Gestational TCBPA exposure impairs placental function and fetal Development: Mechanisms of syncytialization disruption and fetal growth restriction

Introduction Tetrachlorobisphenol A (TCBPA), a BPA alternative, has been identified as a potential toxin, yet its reproductive toxicity remains poorly understood. This study aimed to investigate the effects of gestational TCBPA exposure on fetal development and placental function, focusing on syncytialization and TauT expression. Methods Pregnant ICR mice were divided into three groups: TCBPA-treated (50 mg/kg/day), vehicle-treated (corn oil), and control (water). Treatments were administered until embryonic day 12.5 (E12.5) and 18.5 (E18.5). Embryos and placentas were collected at E12.5 for histological, immunofluorescence, western blotting, and quantitative PCR analyses of placental development and fetal growth. In vitro BeWo cell experiments were conducted to assess TCBPA's effects on syncytialization. Results Gestational TCBPA exposure led to fetal growth restriction (FGR) and impaired placental development, including reduced labyrinth area, disorganized vascular patterns, and disrupted syncytialization. Key syncytialization markers, such as Syncytin1 and β-hCG, were significantly reduced, while E-Cadherin was elevated. Both the localization and expression levels of syncytiotrophoblast polarity markers MCT1 and MCT4 were decreased. Mechanistically, TCBPA downregulated the PPARγ/RXRα/SP-1 signaling pathway and reduced TauT expression. In vitro, TCBPA disrupted syncytialization in BeWo cells. Discussion Gestational TCBPA exposure disrupts placental function, particularly syncytialization, resulting in fetal growth restriction. The downregulation of Syncytin-1, β-hCG, TauT, and the altered localization and expression of MCT1 and MCT4 point to key mechanisms underlying TCBPA-induced placental dysfunction. These findings highlight the reproductive risks of TCBPA and emphasize the need for further investigation and caution in its use during pregnancy.