孕期镉暴露对胎盘类固醇激素分泌的影响及其与子痫前期关系的研究

Preeclampsia, one of the most common medical complication of pregnancy, it’s pathogen is not fully understood. Since preeclampsia is a pregnancy-related disorder and symptoms of preeclampsia disappear quickly after delivery, it is rational to suppose that the placenta may play a central role in the pathogenesis of preeclampsia. Cadmium is a widespread, highly toxic environmental pollutant, which can acting as endocrine disruptor. In the status of pregnancy, pregnant women and fetus are increased sensitivity to cadmium toxicity. It’s well known that cadmium can lead to hypertension in animal model, while the relationship between preeclampsia and cadmium is unclear. Previous experiments found that cadmium exposure during pregnancy induce symptoms of preeclampsia in pregnant rats and fetal growth restriction, and result in increasing the level of glucocorticoids in maternal and placental. Since placenta is a temporary endocrine organ, we investigate placental endocrine function disrupted by cadmium in different gestational age, especially on synthesis and regulation of steroid hormones production. This research focus on the relationship between cadmium and preeclampsia and it’s toxicological effects on development of preeclampsia and fetal growth. The effect of different concentrations of cadmium on steroid hormones synthesis and regulation in the placenta and the underlying mechanisms was further explored systematically at tissue, cell and molecular level. This study provides the theoretical basis for cadmium induced preeclampsia through toxicological effects on endocrine function of placenta. We highlight the important role of the placenta in preeclampsia and provide the basis for the management of preeclampsia.

子痫前期是妊娠期特有的疾病，其病因不明，子痫前期的孕妇分娩后相关症状迅速消失，提示胎盘系子痫前期发生的重要“基地”。镉是一种非常重要的工业、环境毒物，具有内分泌干扰物的特性。孕妇及胎儿作为高危人群对镉污染暴露更为易感。镉与高血压的关系为人们所认识，而与子痫前期的关系尚不明确。前期实验发现镉诱发孕鼠出现子痫前期症状和胎儿宫内生长迟缓，并导致孕鼠及胎盘糖皮质激素水平升高。胎盘是个临时的内分泌器官，本研究通过镉对不同孕周胎盘内分泌功能特别是类固醇激素分泌与调节的干扰，了解镉在子痫前期发病方面的特殊的毒理作用及其对胎儿生长发育的影响。并进一步从组织，细胞和分子水平系统深入探讨不同浓度镉干扰胎盘类固醇激素生成的作用途径与调节机制，为镉对孕期胎盘内分泌干扰毒性提供理论基础。本课题通过胎盘内分泌失衡探索胎盘在子痫前期发生中的重要作用，为子痫前期的防治策略提供依据。

本课题探讨镉中毒与子痫前期发生发展及胎儿发育的关系。阐明镉通过干扰胎盘局部糖皮质激素的合成以及对母体免疫系统的影响和调控诱发子痫前期。通过临床研究比较镉在子痫前期及正常妊娠母血及脐血的浓度的差异，与健康孕妇相比先兆子痫妇女的血液和胎盘镉水平增加有统计学意义。两组脐带血中的镉含量没有差异。在先兆子痫组中，高镉状态与出生体重下降显著相关。采用不同剂量镉给孕鼠腹腔注射，发现怀孕后大鼠予注射0.5mg/kg/d的镉，成功诱发孕鼠出现高血压及蛋白尿临床症状，肾小球内皮增生，胎盘异常等病理损伤以及胎儿宫内生长迟缓，符合子痫前期样的症状及病变特征。接着从体外细胞培养，从组织，细胞和分子水平系统探讨镉诱发子痫前期作用的原理及调节机制。注射0.5mg/kg/d镉的孕鼠，大鼠胎盘皮质酮和孕鼠、胎儿血浆皮质酮水平均增加。21羟化酶（CYP21）、11beta-羟化酶（CYP11B1）和皮质激素合成所必需的酶的表达在镉暴露胎盘中亦增加。免疫组化的结果显示CYP11B1表达于大鼠胎盘的迷路区，人胎盘的合体滋养层细胞的胞膜，在子痫前期的表达明显高于对照组。用1µM的镉刺激JEG-3细胞24h后，CYP11A1及CYP11B1基因及蛋白的表达明显升高。主要的负性调节局部糖皮质激素水平的酶，11β-羟基类固醇脱氢酶（11beta-hsd2），在镉暴露的胎盘中降低。子痫前期胎盘免疫组化的结果显示与基因表达一致。用1µM的镉刺激JEG-3细胞24h后，11β-HSD2基因及蛋白的表达明显下降。胎盘局部分泌的糖皮质激素不受ATCH及cAMP的调控。同时低剂量氯化镉激活雌激素受体上调B淋巴细胞中活化诱导的胞嘧啶核苷脱氨酶的表达，从而促进血管紧张素II1型受体自身抗体产生过多，激活补体，造成器官损伤，最终出现子痫前期样症状。总之，母体循环中镉水平升高可能增加子痫前期的风险。胎盘在病理情况下可以从头独立合成糖皮质激素，镉通过刺激胎盘皮质激素合成酶的表达和减少糖皮质激素的灭活使血皮质酮的浓度的升高以及通过免疫调控，促进子痫前期的发生和胎儿宫内生长迟缓。