羟基/甲氧基多溴联苯醚的母体-胎儿传递与胎盘转运和屏障作用机制

Hydroxylated/methoxylated polybrominated diphenyl ethers (OH/MeO-PBDEs), which have natural sources, are the metabolites of polybrominated diphenyl ethers. They are persistent in the environment and can bioaccumulate, and can be transferred from mothers to fetuses through placentas. Because of their higher toxicity (such as capability of endocrine disruption) compared to the parent compounds (PBDEs), OH/MeO-PBDEs are more important in the health risk assessment for fetus. Higher brominated BDEs can be metabolized to lower brominated BDEs and OH/MeO-PBDEs in the human body. Currently, decabrominated diphenyl ethers are still produced and used in large amounts in China. As a result, the concentrations of OH/MeO-PBDEs in the human body and the associated health risks are expected to increase if nothing is done with decabrominated diphenyl ethers. Therefore, the investigations on the chemicals are very important to decide whether production of decabrominated diphenyl ethers should be regulated. The present project will focus on OH/MeO-PBDEs and we plan (1) to investigate the transfer efficiencies and characteristics of the chemicals from dams to fetuses by studying exposure of pregnant female rats to the chemicals; (2) to investigate the factors influencing the placental transfer and barrier effect and the transporter proteins that are involved in the transfer processes by using the BeWo cell model; (3) to screen the key transporter proteins that are involved in the processes of placental transfer and barrier. The screening will be performed by identifying the target genes with RNAi and gene transfection techniques, and establishing cell lines with the target genes being well expressed. The obtained results will help us understand the influence of exposure to OH/MeO-PBDEs on offspring, and the mechanisms of the placental transfer and barrier effect, providing an explanation to the transfer of OH/MeO-PBDEs from mothers to fetuses.

羟基/甲氧基多溴联苯醚是多溴联苯醚的代谢产物，同时还有自然源。它们有环境持久性和生物累积性，有干扰内分泌等比母体更高的毒性，可通过胎盘传递至胎儿，在胎儿健康风险评价中意义更重要。高溴的多溴联苯醚在人体可代谢为低溴的多溴联苯醚和羟基/甲氧基产物。我国还在大量生产和使用十溴联苯醚，若不采取措施，人体中这类代谢物的浓度必将升高，风险必将加大。这类化合物的研究对是否需要控制十溴联苯醚也有重要意义。项目以羟基/甲氧基多溴联苯醚为目标物，通过动物染毒研究其母体-胎儿传递效率与特征；再用BeWo细胞模型研究影响胎盘转运和屏障作用的因素及可能参与的转运蛋白；最后筛选目标基因，利用RNA干扰及基因转染等方法改变BeWo细胞中目标基因的表达，构建目标基因稳定表达的细胞，筛选出胎盘转运和屏障作用的关键转运蛋白。结果可多方位了解目标物暴露对子代的影响特征及胎盘转运和屏障作用机制，对母体-胎儿传递进行科学解释。

多溴联苯醚（PBDEs）是一类常用的溴系阻燃剂，可在人体代谢产生羟基和甲氧基多溴联苯醚（OH/MeO-PBDEs）。环境中也存在OH/MeO-PBDEs,这些污染物可以通过环境介质以及食物暴露进入人体并在人体富集。进一步，这些污染物可能通过代际传递迁移到胎儿或子代。项目利用人体（母血、脐带血、胎盘）、动物实验并结合细胞实验和理论计算研究了PBDEs、MeO-PBDEs以及PBDEs的替代品德克隆（DP）的胎盘转运与屏障作用机制。研究结果表明，PBDEs可以在胎盘和脐带血中检测出，PBDEs从母体迁移到脐带血的迁移率约0.46。动物实验结果表明，灌胃暴露吸收的PBDEs可快速到达胎盘并迁移到胎鼠，低溴PBDEs迁移速率高于高溴PBDEs，符合伪一级动力学过程。迁移过程以被动扩散为主，存在主动转运。对DP的研究发现，大分子的DP主要是通过母乳传递到胎儿，胎盘转运有限。为了进一步了解这些污染物的迁移机制，项目利用BeWo细胞单层模型，研究了各种外排蛋白和流入蛋白在MeO-PBDEs和PBDEs迁移中的作用。研究结果表明，多药耐药相关蛋白和乳腺癌耐药蛋白可能参与了MeO-PBDEs的胎盘转运过程，外排蛋白P-糖蛋白没有发现类似现象。然而，外排蛋白P-糖蛋白参与了PBDEs的胎盘转运和屏障作用。结合分子对接技术研究发现，这个过程中P-糖蛋白上的氨基酸残基与PBDEs结合从而将PBDEs外排到母体侧，这可能是胎盘屏障作用的主要机制。项目研究结果对环境有机污染物的胎盘转运与屏障作用机制的了解以及在人体健康风险，特别是对胎儿以及子代的健康风险研究中具有极为重要的科学意义。