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- Title
BPDE, the Migration and Invasion of Human Trophoblast Cells, and Occurrence of Miscarriage in Humans: Roles of a Novel lncRNA-HZ09.
- Authors
Mengyuan Dai; Wenxin Huang; Xinying Huang; Chenglong Ma; Rong Wang; Peng Tian; Weina Chen; Ying Zhang; Chenyang Mi; Huidong Zhang
- Abstract
BACKGROUND: Recurrent miscarriage (RM) affects 1%–3% of pregnancies. However, in almost 50% of cases, the cause is unknown. Increasing evidence have shown that benzo(a)pyrene [B(a)P], a representative of polycyclic aromatic hydrocarbons (PAHs), is correlated with miscarriage. However, the underlying mechanisms of B(a)P/benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE)-induced trophoblast cell dysfunctions and miscarriage remain largely unknown. OBJECTIVE: The objective was to discover the role(s) of a novel lncRNA, lnc-HZ09, in the regulation of BPDE-inhibited migration and invasion of trophoblast cells and the occurrence of miscarriage. METHOD: Human trophoblast cells were treated with 0, 0.25, 0.5, 1:0, or 1:5 μM BPDE with or without corresponding lnc-HZ09 silencing or overexpression. Using these cells, we evaluated cell migration and invasion, the mRNA and protein levels of members of the PLD1/RAC1/CDC42 pathway, the regulatory roles of lnc-HZ09 in PLD1 transcription and mRNA stability, and lnc-HZ09 transcription and stability. Human villous tissues were collected from RM (푛=15) group and their matched healthy control (HC, 푛=15) group. We evaluated the levels of BPDE-DNA adducts, lnc-HZ09, and the mRNA and protein expression of members of the PLD1/RAC1/CDC42 pathway, and correlated their relative expression levels. We further constructed 0, 0.05 or 0:2 mg/kg B(a)P-induced mouse miscarriage model (each 푛=6), in which the mRNA and protein expression of members of the Pld1/Rac1/Cdc42 pathway were measured. RESULTS: We identified a novel lnc-HZ09. Human trophoblast cells treated with lnc-HZ09 exhibited less cell migration and invasion. In addition, the levels of this lncRNA were higher in villous tissues from women with recurrent miscarriage than those from healthy individuals. SP1-mediated PLD1mRNAlevels were lower, and HuR-mediated PLD1 mRNA stability was less in trophoblast cells overexpressing lnc-HZ09. However, trophoblast cells treated with MSX1 had higher levels of lnc-HZ09, and METTL3-mediated m6A methylation on lnc-HZ09 resulted in greater lnc-HZ09 RNA stability. In BPDE-treated human trophoblast cells and in RM villous tissues, MSX1-mediated lnc-HZ09 transcription and METTL3-mediated lnc-HZ09 stability were both greater. In our mouse miscarriage model, B(a)P-treated mice had lower mRNA and protein levels of members of the Pld1/Rac1/Cdc42 pathway. DISCUSSION: These results suggest that in human trophoblast cells, BPDE exposure up-regulated lnc-HZ09 level, suppressed PLD1/RAC1/CDC42 pathway, and inhibited migration and invasion, providing new insights in understanding the causes and mechanisms of unexplained miscarriage.
- Subjects
HYDROCARBON metabolism; RISK factors in miscarriages; BLASTOCYST; PROTEINS; IN vitro studies; ANIMAL experimentation; WESTERN immunoblotting; RNA; PRECIPITIN tests; CELL motility; HYDROCARBONS; RISK assessment; COMPARATIVE studies; GENE expression; MOLECULAR biology; METHYLATION; DATA analysis software; MICE
- Publication
Environmental Health Perspectives, 2023, Vol 131, Issue 1, p017009-1
- ISSN
0091-6765
- Publication type
Article
- DOI
10.1289/EHP10477