十溴二苯醚(BDE-209)的环境存在,对男性生殖系统有毒,是广泛的。本研究探讨了其对小鼠的毒性作用机制。结果显示,BDE-209诱导DNA损伤,减少减数分裂精子发生和卵子发生特异性碱性螺旋-环-螺旋1(Sohlh1)的启动子的表达,减数分裂相关因素致死(3)恶性脑肿瘤样2(L3MBTL2),PIWI样蛋白2(MILI),细胞周期蛋白依赖性激酶2(CDK2),细胞周期蛋白A,突触复合体蛋白1(SYCP1)和突触复合体蛋白3(SYCP3),并导致生精细胞凋亡,导致精子数量和质量下降。此外,BDE-209下调了后期促进复合物/环小体(APC/C)的水平,PIWI样蛋白1(MIWI)在延伸精子细胞的细胞质中的表达增加,并降低了RING指蛋白8(RNF8)的核水平,泛素化(ub)-H2A/ub-H2B,和鱼精蛋白1(PRM1)/鱼精蛋白2(PRM2),同时增加精子细胞中的H2A/H2B核水平。在停用BDE-209暴露后,生殖毒性持续了50天。结果表明,BDE-209通过降低Sohlh1的表达来抑制减数分裂的开始。此外,L3MBTL2的表达降低通过抑制减数分裂调节因子的表达来抑制染色体突触复合物的形成,从而影响减数分裂进程,并且还抑制组蛋白泛素化,防止鱼精蛋白替代组蛋白,通过阻止RNF8进入细胞核,这影响了精子向成熟精子的进化。
The environmental presence of decabromodiphenyl ether (BDE-209), which is toxic to the male reproductive system, is widespread. The current study investigated its mechanism of toxicity in mice. The results showed, that BDE-209 induced DNA damage, decreased the expression of the promoter of meiosis spermatogenesis- and oogenesis-specific basic helix-loop-helix 1 (Sohlh1), meiosis related-factors Lethal (3) malignant brain tumor like 2 (L3MBTL2), PIWI-like protein 2 (MILI), Cyclin-dependent kinase 2 (CDK2), Cyclin A, synaptonemal complex protein 1 (SYCP1) and synaptonemal complex protein 3 (SYCP3), and caused spermatogenic cell apoptosis, resulting in a decrease in sperm quantity and quality. Furthermore, BDE-209 downregulated the levels of anaphase-promoting complex/cyclosome (APC/C), increased the expression of PIWI-like protein 1 (MIWI) in the cytoplasm of elongating
spermatids, and decreased the nuclear levels of RING finger protein 8 (RNF8), ubiquitinated (ub)-H2A/ub-H2B, and Protamine 1 (PRM1)/Protamine 2 (PRM2), while increasing H2A/H2B nuclear levels in
spermatids. The reproductive toxicity was persistent for 50 days following the withdrawal of BDE-209 exposure. The results suggested that BDE-209 inhibits the initiation of meiosis by decreasing the expression of Sohlh1. Furthermore, the reduced expression of L3MBTL2 inhibited the formation of chromosomal synaptonemal complexes by depressing the expression of meiosis regulators affecting the meiotic progression and also inhibited histone ubiquitination preventing the replacement of histones by protamines, by preventing RNF8 from entering nuclei, which affected the evolution of
spermatids into mature sperm.