生命早期二噁英类化合物暴露通过慢性炎症增加糖尿病易感性的研究

Early life exposure to chemical contaminants increases the risk of chronic metabolic diseases in adulthood. Our previous studies have found that the body burden of dioxin-like compounds (DLCs), such as polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (DL-PCBs), in residents from the electronic waste (e-waste) recycling area are higher than these in other areas, and lead to the prophase of chronic inflammation. Animal experiments have proved that chronic inflammation is associated with some chronic metabolic diseases, such as diabetes. We speculate that DLCs in early life can enter the offspring through the placental barrier and cause a chronic inflammatory status, which further result in insulin resistance as well as methylation changes in diabetes susceptibility genes and glycometabolism-related genes, finally increasing the diabetes susceptibility in adulthood. To verify the above scientific hypothesis, the accumulation of DLCs in human samples including maternal (venous blood and urine) and neonatal (cord blood, placenta and umbilical cord) samples will be detected, and the interaction between DLC levels and inflammatory indicators (inflammatory mediators, maternity body temperature, blood routine examination) as well as the alterations of diabetes-related genes, glycometabolism-related genes, blood glucose and insulin will be analyzed. We hope to demonstrate the impacts of early-life exposure to DLCs on the methylation status and transcriptional level of diabetes-related genes, and to illuminate the underlying molecular mechanisms and epigenetics of increasing the diabetes susceptibility via inflammatory pathways, and to provide scientific basis for early screening and prediction of diabetes.

生命早期化学污染物暴露可增加成年期慢性代谢性疾病发生风险。我们前期研究发现电子垃圾污染区人体二噁英类化合物（DLCs: PCDDs、PCDFs、DL-PCBs）含量高于其它地区，使人体处于慢性炎症前期；动物实验证明慢性炎症与慢性代谢性疾病如糖尿病有关。我们推测生命早期DLCs可通过胎盘屏障进入子代，诱发慢性炎症，慢性炎症一方面可造成胰岛素耐受，另一方面也可导致胎儿糖尿病易感基因和糖代谢相关基因甲基化水平发生变化，增加糖尿病易感性。为验证以上科学假设，本项目将通过采集母体（静脉血、尿液）和新生儿样本（脐带血、胎盘和脐带），检测DLCs在人体蓄积水平，分析DLCs水平、炎症指标（炎症介质、产妇体温和血常规）与糖尿病相关基因的交互作用，及其对血糖、胰岛素、脂质代谢物等的影响，揭示生命早期DLCs暴露通过炎症通路，增加糖尿病易感性的分子机制和表观遗传效应，为糖尿病的早期筛查和预测预警提供科学依据。

通过以上工作，我们发现：①贵屿电子垃圾拆解区新生儿脐带血∑PCDF、∑PCDD、∑PCDD/F、∑DL-PCB、∑Marker-PCB、∑PCB、∑PBDE浓度均显著高于对照组；②较高的PM2.5浓度导致暴露于电子垃圾的孕妇PM2.5的个体每日摄入剂量较高，母体PM2.5暴露与新生儿BAI1在2个CpG处的甲基化有关；③检测新生儿的THs水平，包括TSH，FT3和FT4，发现暴露组FT4的平均水平显着高于对照组(15.40 vs. 13.97 pmol/L) ，而新生儿TSH 或FT3浓度在两个研究组之间没有显着差异；④新生儿中的甲基化可能起到介导作用，怀孕期间母亲暴露于电子废物的大气PM2.5与出生头围呈负相关；⑤检测胎盘中的多溴联苯醚污染物，暴露组胎盘中的8种多溴联苯醚同系物的含量均显著高于对照组，∑BDEs浓度中位数分别为0.84和7.05 ng/g lw，且发现胎盘中的多溴联苯醚暴露与新生儿的头围和1分钟Apgar的生理减少有关；⑥暴露组学龄前儿童血糖和血脂水平与对照组存在显著差异，提示暴露组儿童出现糖脂代谢异常的风险高于对照组，可能是增加儿童糖尿病易感性的影响因素。

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