发育期微囊藻毒素-LR暴露致大鼠胰腺发育的损伤效应及其引发的糖尿病易感风险研究

Toxic cyanobacteria and their metabolites are widely distributed in water systems and have been recognized as a major threat to public health. However, the toxicity of cyanotoxins to human health is still largely unknown. In our previous studies, we found that exposure to microcystin (MC) inhibited cell viability and function of rat insulinoma (INS-1) cells and also altered the expression of several key genes involved in insulin secretion including the diabetes gene Pdx1. These results indicate that MC exposure may disturb pancreatic development and function and contributing to the pathogenesis of diabetes in mammals. However, the exact mechanisms of the developmental toxicity of MC to pancreas are still not clear. Therefore, based on our previous studies, this project is trying to explore the developmental toxicity of MC-LR to pancreas of rats and the involved epigenetic mechanisms by utilizing toxicological, biochemical, omics and molecular analysis. Meantime, islet function as well as susceptibility to diabetes and its heritability in rat offspring which could be induced by impaired pancreatic development after developmental exposure to MC will also be measured. These studies will help us to fully understand and estimate the toxicity of MC to the environment and the potential contribution to human diseases.

蓝藻毒素广泛分布在自然水体中，给水生态系统和环境健康带来了巨大危害。而目前，蓝藻毒素人群健康效应的相关研究还非常有限。我们前期研究发现，微囊藻毒素（Microcystin，MC）暴露抑制了大鼠胰岛β细胞瘤（INS-1）细胞活性和胰岛素分泌能力，同时诱导了包括糖尿病基因Pdx1在内的一批与胰岛素分泌调控相关的基因的差异表达。这些结果预示MC暴露可能对哺乳动物胰腺发育和功能以及成年期糖尿病的发生发展有重要影响，但其具体作用途径和机制并不清楚。因此，本项目拟在前期研究基础上，以模式动物大鼠为实验材料，应用毒理学、生物化学、分子生物学和组学等研究方法，详细探讨MC暴露对大鼠胰腺发育的损伤效应及其表观遗传机制，并对MC发育期暴露可能引发的成年期胰岛功能损伤、糖尿病易感风险及可遗传性等问题进行深入的研究。项目的开展有助于人们深入了解和评估蓝藻毒素的环境健康风险及发育期暴露对人类高发疾病发生的潜在贡献。

我国是世界上蓝藻水华暴发较为严重的国家之一。堆积的蓝藻水华及其释放的蓝藻毒素严重影响了饮用水安全，对人类健康产生了极大的危害。微囊藻毒素（Microcystin，MC）是淡水系统中分布最广、毒性最强的一类蓝藻毒素，具有较强的肝毒性。研究发现，MC特异性转运载体不仅存在于在肝细胞，也在人类胰岛细胞中表达，表明MC可在胰岛细胞中富集并可能影响哺乳动物胰岛功能引发相关疾病。本研究以哺乳动物大鼠为实验对象，从胰腺发育角度探讨了大鼠发育期MC暴露对成年子代糖代谢功能和糖尿病易感性的影响及可能的跨代遗传效应。研究结果表明：（1）孕期MC暴露可通过抑制HPA轴的调控作用引发F1代胎鼠生长受限、糖代谢功能降低，以及胰岛β细胞数目不足、胰岛素关键代谢基因表达抑制和胰腺发育关键基因甲基化程度增加等胰腺发育异常；（2）F1代子鼠出生体重显著降低，后呈现明显的“追赶性生长”，呈现显著的HPA轴高敏感性。主要表现为HPA轴关键激素、胰岛素及相关代谢基因高表达，成年子鼠出现糖耐量增强和胰岛素敏感性增加的糖代谢表型；F1代子鼠在成年后给予的阶段性高脂饲养期及高脂结束后的老年期，HPA轴核心激素水平和胰岛素代谢相关基因均呈现显著降低趋势，糖代谢能力也显著下降，出现了典型的糖耐量降低和胰岛素抵抗的糖尿病样反应，说明MC组F1代在高脂不良因素作用后增加了糖尿病的易感性，而F1代糖代谢高敏感性是增加子代成年后糖尿病发病风险的主要诱因；（3）F2代成年后也表现出糖耐量降低和胰岛素敏感性下降的现象，表明孕期MC暴露对胰腺发育的影响具有明显的跨代效应。当父本和母本均来自于MC暴露组时，跨代效应更加显著。所有结果表明，孕期MC暴露引发的胰腺宫内发育编程改变是成年子代大鼠糖代谢损伤、糖尿病易感和跨代遗传的根源。本项目的开展有助于人们更加深入了解蓝藻毒素的环境健康效应以及对人类高发疾病的潜在贡献。