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

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. Environmental Implication Benzo (a) pyrene (BaP), a typical representative of polycyclic aromatic hydrocarbons, and its ultimate metabolite benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), belong to persistent organic pollutants and endocrine disrupting chemicals, which are inevitable chemical pollutants and have shown genetic toxicity, mutagenicity, and carcinogenicity in human. This study reveals the association and causality of BaP/BPDE exposure with lnc-HZ06, IL1B, trophoblast cell dysfunctions, and miscarriage, discovers novel regulatory mechanisms of lnc-HZ06 and IL1B, and also provides potential targets for detection and therapy of unexplained miscarriage induced by BaP/BPDE exposure.The chemicals used in this study do not affect the human body or the environment and are well under control.