胎盘屏障对胚胎环境因素暴露的保护机制研究

Gene and environment interactions contribute to the etiology of major birth defects,such as congenital heart disease (CHD). Placenta is a significant barrier protecting embryos against teratogenic exposures including drugs and toxicants. P-glycoprotein (P-gp) effluxing teratogens from the fetus, which is a vital molecular switch in blood-placenta barrier. Our previous studies concerning genetic polymorphism of P-gp and the animal model of CHD induced by environmental exposure, have demonstrated placenta P-gp states play a crucial role to abate teratogenicity of drugs and toxicants. Class I HDACs are highly expressed in placental tissues. Our previous researches confirmed correlations between class I HDACs inhibition and P-gp induction in placental cells, which is highly consistent with class I HDACs inhibition resulting in drug resistance in carcinomas, accompanied with upregulation of P-gp. Meanwhile, the inhibitory functions targeting class I HDACs, found in bioactive components in dietary, provide a safer way to clinically regulate placental P-gp by means of epigenetics. Therefore, elucidating the regulatory functions of class I HDACs to placental P-gp, upregulating its expressions and functions in due time, screening the specific interventional target-alleviating or blocking teratogen impairments to developing organs and systems of the embryo, will serve as a novel breakthrough to the dilemma of primary prevention to birth defects.

先天性心脏病（先心病）等重大出生缺陷的发生与环境-遗传交互作用密切相关。胎盘是保护胚胎免受毒物、药物等致畸因素暴露的重要屏障，胎盘P-糖蛋白（P-gp）是血胎屏障关键分子开关，可外排进入胎儿侧的致畸物。本团队关于P-gp基因多态性及环境暴露致先心病模型研究证实，胎盘P-gp对减少毒物、药物致畸具有重要保护作用。胎盘组织高表达I类HDACs，我们进一步研究证实在胎盘细胞中抑制I类HDACs与P-gp上调具有关联性，与抑制肿瘤细胞I类HDACs可上调P-gp导致肿瘤药物耐药现象高度吻合。食物中具有I类HDACs抑制作用的天然生物活性组分的发现，为临床提供了更为安全的胎盘P-gp表观遗传调控手段。本研究拟阐明I类HDACs对胎盘P-gp的调控作用并在妊娠期特定阶段上调其表达及功能，筛选特异性干预靶点，减少或阻断致畸物暴露对胚胎器官系统的发育损伤，从全新角度突破出生缺陷一级预防的研究瓶颈。

先天性心脏病（先心病）等重大出生缺陷的发生与环境-遗传交互作用密切相关。胎盘是保护胚胎免受毒物、药物等致畸因素暴露的重要屏障，本团队关于胎盘P-糖蛋白（P-gp）基因多态性及环境暴露致先心病模型研究证实，胎盘P-gp状态对减少毒物、药物致畸的重要保护作用。胎盘组织高表达I类HDACs，我们进一步研究证实在胎盘细胞中抑制I类HDACs与P-gp上调具有关联性。食物中具有I类HDACs抑制作用的天然生物活性组分的发现，为临床提供了更为安全的胎盘P-gp表观遗传调控手段。本研究拟阐明I类HDACs中对胎盘P-gp具有调控作用的特异性干预靶点，减少或阻断致畸物暴露对胚胎器官系统的发育损伤，从全新角度突破出生缺陷一级预防的研究瓶颈。主要研究内容包括：1）观察HDAC抑制剂对胎盘P-gp表达的影响，阐明I类HDACs与P-gp的相关性；2）明确可调控胎盘细胞P-gp表达及功能的I类HDACs类型；3）采用I类HDACs特异性siRNA，进一步在体内实验验证I类HDACs对胎盘P-gp表达及功能的调控作用；4）验证抑制I类HDACs上调胎盘P-gp对毒物致先心病的阻断作用。相关研究结果证实：1）HDAC抑制剂（SAHA、TSA）可诱导胎盘细胞P-gp表达；2）利用特异性siRNA靶向抑制胎盘细胞HDAC1/2/3表达后显示，抑制HDAC2表达可上调胎盘P-gp表达及外排功能；3）动物实验进一步验证了HDAC2对胎盘P-gp表达、药物外排功能的调控作用；4）通过邻苯二甲酸二乙酯（DEHP）致胎鼠先心病动物模型证实：抑制HDAC2上调胎盘P-gp，可降低DEHP对胎鼠死亡率、先心病发生率及心脏发育核心转录因子的影响，进一步验证了上调胎盘P-gp对毒物（塑化剂）所致先心病的阻断作用。上述研究明确了Ⅰ类HDACs介导胎盘P-gp上调对毒物致心脏发育异常的阻断作用，筛选出了增强胎盘屏障功能、降低先心病等重大出生缺陷的表观遗传调控干预靶点，为先心病的一级预防提供了实验室依据。