Liang Tingting, Xie Jiayu, Zhao Jingsong, Huang Wenxin, Xu Zhongyan, Tian Peng, Mi Chenyang, Dai Mengyuan, Zhang Shuming, Zhang Huidong
Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health & West China Fourth Hospital, Sichuan University, Chengdu, 610041, China.
Cell Biol Toxicol. 2021 Dec;37(6):951-970. doi: 10.1007/s10565-021-09583-3. Epub 2021 Feb 10.
Normal pregnancy is essential for human reproduction. However, environmental BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) induce dysfunctions of human trophoblastic cells, which could further result in miscarriage. Yet, the molecular mechanisms remain poorly understood. In this work, a novel lnc-HZ03 and a novel miR-hz03 were identified. Both lnc-HZ03 and miR-hz03 were highly expressed in human recurrent miscarriage villous tissues and in BPDE-exposed trophoblastic cells. Lnc-HZ03 and miR-hz03 upregulated each other, forming a positive feedback loop. MiR-hz03 could also upregulate p53 level by enhancing its mRNA stability. Both lnc-HZ03 and p53 mRNA contained the target site for miR-hz03 and could directly interact with miR-hz03. It was this target site instead of its mutant on lnc-HZ03 that regulated p53 expression. Subsequently, the upregulated p53 facilitated SAT1 transcription and enhanced SAT1-catalyzed spermine metabolism, which further resulted in trophoblastic cell apoptosis and induced miscarriage. All together, the p53/SAT1 pathway upregulated by lnc-HZ03 and miR-hz03 could promote BPDE-induced human trophoblastic cell apoptosis and the occurrence of miscarriage, shedding novel light on the causes of miscarriage. Graphical abstract Lnc-HZ03 and miR-hz03 regulate the occurrence of recurrent miscarriage (RM). In human trophoblastic cells, lnc-HZ03 upregulates miR-hz03 level. MiR-hz03 increases the RNA stability of lnc-HZ03 and p53 mRNA. P53 promotes SAT1 transcription and reduces its cellular spermine content, resulting in cell apoptosis. Under normal conditions, lnc-HZ03/miR-hz03 and p53/SAT1 pathways are downregulated, maintaining normal pregnancy. After exposure to BPDE, lnc-HZ03/miR-hz03 and p53/SAT1 pathways are upregulated and finally induce miscarriage.
正常妊娠对人类生殖至关重要。然而，环境中的苯并(a)芘（BaP）及其代谢产物苯并(a)芘 - 7,8 - 二氢二醇 - 9,10 - 环氧化物（BPDE）会导致人滋养层细胞功能障碍，进而可能导致流产。然而，其分子机制仍知之甚少。在这项研究中，鉴定出了一种新型长链非编码RNA lnc - HZ03和一种新型微小RNA miR - hz03。lnc - HZ03和miR - hz03在人复发性流产绒毛组织和BPDE处理的滋养层细胞中均高表达。lnc - HZ03和miR - hz03相互上调，形成一个正反馈环。miR - hz03还可通过增强p53的mRNA稳定性来上调p53水平。lnc - HZ03和p53 mRNA均含有miR - hz03的靶位点，并能直接与miR - hz03相互作用。正是lnc - HZ03上的这个靶位点而非其突变体调节p53的表达。随后，上调的p53促进精胺乙酰转移酶1（SAT1）转录并增强SAT1催化的精胺代谢，进而导致滋养层细胞凋亡并引发流产。总之，lnc - HZ03和miR - hz03上调的p53/SAT1通路可促进BPDE诱导的人滋养层细胞凋亡及流产的发生，为流产原因提供了新的线索。图形摘要：lnc - HZ03和miR - hz03调节复发性流产（RM）的发生。在人滋养层细胞中，lnc - HZ03上调miR - hz03水平。miR - hz03增加lnc - HZ03和p53 mRNA的RNA稳定性。p53促进SAT1转录并降低其细胞内精胺含量，导致细胞凋亡。在正常情况下，lnc - HZ03/miR - hz03和p53/SAT1通路下调，维持正常妊娠。暴露于BPDE后，lnc - HZ03/miR - hz03和p53/SAT1通路上调，最终导致流产。
