Key Laboratory of Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, China; Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health & West China Fourth Hospital, Sichuan University, Chengdu 610041, China; Chengdu Qingyang District for Disease Control and Prevention, Chengdu 610031, China.
Key Laboratory of Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, China; Key Laboratory of Environment and Female Reproductive Health, West China School of Public Health & West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
J Hazard Mater. 2024 Sep 5;476:134741. doi: 10.1016/j.jhazmat.2024.134741. Epub 2024 Jun 11.
Exposure to environmental BaP or its metabolite BPDE causes trophoblast cell dysfunctions to induce miscarriage (abnormal early embryo loss), which might be generally regulated by lncRNAs. IL1B, a critical inflammatory cytokine, is closely associated with adverse pregnancy outcomes. However, whether IL1B might cause dysfunctions of BaP/BPDE-exposed trophoblast cells to induce miscarriage, as well as its specific epigenetic regulatory mechanisms, is completely unexplored. In this study, we find that BPDE-DNA adducts, trophoblast cell dysfunctions, and miscarriage are closely associated. Moreover, we also identify a novel lnc-HZ06 and IL1B, both of which are highly expressed in BPDE-exposed trophoblast cells, in villous tissues of recurrent miscarriage patients, and in placental tissues of BaP-exposed mice with miscarriage. Both lnc-HZ06 and IL1B suppress trophoblast cell migration/invasion and increase apoptosis. In mechanism, lnc-HZ06 promotes STAT4-mediated IL1B mRNA transcription, enhances IL1B mRNA stability by promoting the formation of METTL3/HuR/IL1B mRNA ternary complex, and finally up-regulates IL1B expression levels. BPDE exposure promotes TBP-mediated lnc-HZ06 transcription, and thus up-regulates IL1B levels. Knockdown of either murine lnc-hz06 (which down-regulates Il1b levels) or murine Il1b could alleviate miscarriage in BaP-exposed mice. Collectively, this study not only discovers novel biological mechanisms and pathogenesis of unexplained miscarriage but also provides novel potential targets for treatment against BaP/BPDE-induced miscarriage.
暴露于环境中的 BaP 或其代谢物 BPDE 会导致滋养层细胞功能障碍，从而引发流产（早期胚胎异常丢失），这可能通常受 lncRNAs 调控。IL1B 是一种关键的炎症细胞因子，与不良妊娠结局密切相关。然而，IL1B 是否会导致 BaP/BPDE 暴露的滋养层细胞功能障碍，从而引发流产，以及其具体的表观遗传调控机制，目前仍完全未知。在本研究中，我们发现 BPDE-DNA 加合物、滋养层细胞功能障碍和流产密切相关。此外，我们还鉴定了一种新型 lnc-HZ06 和 IL1B，它们在 BPDE 暴露的滋养层细胞、复发性流产患者的绒毛组织以及 BaP 暴露的流产小鼠的胎盘组织中均高度表达。lnc-HZ06 和 IL1B 均抑制滋养层细胞迁移/侵袭，并增加细胞凋亡。在机制上，lnc-HZ06 促进 STAT4 介导的 IL1B mRNA 转录，通过促进 METTL3/HuR/IL1B mRNA 三元复合物的形成来增强 IL1B mRNA 的稳定性，最终上调 IL1B 的表达水平。BPDE 暴露促进 TBP 介导的 lnc-HZ06 转录，从而上调 IL1B 水平。敲低小鼠 lnc-hz06（下调 Il1b 水平）或小鼠 Il1b 均可缓解 BaP 暴露小鼠的流产。综上所述，本研究不仅揭示了不明原因流产的新的生物学机制和发病机制，还为 BaP/BPDE 诱导的流产提供了新的潜在治疗靶点。
