全氟化合物对妊娠期糖尿病发生及对子代近期和远期健康风险的影响及机制研究

Perfluoroalkyl substances (PFASs) were frequently detected in serum of pregnant women. However, the studies on the relationship between perinatal intrauterine exposure to PFASs and its potential health impact of mother and offspring are lacking. Our team established a large of cohort of pregnant women and their children from 2010 to 2012 with detailed documentation of clinical and biochemical profiles longitudinally from their first antenatal care visit, screening for gestational diabetes mellitus (GDM) in the mid-trimester and delivery. Based on this cohort, 2200 blood serum samples were collected and stored during early pregnancy. This current study will conduct a nested case-control study by selecting 200 GDM women and 600 non-GDM women (1:3 matched according to age, BMI and family history of diabetes) from women with stored samples. The PFASs levels will be measured in 800 stored samples by HPLC-MS/MS method. We will assess the association between maternal PFASs levels and GDM risk, and the impact on fetal outcome of maternal exposure to PFASs. The levels of plasma candidate circulating miRNA will be assayed by real-time PCR and compared between 20 GDM women and 20 non-GDM women, to analyze whether miRNA expression plays a role in the association between PFASs exposure in early pregnancy and the risk of GDM. Then, the growth and development information between 1-6 years old of their offspring will be collected by Tianjin Women and Children Health Information System. The influence of maternal PFASs levels on children growth and development will be evaluated. Among children whose mother with measured PFASs levels, 500 children aged 5 to 6 will be recruited to have anthropometric measurements, blood glucose, lipid and uric acid measurements, and neurobehavioral development evaluation. We will assess the association between maternal PFASs levels and overweight and obesity, glucose and lipid metabolism and neurobehavioral development of offspring aged 5 to 6. This study will prospectively and longitudinally evaluate the association between maternal PFASs levels during early pregnancy and GDM risk and offspring short-term and long-term health outcomes，and explore its potential mechanism. The conclusion could provide support for the establishment of related environmental standards and pollution control measures.

全氟化合物（PFASs）在孕妇血中频繁检出，但孕早期PFASs水平对母婴健康风险研究缺乏。我们在2010-2012年建立了大型母婴队列，留存孕早期血样并收集了孕期及分娩信息。拟基于上述队列用巢式病例对照研究，收集妊娠期糖尿病（GDM）200例，匹配非GDM 600例，用HPLC-MS/MS法检测留存血中PFASs水平，分析其与GDM发病关联及对分娩结局影响。通过RT-qPCR检测部分GDM和非GDM孕妇留存血中候选miRNA水平，分析miRNA表达在PFASs暴露与GDM发病关联中的作用。收集子代1-6岁健康信息，分析孕早期PFASs水平对子代生长发育影响。在子代5-6岁时，召回500例分析PFASs水平对5-6岁儿童超重肥胖、糖脂代谢及神经行为发育的影响。本研究前瞻性系统评估孕早期PFASs水平对GDM发病及子代近期/远期多系统的健康风险及可能的发病机制，为政府出台污染控制对策提供依据。

我们在2010-2012年建立了大型母婴队列，留存孕早期血样并收集了孕期及分娩信息。基于上述队列用巢式病例对照研究，收集GDM240例，匹配非GDM240例，用HPLC-MS/MS法检测留存血中32种PFASs（17种常见直链PFASs、11种PFOA和PFOS的同分异构体、4种PFASs替代物），分析其与GDM发病关联及对分娩结局影响。收集子代1-6岁健康信息，分析孕早期PFASs水平对子代生长发育影响。在子代5-6岁时召回188例分析孕早期PFASs水平对5-6岁儿童超重肥胖、糖脂代谢的影响。结果显示：1）32种PFASs中有10种均未检出，PFOA、PFNA、PFPeS、PFHxS、PFOS、PFUdA均100%检出；6:2Cl-PFESA浓度几何平均值最高，为5.21ng/mL，其次依次为PFOS4.96ng/mL、PFOA2.59ng/mL、PFPeS1.07ng/mL，其他均低于1ng/mL。2）孕早期血清PFOA、PFNA、PFPeS浓度越高，GDM发生风险越高。3）孕早期PFNA、PFDA浓度越高，子代在较低出生体重组的可能性越高。4）孕早期PFPeS、6:2Cl-PFESA、iso-PFOS、PFTrDA、TotalPFAS浓度越高，子代早产发生风险越低。5）在调整孕妇受教育年限后，孕早期6:2Cl-PFESA、PFTrDA、8:2Cl-PFESA、TotalPFAS浓度越高，越易分娩男孩。6）可能由于孕早期PFASs导致更低的出生体重，因此在子代6岁前孕早期PFASs水平与子代的年龄别体重、身长别体重、超重肥胖的发生要么是负关联（特别是6月龄、12月龄），要么是无关联，但与年龄别身长（身高）要么是正关联（特别是6月龄、12月龄），要么是无关联。7）子代在6岁后开始逆转，孕早期PFOA浓度越高，子代6岁时发生超重肥胖的风险越高；孕早期PFNA、PFDA、PFTrDA浓度越高，子代6岁出现血脂异常的风险越高。通过系统评估母体孕期PFASs暴露对GDM发生风险及对子代近期和远期的健康风险，可以在GDM病因上添加一个新颖的环境影响因子，也可以将其作为早期筛查标志物，从孕产妇人群中及早发现GDM的高危人群，在没发病前采取早期健康教育等手段，避免母子健康危害，可以为我国制定相应环境标准、规划和管理政策提供科学依据。