Division of Urology, Rhode Island Hospital, Providence, RI, USA; Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.
Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.
Reprod Toxicol. 2021 Sep;104:44-51. doi: 10.1016/j.reprotox.2021.06.012. Epub 2021 Jun 24.
Assessing male reproductive toxicity of environmental and therapeutic agents relies on the histopathology of the testis and epididymis in a pre-clinical setting. Animal histopathology poorly correlates with human sperm parameters, and none of these current methods are strong indicators of sperm health or reproductive potential. Therefore, there is an urgent need to identify a translatable, non-invasive and reliable approach to monitor environmental and therapeutic agents' effects on male reproductive health. mRNA sequences were analyzed in mouse, rat and human sperm samples to identify sperm transcriptomic similarities across species that could be used as biomarkers to predict male reproductive toxicity in animal models. Semen specimens were collected from men aged 18 to 55 years with proven fertility. Rat and mouse semen specimens were collected via needle punctures of the cauda epididymides. Sperm RNAs were extracted using an optimized sperm RNA isolation protocol and subjected to polyA-purified mRNA-sequencing. Bioinformatics analyses, including differential abundance and gene set enrichment analysis, were used to investigate the biological and molecular functions of all shared and differentially abundant transcripts across species. Transcriptome profiling identified 6,684 similarly expressed transcripts within the three species of which 1,579 transcripts were found to be involved in spermatogenic functions. Our findings have shown that sperm transcriptome is highly species dependent, however, there are some key similarities among transcripts that are required for fertility. Based on these similarities, sperm mRNA biomarker may be developed to monitor male reproductive toxicity where rodent models would make suitable laboratory substitutes for human.
在临床前阶段，评估环境和治疗剂对男性生殖毒性依赖于睾丸和附睾的组织病理学。动物组织病理学与人类精子参数相关性较差，目前这些方法都不是精子健康或生殖潜能的强有力指标。因此，迫切需要确定一种可转化、非侵入性和可靠的方法来监测环境和治疗剂对男性生殖健康的影响。分析了小鼠、大鼠和人精子样本中的 mRNA 序列，以鉴定跨物种的精子转录组相似性，这些相似性可作为生物标志物，用于预测动物模型中的男性生殖毒性。从年龄在 18 至 55 岁之间、具有生育能力的男性中收集精液标本。通过对附睾尾部进行针刺收集大鼠和小鼠的精液标本。使用优化的精子 RNA 分离方案提取精子 RNA，并进行 polyA 纯化 mRNA 测序。使用生物信息学分析，包括差异丰度和基因集富集分析，研究所有共享和跨物种差异丰度转录本的生物学和分子功能。转录组分析鉴定出 6684 个在三个物种中表达相似的转录本，其中 1579 个转录本被发现参与精子发生功能。我们的研究结果表明，精子转录组高度依赖于物种，但对于生育能力而言，一些关键的相似转录本是必需的。基于这些相似性，可能开发精子 mRNA 生物标志物来监测男性生殖毒性，其中啮齿动物模型可以作为人类的合适实验室替代物。
