BaP/BPDE exposure causes human trophoblast cell dysfunctions and induces miscarriage by up-regulating lnc-HZ06-regulated IL1B

• Published in: Journal of hazardous materials 2024-09, Vol.476, p.134741, Article 134741
• Main Authors: Guo, Jiarong, Zhao, Jingsong, Tian, Peng, Xu, Zhongyan, Wang, Rong, Chen, Weina, Wang, Xiaoqing, Wan, Shukun, Yang, Yang, Zhang, Huidong
• Format: Article
• Language: English
• Subjects: BaP or BPDE; Cell apoptosis, migration/invasion; Lnc-HZ06 and IL1B; M6A RNA modification; Swan 71 or HTR-8/SVneo cells; Unexplained recurrent miscarriage
• ISSN: 0304-3894; 1873-3336; 1873-3336
• DOI: 10.1016/j.jhazmat.2024.134741

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. [Display omitted] •This study reveals the association and causality of BaP/BPDE exposure with lnc-HZ06, IL1B, trophoblast cell dysfunctions, and miscarriage.•This study discovers novel regulatory mechanisms of lnc-HZ06 and IL1B.•It provides potential targets for detection and therapy of unexplained miscarriage induced by BaP/BPDE exposure.