Department of Environmental Energy Engineering, Seoul National University of Science and Technology, Seoul 01811, Republic of Korea.
BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
J Hazard Mater. 2021 Aug 15;416:125956. doi: 10.1016/j.jhazmat.2021.125956. Epub 2021 Apr 27.
Exposure to a single organochlorine pesticide (OCP) at high concentration and over a short period of exposure constrain our understanding of the contribution of chemical exposure to type 2 diabetes (T2D). A total of 450 male and female zebrafish was exposed to mixtures of five OCPs at 0, 0.05, 0.25, 2.5, and 25 μg/L for 12 weeks. T2D-related hematological parameters (i.e., glucose, insulin, free fatty acid, and triglycerides) and mitochondrial complex I to IV activities were assessed. Metabolomics, proteomics, and transcriptomics were analyzed in female livers, and their data-driven integration was performed. High fasting glucose and low insulin levels were observed only at 0.05 μg/L of the OCP mixture in females, indicating a nonlinear and sexually dependent response. We found that exposure to the OCP mixture inhibited the activities of mitochondrial complexes, especially III and IV. Combining individual and integrated omics analysis, T2D-linked metabolic pathways that regulate mitochondrial function, insulin signaling, and energy homeostasis were altered by the OCP mixture, which explains the observed phenotypic hematological effects. We demonstrated the cause-and-effect relationship between exposures to OCP mixture and T2D using zebrafish model. This study gives an insight into mechanistic research of metabolic diseases caused by chemical exposure using zebrafish.
暴露于单一有机氯农药（OCP）高浓度且暴露时间短，这限制了我们对化学暴露对 2 型糖尿病（T2D）的贡献的理解。总共将 450 只雄性和雌性斑马鱼暴露于五种 OCP 混合物中，浓度分别为 0、0.05、0.25、2.5 和 25μg/L，暴露时间为 12 周。评估了与 T2D 相关的血液学参数（即葡萄糖、胰岛素、游离脂肪酸和甘油三酯）和线粒体复合物 I 至 IV 的活性。分析了雌性肝脏中的代谢组学、蛋白质组学和转录组学，并对其进行了数据驱动的整合。仅在雌性的 0.05μg/L OCP 混合物中观察到空腹高血糖和低胰岛素水平，表明存在非线性和性别依赖性反应。我们发现，暴露于 OCP 混合物抑制了线粒体复合物的活性，特别是复合物 III 和 IV。结合个体和综合组学分析，调节线粒体功能、胰岛素信号和能量稳态的与 T2D 相关的代谢途径被 OCP 混合物改变，这解释了观察到的表型血液学效应。我们使用斑马鱼模型证明了 OCP 混合物暴露与 T2D 之间的因果关系。本研究为使用斑马鱼研究化学暴露引起的代谢性疾病的机制研究提供了新的视角。
