Zhang Hao, Zha Xia, Zheng Yi, Liu Xiaoyun, Elsabagh Mabrouk, Wang Hongrong, Jiang Honghua, Wang Mengzhi
Laboratory of Metabolic Manipulation of Herbivorous Animal Nutrition, College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, P. R. China.
Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou, 225009, P. R. China.
J Anim Sci Biotechnol. 2023 Sep 11;14(1):117. doi: 10.1186/s40104-023-00919-z.
Exposure to bisphenol A (BPA), an environmental pollutant known for its endocrine-disrupting properties, during gestation has been reported to increase the risk of fetal growth restriction (FGR) in an ovine model of pregnancy. We hypothesized that the FGR results from the BPA-induced insufficiency and barrier dysfunction of the placenta, oxidative stress, inflammatory responses, autophagy and endoplasmic reticulum stress (ERS). However, precise mechanisms underlying the BPA-induced placental dysfunction, and subsequently, FGR, as well as the potential involvement of placental ERS in these complications, remain to be investigated.
In vivo experiment, 16 twin-pregnant (from d 40 to 130 of gestation) Hu ewes were randomly distributed into two groups (8 ewes each). One group served as a control and received corn oil once a day, whereas the other group received BPA (5 mg/kg/d as a subcutaneous injection). In vitro study, ovine trophoblast cells (OTCs) were exposed to 4 treatments, 6 replicates each. The OTCs were treated with 400 μmol/L BPA, 400 μmol/L BPA + 0.5 μg/mL tunicamycin (Tm; ERS activator), 400 μmol/L BPA + 1 μmol/L 4-phenyl butyric acid (4-PBA; ERS antagonist) and DMEM/F12 complete medium (control), for 24 h.
In vivo experiments, pregnant Hu ewes receiving the BPA from 40 to 130 days of pregnancy experienced a decrease in placental efficiency, progesterone (P4) level and fetal weight, and an increase in placental estrogen (E2) level, together with barrier dysfunctions, OS, inflammatory responses, autophagy and ERS in type A cotyledons. In vitro experiment, the OTCs exposed to BPA for 24 h showed an increase in the E2 level and related protein and gene expressions of autophagy, ERS, pro-apoptosis and inflammatory response, and a decrease in the P4 level and the related protein and gene expressions of antioxidant, anti-apoptosis and barrier function. Moreover, treating the OTCs with Tm aggravated BPA-induced dysfunction of barrier and endocrine (the increased E2 level and decreased P4 level), OS, inflammatory responses, autophagy, and ERS. However, treating the OTCs with 4-PBA reversed the counteracted effects of Tm mentioned above.
In general, the results reveal that BPA exposure can cause ERS in the ovine placenta and OTCs, and ERS induction might aggravate BPA-induced dysfunction of the placental barrier and endocrine, OS, inflammatory responses, and autophagy. These data offer novel mechanistic insights into whether ERS is involved in BPA-mediated placental dysfunction and fetal development.
在绵羊妊娠模型中，孕期暴露于双酚A（BPA）这种具有内分泌干扰特性的环境污染物下，据报道会增加胎儿生长受限（FGR）的风险。我们推测，FGR是由BPA诱导的胎盘功能不全、屏障功能障碍、氧化应激、炎症反应、自噬和内质网应激（ERS）所致。然而，BPA诱导胎盘功能障碍以及随后导致FGR的精确机制，以及胎盘ERS在这些并发症中的潜在作用仍有待研究。
体内实验中，16只怀有双胞胎的湖羊母羊（妊娠第40天至130天）被随机分为两组（每组8只）。一组作为对照，每天接受玉米油，而另一组接受BPA（皮下注射，5mg/kg/d）。体外研究中，绵羊滋养层细胞（OTCs）接受4种处理，每种处理6个重复。将OTCs分别用400μmol/L BPA、400μmol/L BPA + 0.5μg/mL衣霉素（Tm；ERS激活剂）、400μmol/L BPA + 1μmol/L 4-苯基丁酸（4-PBA；ERS拮抗剂）和DMEM/F12完全培养基（对照）处理24小时。
体内实验中，在妊娠40至130天接受BPA的湖羊母羊，胎盘效率、孕酮（P4）水平和胎儿体重下降，胎盘雌激素（E2）水平升高，同时A类子叶出现屏障功能障碍、氧化应激（OS）、炎症反应、自噬和ERS。体外实验中，暴露于BPA 24小时的OTCs，E2水平以及自噬、ERS、促凋亡和炎症反应的相关蛋白和基因表达增加，P以及抗氧化、抗凋亡和屏障功能的相关蛋白和基因表达下降。此外，用Tm处理OTCs会加重BPA诱导的屏障和内分泌功能障碍（E2水平升高和P4水平降低）、OS、炎症反应、自噬和ERS。然而，用4-PBA处理OTCs可逆转上述Tm的抵消作用。
总体而言，结果表明BPA暴露可导致绵羊胎盘和OTCs发生ERS，ERS的诱导可能会加重BPA诱导的胎盘屏障和内分泌功能障碍、OS、炎症反应和自噬。这些数据为ERS是否参与BPA介导的胎盘功能障碍和胎儿发育提供了新的机制见解。
