邻苯二甲酸酯暴露与妊娠期高血压疾病的关系及机制研究

A series of studies have shown that phthalates (PAEs) can induce elevated blood pressure levels in the general population through oxidative stress injury, vascular endothelial dysfunction and inflammatory effects. Pregnant women are more sensitive to the toxic effects of environmental pollutants, however, whether PAEs could also increase the risk of hypertensive disorders of pregnancy (HDP) need to be confirmed. The project is based on an ongoing pregnancy cohort study conducted in Beijing urban area (4027 pregnant women enrolled before 14 weeks of gestation, hair and venous blood samples in first trimester collected during the recruitment, and 391 cases of HDP having been followed up, respectively). In the cohort, we select 200 women with HDP and 200 controls matched by ethnicity, age, and gestational age, respectively. The nested case-control study design is used for measurement of hair PAEs, serum oxidative stress, endothelial dysfunction, as well as inflammatory cytokines. We aim to explore the impact of pregnant women’s PAEs exposure on the risk of HDP and its possible mechanisms. Our considerable progress has been made to explore the effects of environmental pollution on HDP, which could lay a solid foundation for exploring the causes and mechanism of PAEs on HDP. The relevant results may provide evidence for the etiology and pathogenesis of HDP and have important reference value for the prevention of HDP.

系列研究表明邻苯二甲酸酯（PAEs）可通过氧化应激损伤、血管内皮功能障碍和炎症效应诱发一般人群血压水平升高。孕妇对环境污染物的致毒效应更为敏感，但PAEs是否会增加妊娠期高血压疾病（HDP）的发生风险有待证实。本项目拟基于正在北京城区开展的孕期队列（该队列已募集孕14周内妇女4027名，采集孕早期发样和静脉血并保存，已随访观察到HDP病例391例），开展巢式病例对照研究，选取200例HDP病例，并按照民族、年龄、孕周匹配200例对照，测定孕早期头发PAEs浓度，以及血清氧化应激、血管内皮功能障碍和炎性因子标志物水平，以期探讨孕早期PAEs暴露水平对HDP发生风险的影响及其可能机制。申请人前期在HDP的环境影响因素和发病机制研究方面有较好基础，可为探索PAEs对HDP的影响及机制提供重要支持。预期本项目研究结果可为HDP的病因及发病机制提供证据，并对我国HDP的预防具有一定参考价值。

系列研究表明邻苯二甲酸酯（PAEs）可通过氧化应激损伤效应诱发一般人群血压水平升高。孕妇对环境污染物的致毒效应更为敏感，但PAEs是否会增加妊娠期高血压疾病（HDP）的发生风险有待证实。本项目基于正在北京城区开展的孕期队列，持续募集孕早期妇女病随访妊娠结局，采集孕早期发样和静脉血并保存，我们纳入430名孕妇（215名HDP病例，随机选取215名对照）作为人群关联结果的研究分析对象，检测头发PAEs水平和血清8-OhdG水平。结果提示与低水平头发DEEP浓度相比，高水平DEEP浓度与妊娠高血压存在显著正相关(调整OR = 1.84, 95% CI: 1.07–3.17)。在孕前BMI<24 kg/m2的孕妇中，DEEP对妊娠高血压的ORs较总体孕妇人群更高，而在孕前BMI≥24 kg/m2的孕妇中，DEEP与妊娠高血压无显著相关性。上述结果提示，适当体重的孕妇在暴露于较高水平的DEEP时，比超重或肥胖的孕妇更容易发生妊娠高血压。我们进一步检测残余孕妇发样内部的各种金属水平，我们在318名（41例先兆子痫，匹配277名健康对照）孕妇中探索各种金属水平与HDP的关系，研究结果提示高浓度铅元素组的子痫前期相对风险是低浓度铅元素组的2.53倍（调整OR=2.53, 95% CI: 1.31-4.86），在调整混杂因素模型中，混合WQS指数依然与子痫前期风险显著相关（P=0.035），按照贡献值依次为铅>砷>锑>铬>汞>银>锡。铅元素对混合WQS指数的贡献值最大，在调整混杂模型中为39.77%。本团队还利用脂多糖诱导子痫前期小鼠模型，在模型组（n=13）和对照组（n=8）中通过通过超高效液相色谱-质谱联用技术非靶向检测胎盘的代谢物水平，发现氨基酸可能是子痫前期诱发的可能小分子机制。本项目研究结果可为HDP的病因及发病机制提供证据，并对我国HDP的预防具有一定参考价值。