Bisphenol B Exposure Induces Miscarriage by Suppressing Migration/Invasion and Migrasome Formation

Unexplained miscarriage (UM) remains challenge due to unclear pathogenesis and biological mechanisms. BPB (Bisphenol B), an extensively used endocrine disrupting chemical, has been widely detected out in human. Migrasomes are newly identified cellular organelles with a large number of unknown functions. However, whether and how BPB exposure may suppress migrasome formation (MF) to induce miscarriage are completely unknown. In this study, it is found that higher urinary BPB levels are associated with the suppressed MF in villous tissues and unexplained miscarriage. It is further confirmed that BPB exposure suppresses MF in the mouse placenta and thus induces miscarriage. Supplement with Pkca or Tspan4, two essential proteins for migration/invasion (MI) and MF, can efficiently treat against BPB-induced miscarriage. In biological mechanisms, BPB up-regulates ER levels, enhances its interactions with the lnc-HZ04 promoter region, and thus promotes ER-mediated lnc-HZ04 transcription. Subsequently, lnc-HZ04 suppresses TCF4-mediated PKCA transcription and subsequently suppresses MI and MF. Collectively, this study not only identifies BPB as a novel risk factor for unexplained miscarriage, discovers novel pathogenesis and biological mechanisms in BPB-induced miscarriage, but also provides potential targets for treatment against unexplained miscarriage.