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Bisphenol B Exposure Induces Miscarriage by Suppressing Migration/Invasion and Migrasome Formation
Wenxin Huang1, Manli Wang1, Yi Sun1
1Research Center for Environment and Female Reproductive Health, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, China.
Abstract:
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.
Insights
Bisphenol B (BPB) exposure suppresses migrasome formation, leading to unexplained miscarriage. Supplementation with Pkca or Tspan4 offers a potential treatment against BPB-induced pregnancy loss.
Area of Science:
- Reproductive Biology
- Endocrinology
- Cell Biology
Background:
- Unexplained miscarriage (UM) pathogenesis is poorly understood.
- Bisphenol B (BPB) is an endocrine-disrupting chemical found in humans.
- Migrasomes are newly identified organelles with largely unknown functions.
Purpose of the Study:
- To investigate the association between BPB exposure and unexplained miscarriage.
- To explore the role of BPB in suppressing migrasome formation (MF).
- To elucidate the underlying biological mechanisms of BPB-induced miscarriage.
Main Methods:
- Association study of urinary BPB levels with MF in villous tissues.
- In vivo studies using mouse models to assess BPB effects on placental MF and miscarriage.
- Investigating the molecular pathway involving ER, lnc-HZ04, and PKCA.
Main Results:
- Higher urinary BPB levels correlate with suppressed MF and UM.
- BPB exposure in mice suppresses placental MF and induces miscarriage.
- Pkca or Tspan4 supplementation mitigates BPB-induced miscarriage.
- BPB up-regulates ER, promoting lnc-HZ04 transcription, which suppresses PKCA, impacting migration/invasion (MI) and MF.
Conclusions:
- BPB is identified as a novel risk factor for unexplained miscarriage.
- A new pathogenic pathway for BPB-induced miscarriage involving ER-mediated lnc-HZ04 and PKCA suppression is discovered.
- Pkca and Tspan4 represent potential therapeutic targets for BPB-induced miscarriage.
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