二噁英类物质暴露与妊娠期糖尿病关系及相关microRNA差异表达研究

Dioxin-like compounds are environmental endocrine disruptors. Experimental studies have indicated that they could disrupt the insulin synthesis, secretion and signaling pathway which could lead insulin resistance and/or β-cell dysfunction, and finally, the development of abnormal glucose metabolism. Some previous epidemiological investigations have shown that there are significant relations between the abnormal glucose metabolism and exposure to Dioxin-like compounds in human being. Abnormal glucose metabolism during pregnancy, such as gestational diabetes (GDM), has relatively high incidence..GDM can pose a seroious risk to mother and child and result in huge social burden. So, to investigate the relationship between human exposure to dioxin-like compounds and GDM, a prospectively nested case-control study will be conducted in the present research. GDM patients and mathcing healthy pregnant women would be enrolled in the final study cohort, and certain biological materials, including blood and human breast milk, and population characteristics would be collected. A method will be established to accurately determine the extreme trace levels of PCDD/Fs and PCBs in small volume of human blood sample. And then, concentrations of dioxin-like compounds and some certain pollutants in these specimans would be measured to represent the level of human exposure. A multivariate model would be established to investigate the risk of the onset of GDM resulted by dioxin-like compounds exposure, and the dose-response relationship would be tested. Furthermore, the possible role of epigenetics in GDM will be investigated by examining differential expression of microRNAs from GDM patients and healthy pregnant women. Combined with the data of human exposure to dioxin-like compounds, effect biomarkers represented the relationship between the pollutants exposure and the onset of GDM would be determined, which would be useful to explore potential epigenetic pathogenic mechanism of GDM resulted by dioxin-like compounds exposure.

二噁英类物质是典型内分泌干扰物。研究显示二噁英类物质可干扰胰岛素合成、分泌和信号通路等导致胰岛素抵抗和胰岛β细胞缺陷，发生糖代谢异常。流行病学研究表明人体二噁英类物质暴露与糖代谢异常存在可能联系。孕期糖代谢异常如妊娠期糖尿病（GDM）具有较高的发病率。鉴于GDM对患者本人和子代的严重健康威胁以及会导致极大社会的负担，本研究拟开展前瞻性研究分析二噁英类物质暴露与GDM发病关系并探讨此过程中可能的表观遗传机制。研究内容包括：开发用小体积生物样本测定二噁英类物质含量方法。采用前瞻性巢式病例对照研究设计，招募GDM患者和匹配健康对照，采集血液、母乳、尿液等样本，测定其中多种化学污染物含量表征机体暴露水平，构建多元统计模型，分析二恶英类物质暴露致GDM风险，判断因果关系，检验"剂量-效应"关系。测定microRNAs差异表达，寻找二噁英类物质暴露致GDM效应标志物，探讨可能表观遗传学机制。

研究显示二噁英类物质可干扰胰岛素合成、分泌和信号通路等导致胰岛素抵抗和胰岛β细胞缺陷，发生糖代谢异常。孕期糖代谢异常如妊娠期糖尿病（GDM）具有较高的发病率。本研究开展前瞻性研究分析二噁英类物质等典型持久性有机污染物人体暴露与GDM 发病关系并探讨此过程中可能的表观遗传机制。研究内容包括：开发用小体积生物样本测定二噁英类物质含量方法。采用前瞻性巢式病例对照研究设计，招募GDM 患者和匹配健康对照，采集血液样本，测定其中多种化学污染物含量表征机体暴露水平，构建多元统计模型，分析二恶英类物质等POPs暴露致GDM 风险，判断因果关系，检验“剂量-效应”关系。测定microRNAs 差异表达，寻找二噁英类物质暴露致GDM 效应标志物，探讨可能表观遗传学机制。.本项目首先建立了少量血清样品中PCDD/Fs、PCBs 等环境污染物测定的同位素稀释程序升温大体积进样高分辨气相色谱-高分辨磁质谱方法。同时在北京市西城区妇幼保健院招募志愿者开展巢式病例对照研究。最终招募到77名妊娠糖尿病患者组成病例组，并根据年龄作为匹配因素，按1：2匹配了１５４名健康孕妇作为对照组。采用本项目中建立的分析方法，完成了这些志愿者孕早期静脉血中PCDD/Fs, PCBs,PBDEs和PFASs等多种持久性有机污染物含量分析。通过统计分析发现了一些POPs物质是妊娠糖尿病潜在的风险因素。根据PCDD/Fs和DL-PCBs与GDM的相关系数计算了各物质的REP，为二恶英类物质毒性当量因子的重新评估提供了新的基于流行病学研究的数据。对于PFASs类物质，本项目根据这些物质的结构特点分组后发现了短链PFCAs是妊娠糖尿病的风险因素，这一发现为评估PFOA和PFOS替代物的健康风险提供了新的思路和证据。在采用芯片筛选的基础上，对于病例-对照人群血清中microRNAs 差异进行了分析。虽然在两组人群中未发现具有显著性差异的microRNAs，但是一些microRNAs在POPs暴露分组与GDM疾病分组中具有交叉重叠。这一发现提示这些microRNAs与机体POPs暴露水平和GDM 发病之间具有可能的关系，为下一步开展深入研究提供了线索。