lncRNA-MEG3/miR-770-5p/STEAP4通路在孕期PFOS暴露致胎儿生长受限中的作用及机制

Fetal growth restriction (FGR) is one of the most significant complications in the perinatal period, and placental insufficiency of structure and function represents the cause of FGR. Studies have suggested that PFOS exposure may cause FGR; however, the mechanism remains to be elaborated. Accumulating evidences have demonstrated that the long non-coding RNA (lncRNA) MEG3 has received growing attention of the roles in the development of placenta and embryo. According to our previous studies, we have proposed that PFOS may induce unbalanced proliferation and apoptosis of placental trophoblasts cells through enhancing lncRNA-MEG3 and its intronic miR-770-5p, suppressing the target gene STEAP4, and then lead to the occurrence of FGR. In this project, we will apply the methods of molecular biology, epigenetics, bioinformatics, and systematically access the effect of PFOS on placental and embryonic development, clarify the role and mechanism of lncRNA-MEG3/miR-770-5p/STEAP4 signaling pathway in the occurrence of FGR in vivo and in vitro. This project will provide not only new theoretical evidence for the mechanisms of FGR, but also make contributions to improve the prevention and treatment of FGR, and the quality of the population health.

胎儿生长受限（FGR）是妊娠期的严重并发症之一，胎盘细胞增殖减少、过度凋亡是导致FGR发病的重要原因。母亲孕期暴露全氟辛烷磺酸盐（PFOS）可导致FGR，但机制尚未明确。近年研究发现，长链非编码RNA（lncRNA）MEG3在胎盘及胚胎生长发育过程中发挥重要的作用。我们的前期研究结果提示PFOS可能通过上调lncRNA-MEG3及其内含子miR-770-5p而抑制靶基因STEAP4表达，进而引起胎盘细胞增殖、凋亡异常，导致FGR的发生。本项目拟结合动物及细胞实验，综合应用分子生物学、表观遗传学、生物信息学等研究手段，系统研究孕期PFOS暴露对胎盘及胚胎发育的影响，阐明lncRNA-MEG3/miR-770-5p/STEAP4通路在PFOS致FGR效应中的作用与机制。本研究可为FGR的发生机制提供新的理论依据，也为FGR的临床防治、提高人口质量作出贡献。

胎儿生长受限（FGR）是妊娠期的严重并发症之一，它不仅直接影响胎儿及新生儿的健康，也会增加其成年后对多种疾病的易感性。近年来研究发现，孕期PFOS暴露是导致FGR发生的重要因素，lncRNA-MEG3在胎盘及胚胎生长发育过程中发挥重要的作用。项目组主要以lncRNA研究为切入点，应用分子生物学等研究手段，结合体内体外实验，阐明PFOS是否通过下调lncRNA-MEG3及其内含子miR-770-5p而促进靶基因PXT3表达导致FGR的发生。结果发现孕期PFOS染毒可导致小鼠FGR的发生，小鼠胎盘组织中lncRNA-MEG3、miR-770-5p基因表达下调，而靶基因PTX3 mRNA和蛋白均表达下调，从DNA甲基化角度分析MEG3异常低表达的机制。通过体外细胞模型研究PFOS致lncRNA-MEG3、miR-770-5p低表达的机制及其对靶基因PTX3的调控作用，揭示了lncRNA-MEG3、miR-770-5p在PFOS致FGR发生过程中的细胞生物学功能和分子机制，为FGR的病因学及其机制，早期预防和治疗提供理论和实践依据。