双酚A（BPA）替代物孕期暴露对胎盘发育的影响及其分子机制

Several bisphenol analogues (BPS, BPF and BPAF), with endocrine disruption effects similar to BPA, have been produced in various applications. Epidemiological and experimental studies have shown that maternal bisphenol analogues exposure can affect the development of the offspring. In addition, abnormal placental development is the key bridge linked maternal exposure to pollutants and adverse health outcomes in the offspring. Our present study intend to explore the effects of maternal BPA analogues exposure on placental development and related molecular mechanisms. (1) We intend to establish in vitro and maternal exposure model of BPA analogues, detect the concentrations of pollutants in both sides of the in vitro model of placenta and placenta of the pregnant mice, and investigate the transplacental efficiency of these analogues and fetal growth in utero. (2) We try to explore the effects of maternal BPA analogues exposure on placental transport capacity for nutrients and vascular development by detecting placental function and evaluating the expression of key factor participated in these processes. (3) We examine the effects of maternal BPA analogues exposure on the thyroid hormone signaling pathway in the placenta in vitro and in vivo; combined with the specific thyroid receptor intervention experiment, we further determine the important role of thyroid hormone signaling pathway in the placental development. Our present study aims to provide a scientific basis for the comprehensive assessment of the toxicological effects and health risks of BPA analogues.

双酚A（BPA）替代物（BPS、BPF和BPAF等）近年来广泛应用于工业生产，且具有与BPA类似的内分泌干扰效应。流行病学和实验研究表明BPA替代物孕期暴露会影响子代生长发育，而胎盘发育异常是衔接孕期污染物暴露与子代不良健康结局的关键环节。为此，本项目拟深入探讨孕期BPA替代物暴露对胎盘发育的影响及分子机制。（1）建立BPA替代物体外暴露和孕期暴露模型，检测模拟胎盘或孕鼠胎盘两侧污染物浓度，考察受试污染物的跨胎盘效率和胎儿的宫内生长状况；（2）结合形态观察、功能检测和关键因子表达，探究孕期污染物暴露对胎盘营养物质转运功能以及血管发育的影响；（3）通过体外和体内实验考察孕期污染物暴露后胎盘组织中甲状腺激素信号通路的响应特征，结合特异性干预实验，确定甲状腺激素信号通路在胎盘发育中的重要作用。本项目旨在为全面评估BPA替代物的毒理学效应和健康风险提供科学依据。

双酚A（BPA）替代物（BPB和BPAF等）近年来广泛应用于工业生产，且具有与BPA类似的内分泌干扰效应。子代生长发育和胎盘发育稳态是衔接孕期污染物暴露与子代不良健康结局的关键环节。为此本项目建立孕期BPA及其替代物暴露模型，考察其对对胎儿发育和胎盘结构功能的影响。研究结果发现：（1）结合组织病理分析、代谢组学和PET/CT等检测手段和技术，从母体妊娠特征、胎儿发育状况、胎盘结构和血管发育等多角度全方面探讨孕期BPA/BPB/BPAF暴露的健康风险。初步发现孕期母体暴露于BPA替代物可导致妊娠后期胎儿体重升高，而BPA组则表现出相反的趋势；（2）发现孕期BPA/BPB/BPAF暴露可使胎盘营养运输功能受到干扰，并且BPB组和BPAF组的葡萄糖转运效率均高于对照组，比BPA表现出更严重的胎盘功能障碍，这可能是胎儿体重显著增加的重要诱因。此外，BPAF组和BPA组成年雌性子代的葡萄糖耐量受损，这意味着增加了罹患糖尿病的风险；（3）在上述研究结果基础上，构建了BPA/BPB/BPAF/BPS/BPE/BPF的胎盘绒毛膜滋养层细胞染毒模型。通过体外分析甲状腺激素受体对污染物的响应情况，发现BPA及其替代物均能成功地插入到TRs的配体结合腔中，诱导TRs的构象变化、静态猝灭和二级结构的改变。BPA及其替代物与TRs的相互作用触发胎盘滋养层细胞的凋亡和氧化应激水平的改变，进一步明确了甲状腺激素信号通路可能参与了BPA及其替代物介导的胎盘功能障碍。项目为成人健康受损的胎儿源性假说提供了新的证据，为BPA及其替代物可能的环境/职业暴露区域健康风险评估提供了实验基础和理论依据。