Protamine-2 Deficiency Initiates a Reactive Oxygen Species (ROS)-Mediated Destruction Cascade during Epididymal Sperm Maturation in Mice
Protamine-2 Deficiency Initiates a Reactive Oxygen Species (ROS)-Mediated Destruction Cascade during Epididymal Sperm Maturation in Mice
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DOI：
10.3390/cells9081789
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发表时间：
2020-08-01
期刊：
影响因子：
6
通讯作者：
Schorle, Hubert
中科院分区：
文献类型：
--
作者：
Schneider, Simon;Shakeri, Farhad;Schorle, Hubert
鱼精蛋白是父系精子基因组的保障。它们在精子发生过程中取代了大部分组蛋白，导致DNA超浓缩，从而保护其基因组免受环境noxa的影响。在许多研究中，受损的前污染与小鼠和人类的雄性不育有关。除了受损的DNA完整性，鱼精蛋白缺乏的人类和小鼠精子表现出多种继发性影响，包括运动力下降和头部形态异常。在这项研究中，我们使用鱼精蛋白-2（Prm 2）缺陷小鼠模型结合无标记定量蛋白质组学来破译这些效应的潜在分子过程。我们发现，精子的抗氧化能力的损失，如超氧化物歧化酶1型（SOD 1）和过氧化物酶5（PRDX 5）的关键蛋白质的下调，最终启动氧化应激介导的破坏级联在附睾精子成熟。附睾精子中8-OHdG水平升高证实了这一点，8-OHdG是氧化应激介导的DNA损伤的生物标志物。Prm 2缺陷的睾丸精子不受影响，并在卵母细胞胞浆内单精子注射（ICSI）后启动囊胚期植入前胚胎的体外正常发育。我们的研究结果为Prm 2及其下游分子对精子功能的作用提供了新的见解，并为研究前污染受损的不育男性的新治疗方案做出了重要贡献。
Protamines are the safeguards of the paternal sperm genome. They replace most of the histones during spermiogenesis, resulting in DNA hypercondensation, thereby protecting its genome from environmental noxa. Impaired protamination has been linked to male infertility in mice and humans in many studies. Apart from impaired DNA integrity, protamine-deficient human and murine sperm show multiple secondary effects, including decreased motility and aberrant head morphology. In this study, we use a Protamine-2(Prm2)-deficient mouse model in combination with label-free quantitative proteomics to decipher the underlying molecular processes of these effects. We show that loss of the sperm's antioxidant capacity, indicated by downregulation of key proteins like Superoxide dismutase type 1 (SOD1) and Peroxiredoxin 5 (PRDX5), ultimately initiates an oxidative stress-mediated destruction cascade during epididymal sperm maturation. This is confirmed by an increased level of 8-OHdG in epididymal sperm, a biomarker for oxidative stress-mediated DNA damage.Prm2-deficient testicular sperm are not affected and initiate the proper development of blastocyst stage preimplantation embryos in vitro upon intracytoplasmic sperm injection (ICSI) into oocytes. Our results provide new insight into the role ofPrm2and its downstream molecular effects on sperm function and present an important contribution to the investigation of new treatment regimens for infertile men with impaired protamination.