附睾 RNase T2 通过附睾小体-精子相互作用导致弱精症和代际代谢紊乱。
Epididymal RNase T2 contributes to astheno-teratozoospermia and intergenerational metabolic disorder through epididymosome-sperm interaction.
机构信息
Department of Histology, Embryology, Genetics and Developmental Biology, Shanghai Key Laboratory for Reproductive Medicine, Shanghai Jiao Tong University School of Medicine, No.280, Chongqing Road (South), Shanghai, 200025, China.
Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
出版信息
BMC Med. 2023 Nov 22;21(1):453. doi: 10.1186/s12916-023-03158-1.
BACKGROUND
The epididymis is crucial for post-testicular sperm development which is termed sperm maturation. During this process, fertilizing ability is acquired through the epididymis-sperm communication via exchange of protein and small non-coding RNAs (sncRNAs). More importantly, epididymal-derived exosomes secreted by the epididymal epithelial cells transfer sncRNAs into maturing sperm. These sncRNAs could mediate intergenerational inheritance which further influences the health of their offspring. Recently, the linkage and mechanism involved in regulating sperm function and sncRNAs during epididymal sperm maturation are increasingly gaining more and more attention.
METHODS
An epididymal-specific ribonuclease T2 (RNase T2) knock-in (KI) mouse model was constructed to investigate its role in developing sperm fertilizing capability. The sperm parameters of RNase T2 KI males were evaluated and the metabolic phenotypes of their offspring were characterized. Pandora sequencing technology profiled and sequenced the sperm sncRNA expression pattern to determine the effect of epididymal RNase T2 on the expression levels of sperm sncRNAs. Furthermore, the expression levels of RNase T2 in the epididymal epithelial cells in response to environmental stress were confirmed both in vitro and in vivo.
RESULTS
Overexpression of RNase T2 caused severe subfertility associated with astheno-teratozoospermia in mice caput epididymis, and furthermore contributed to the acquired metabolic disorders in the offspring, including hyperglycemia, hyperlipidemia, and hyperinsulinemia. Pandora sequencing showed altered profiles of sncRNAs especially rRNA-derived small RNAs (rsRNAs) and tRNA-derived small RNAs (tsRNAs) in RNase T2 KI sperm compared to control sperm. Moreover, environmental stress upregulated RNase T2 in the caput epididymis.
CONCLUSIONS
The importance was demonstrated of epididymal RNase T2 in inducing sperm maturation and intergenerational inheritance. Overexpressed RNase T2 in the caput epididymis leads to astheno-teratozoospermia and metabolic disorder in the offspring.
背景
附睾对于精子在睾丸后的发育至关重要，这个过程被称为精子成熟。在此过程中，通过附睾-精子之间的蛋白质和小非编码 RNA（sncRNA）交换实现了受精能力的获得。更重要的是，附睾上皮细胞分泌的附睾衍生外泌体将 sncRNA 转移到成熟精子中。这些 sncRNA 可以介导种间遗传，进一步影响它们后代的健康。最近，调节附睾精子成熟过程中精子功能和 sncRNA 的关联和机制越来越受到关注。
方法
构建了附睾特异性核糖核酸酶 T2（RNase T2）敲入（KI）小鼠模型，以研究其在发育精子受精能力中的作用。评估了 RNase T2 KI 雄性的精子参数，并对其后代的代谢表型进行了特征描述。Pandora 测序技术对精子 sncRNA 表达谱进行了分析和测序，以确定附睾 RNase T2 对精子 sncRNA 表达水平的影响。此外，还在体外和体内证实了环境应激下附睾上皮细胞中 RNase T2 的表达水平。
结果
RNase T2 的过表达导致小鼠附睾头部严重的弱精症和畸形精子症，并导致后代获得代谢紊乱，包括高血糖、高血脂和高胰岛素血症。Pandora 测序显示，与对照精子相比，RNase T2 KI 精子的 sncRNA 图谱发生了改变，特别是 rRNA 衍生的小 RNA（rsRNA）和 tRNA 衍生的小 RNA（tsRNA）。此外，环境应激上调了附睾头部的 RNase T2。
结论
附睾 RNase T2 在诱导精子成熟和种间遗传方面的重要性得到了证明。附睾头部过表达 RNase T2 会导致精子弱畸形和后代代谢紊乱。
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