Institute of Life Science and School of Life Science, Nanchang University, Nanchang, China.
Traditional Chinese Medicine Department, Jilin Women and Children Health Hospital, Changchun, China.
Curr Drug Metab. 2019;20(8):665-673. doi: 10.2174/1389200220666190729130020.
Triptolide has been shown to exert various pharmacological effects on systemic autoimmune diseases and cancers. However, its severe toxicity, especially reproductive toxicity, prevents its widespread clinical use for people with fertility needs. Noncoding RNAs including lncRNAs and circRNAs are novel regulatory molecules that mediate a wide variety of physiological activities; they are crucial for spermatogenesis and their dysregulation might cause male infertility. However, whether they are involved in triptolide-induced reproductive toxicity is completely unknown.
After exposure of mice to triptolide, the total RNAs were used to investigate lncRNA/circRNA/mRNA expression profiles by strand-specific RNA sequencing at the transcriptome level to help uncover RNA-related mechanisms in triptolide-induced toxicity.
Triptolide significantly decreased testicular weight, damaged testis and sperm morphology, and reduced sperm motility and density. Remarkable deformities in sperm head and tail were also found in triptolide-exposed mice. At the transcriptome level, the triptolide-treated mice exhibited aberrant expression profiles of lncRNAs/circRNAs/mRNAs. Gene Ontology and pathway analyses revealed that the functions of the differentially expressed lncRNA targets, circRNA cognate genes, and mRNAs were closely linked to many processes involved in spermatogenesis. In addition, some lncRNAs/circRNAs were greatly upregulated or inducibly expressed, implying their potential value as candidate markers for triptolide-induced male reproductive toxicity.
This study provides a preliminary database of triptolide-induced transcriptome, promotes understanding of the reproductive toxicity of triptolide, and highlights the need for research on increasing the medical efficacy of triptolide and decreasing its toxicity.
雷公藤内酯醇已被证明对全身性自身免疫性疾病和癌症具有多种药理作用。然而，其严重的毒性，尤其是生殖毒性，阻止了它在有生育需求的人群中广泛的临床应用。非编码 RNA 包括 lncRNA 和 circRNA 是新型调节分子，它们介导广泛的生理活动；它们对精子发生至关重要，其失调可能导致男性不育。然而，它们是否参与了雷公藤内酯醇诱导的生殖毒性尚完全未知。
在将小鼠暴露于雷公藤内酯醇后，使用总 RNA 通过转录组水平的链特异性 RNA 测序来研究 lncRNA/circRNA/mRNA 表达谱，以帮助揭示 RNA 相关机制在雷公藤内酯醇诱导的毒性中的作用。
雷公藤内酯醇显著降低了睾丸重量，损害了睾丸和精子形态，降低了精子活力和密度。在雷公藤内酯醇暴露的小鼠中还发现了精子头部和尾部的明显畸形。在转录组水平上，雷公藤内酯醇处理的小鼠表现出 lncRNA/circRNA/mRNA 的异常表达谱。基因本体论和通路分析表明，差异表达的 lncRNA 靶标、circRNA 同源基因和 mRNAs 的功能与许多与精子发生相关的过程密切相关。此外，一些 lncRNA/circRNA 被极大地上调或诱导表达，暗示它们作为雷公藤内酯醇诱导的男性生殖毒性候选标志物的潜在价值。
本研究提供了雷公藤内酯醇诱导的转录组初步数据库，促进了对雷公藤内酯醇生殖毒性的理解，并强调了需要研究提高雷公藤内酯醇的医学疗效和降低其毒性。
