BaP/BPDE suppresses human trophoblast cell migration/invasion and induces unexplained miscarriage by up-regulating a novel lnc-HZ11 in extracellular vesicles: An intercellular study.

BPDE up-regulates lnc-HZ11, which down-regulates EGR1/NF-κB/CXCL12 pathway and suppresses trophoblast cell migration/invasion at intracellular levels. BPDE promotes donor trophoblast cells to secrete more EV-HZ11, which suppresses migration/invasion of the recipient trophoblast cells at intercellular levels, and is associated with unexplained miscarriage. Knockdown of murine lnc-Hz11 by EV-AS-Hz11 could efficiently alleviate miscarriage in BaP-exposed mice. The levels of EV-HZ11 in serum could predict the risk of miscarriage. [Display omitted] • BPDE up-regulates lnc-HZ11, which suppresses EGR1/NF-κB/CXCL12 and migration/invasion of trophoblast cells. • BPDE or lnc-HZ11 promotes trophoblast cells to secrete more EV-HZ11. • EV-HZ11 is transferred from donor cells to recipient cells and suppresses their migration/invasion. • Lnc-HZ11 and EV-HZ11 are closely associated with miscarriage. • Knockdown of murine lnc-Hz11 recovers migration/invasion and alleviates mouse miscarriage. • EV-HZ11 in serum predicts miscarriage risk. Extracellular vesicles (EVs) mediate the intercellular crosstalk by transferring functional cargoes. Recently, we have discovered that BaP/BPDE exposure suppresses trophoblast cell migration/invasion and induces miscarriage, which are also regulate by lncRNAs at intracelluar levels. However, the EVs-mediated intercellular regulatory mechanisms are completely unexplored. Specifically, whether EVs might transfer BPDE-induced toxic lncRNA to fresh recipient trophoblast cells and suppress their migration/invasion to further induce miscarriage is completely unknown. In this study, we find that BPDE exposure up-regulates a novel lnc-HZ11, which suppresses EGR1/NF-κB/CXCL12 pathway and migration/invasion of trophoblast cells. Intercellular studies show that EV-HZ11 (lnc-HZ11 in EVs), which is highly expressed in BPDE-exposed donor cells, suppresses EGR1/NF-κB/CXCL12 pathway and migration/invasion in recipient cells by transferring lnc-HZ11 through EVs. Analysis of villous tissues collected from UM (unexplained miscarriage) patients and HC (healthy control) group shows that the levels of BPDE-DNA adducts, lnc-HZ11 or EV-lnc-HZ11, and EGR1/NF-κB/CXCL12 pathway are all associated with miscarriage. Mouse assays show that BaP exposure up-regulates the levels of lnc-Hz11 or EV-Hz11, suppresses Egr1/Nf-κb/Cxcl12 pathway, and eventually induces miscarriage. Knockdown of lnc-Hz11 by injecting EV-AS-Hz11 could effectively alleviate miscarriage in BaP-exposed mice. Furthermore, EV-HZ11 in serum samples could well predict the risk of miscarriage. Collectively, this study not only discovers EVs-HZ11-mediated intercellular mechanisms that BaP/BPDE suppresses trophoblast cell migration/invasion and induces miscarriage but also provides new approach for treatment against unexplained miscarriage through EV-HZ11. [ABSTRACT FROM AUTHOR]