mechanisms with EED (embryonic ectoderm development). These candidate activation mechanisms provide the first glimpse into the pathway of GTW-induced gonad toxicity, which is crucial for further research and clinical application.
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DOI：
10.1098/rstb.2010.0026
发表时间：
2010-05-27
期刊：
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
影响因子：
--
作者：
Phillips BT;Gassei K;Orwig KE
通讯作者：
Orwig KE
DOI：
10.1073/pnas.0406325101
发表时间：
2004-11-23
影响因子：
11.1
作者：
Khalil, AM;Boyar, FZ;Driscoll, DJ
通讯作者：
Driscoll, DJ
影响因子：
15
作者：
Chen, Hai-Feng;Luo, Ray
通讯作者：
Luo, Ray
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
--
作者：
CLERMONT, Y
通讯作者：
CLERMONT, Y