Search

Human trophoblast cells are crucial for healthy pregnancy. However, whether the defective homologous recombination (HR) repair of dsDNA break (DSB) in trophoblast cells may induce miscarriage is completely unknown. Moreover, the abundance of BRCA1 (a crucial protein for HR repair), its recruitment to DSB foci, and its epigenetic regulatory mechanisms, are also fully unexplored. In this work, it is identified that a novel lnc‐HZ10, which is highly experssed in villous tissues of recurrent miscarriage (RM) vs their healthy control group, suppresses HR repair of DSB in trophoblast cell. Lnc‐HZ10 and AhR (aryl hydrocarbon receptor) form a positive feedback loop. AhR acts as a transcription factor to promote lnc‐HZ10 transcription. Meanwhile, lnc‐HZ10 also increases AhR levels by suppressing its CUL4B‐mediated ubiquitination degradation. Subsequently, AhR suppresses BRCA1 transcription; and lnc‐HZ10 (mainly 1‐447 nt) interacts with γ‐H2AX; and thus, impairs its interactions with BRCA1. BPDE exposure may trigger this loop to suppress HR repair in trophoblast cells, possibly inducing miscarriage. Knockdown of murine Ahr efficiently recovers HR repair in placental tissues and alleviates miscarriage in a mouse miscarriage model. Therefore, it is suggested that AhR/lnc‐HZ10/BRCA1 axis may be a promising target for alleviation of unexplained miscarriage. [ABSTRACT FROM AUTHOR]

Approximately 15–25% pregnant women end with miscarriage in the world. Environmental BaP (benzo(a)pyrene) and its terminal metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) may result in the dysfunctions of trophoblast cells, which might further lead to RM (recurrent miscarriage). However, potential mechanisms remain unelucidated. In this work, we identified a novel lnc-HZ05 highly expressed and a novel miR-hz05 lowly expressed in both trophoblast cells exposed to BPDE and human RM tissues. MiR-hz05 reduces FOXO3a mRNA level by weakening its mRNA stability. Lnc-HZ05 increases the expression of FOXO3a by acting as a ceRNA for miR-hz05, and then increases P21 level and reduces CDK2 level. Thus, cell cycle is arrested at G0/G1 phase and trophoblast proliferation is inhibited. Lnc-HZ05 harboring wild-type binding site for miR-hz05, but not its mutant site, could upregulate FOXO3a expression. In normal trophoblast cells, relatively less lnc-HZ05 and more miR-hz05 activate FOXO3a/P21/CDK2 pathway and promote trophoblast proliferation, giving normal pregnancy. In RM tissues and BPDE-treated human trophoblast cells, lnc-HZ05 is increased and miR-hz05 is reduced, both of which suppress this pathway and inhibit cell proliferation, and finally lead to miscarriage. Thus, lnc-HZ05 and miR-hz05 simultaneously regulate cell cycle and proliferation of BPDE-exposed trophoblast cells and miscarriage, providing new perspectives and clinical understandings in the occurrence of unexplained miscarriage. [ABSTRACT FROM AUTHOR]

Copper pollution has attracted global environmental concern. Widespread Cu pollution results in excessive Cu accumulation in human. Epidemiological studies and animal experiments revealed that Cu exposure might have reproductive toxicity. Cuproptosis is a recently reported Cu-dependent and programmed cell death pattern. However, the mechanism by which copper exposure might cause cell cuproptosis is largely unknown. We chose trophoblast cells as cell model and found that copper exposure causes trophoblast cell cuproptosis. In mechanism, copper exposure up-regulates lnc-HZ11 expression levels, which increases intracellular Cu2+ levels and causes trophoblast cell cuproptosis. Knockdown of lnc-HZ11 efficiently reduces intracellular Cu2+ levels and alleviate trophoblast cell cuproptosis, which could be further alleviated by co-treatment with DC or TEPA. These results discover novel toxicological effects of copper exposure and also provide potential target for protection trophoblast cells from cuproptosis in the presence of excessive copper exposure. • Cu exposure leads to trophoblast cell cuproptosis. • Cu exposure suppresses Fe-S cluster, lipoylation, and mitochondrial respiration. • Cu exposure up-regulates lnc-HZ11 expression levels. • Lnc-HZ11 induces cuproptosis in copper-exposed trophoblast cells. • Knockdown of lnc-HZ11 alleviates cuproptosis in copper-exposed trophoblast cells. [ABSTRACT FROM AUTHOR]

Increasing evidences have shown that pregnant women might miscarry after exposure with environmental BaP (benzo(a)pyrene). Additionally, BPDE (benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide), the ultimate metabolite of BaP, could induce dysfunctions of human trophoblast cells. However, it is rarely correlated between miscarriage and trophoblast dysfunctions. Moreover, their underlying mechanisms are still largely unidentified. In this study, a novel lncRNA (long non-coding RNA), lnc-HZ08, was identified to be highly expressed in human recurrent miscarriage (RM) tissues and in BPDE-treated human trophoblast cells. Lnc-HZ08 acts as a RNA scaffold to interact with both PI3K and its ubiquitin ligase CBL (Cbl proto-oncogene), enhances their protein interactions, and promotes PI3K ubiquitin degradation. In RM tissues and BPDE-treated trophoblast cells, DNA methylation level in lnc-HZ08 promoter region was reduced, which promotes estrogen receptor 1 (ER)–mediated lnc-HZ08 transcription. Subsequently, this upregulated lnc-HZ08 downregulated PI3K level, suppressed PI3K/p-AKT/p-P21/CDK2 pathway, and thus weakened proliferation, migration, and invasion of human trophoblast cells, which further induces miscarriage. These results may provide novel scientific and clinical insights in the occurrence of unexplained miscarriage. [ABSTRACT FROM AUTHOR]

BPDE (benzo(a)pyren‐7,8‐dihydrodiol‐9,10‐epoxide), a metabolite of environmental carcinogenic BaP, weakens the migration and invasion of human villous trophoblast cells and may further induce miscarriage. However, the underlying mechanisms remain largely unknown. In this study, we identified that in trophoblast Swan 71 and HTR‐8/SVneo cells, miR‐hz02 upregulates the level of lnc‐HZ02, which inhibits the expression of an RNA‐binding protein HuR. HuR could interact with FAK mRNA and promote its mRNA stability, thus upregulating the FAK level and the FAK/SRC/PI3K/AKT pathway, and finally maintaining the normal migration and invasion of trophoblast cells. If trophoblast cells are exposed to BPDE, both miR‐hz02 and lnc‐HZ02 are upregulated, which reduce the level of HuR, weaken the interactions of HuR with FAK mRNA, downregulate FAK level and the FAK/SRC/PI3K/AKT pathway, and finally inhibit cell migration and invasion. This study provides a novel scientific understanding of the dysfunctions of human trophoblast cells. [ABSTRACT FROM AUTHOR]

Human trophoblast cells play important role in embryo-fetal development. However, trophoblast cells are sensitive to environmental carcinogens. Recently, we have discovered that BPDE inhibits trophoblast cell migration, invasion and proliferation, and also increases trophoblast cell apoptosis. Ferroptosis is a newly identified iron-dependent non-apoptotic programmed cell death. Whether BPDE might induce trophoblast cell ferroptosis is completely unknown. In this work, we have discovered that ferroptosis does occur in BPDE-treated human trophoblast cells. Iron metabolism up-regulates intracellular free Fe2+ level, produces excessive ROS (reactive oxygen species), and accelerates lipid peroxidation. GPX4 efficiently eliminates ROS and inhibits lipid peroxidation. Thus, ferroptosis is well suppressed due to the balance of these two pathways in healthy trophoblast cells. However, BPDE exposure could promote iron metabolism, increase intracellular free Fe2+ level, produce excessive ROS, and result in lipid peroxidation. Meanwhile, BPDE also down-regulates GPX4 expression level by promoting its proteasomal degradation, which eventually produces excessive ROS and induces lipid peroxidation. Thus, BPDE exposure induces trophoblast cell ferroptosis by unbalancing these two pathways, providing new insight in understanding BPDE-induced dysfunctions of human trophoblast cells. • BPDE exposure induces human trophoblast cell ferroptosis. • BPDE exposure increases intracellular free Fe2+ level and ROS level. • BPDE promotes GPX4 proteasomal degradation and reduces its protein level. • BPDE produces excessive ROS and induces lipid peroxidation. [ABSTRACT FROM AUTHOR]

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]