BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
Department of Environmental Engineering, Seoul National University of Science and Technology, Seoul 01811, Korea.
Int J Environ Res Public Health. 2022 Apr 20;19(9):4991. doi: 10.3390/ijerph19094991.
Effect of organochlorine pesticides (OCPs) mixtures on development of type 2 diabetes mellitus (T2DM) and the underlying mechanism, especially at protein levels, are largely unknown. We exposed a mixture of five OCPs to zebrafish at concentrations of 0, 0.05, 0.25, 2.5, and 25 μg/L for 12 weeks. Differentially expressed proteins (DEPs) were quantitatively identified in female zebrafish livers, and its functional study was conducted. The significantly high glucose and low insulin levels were observed only at 0.05 μg/L, linking to the different pattern of DEPs than other concentrations. A total of 1082 proteins was quantified, of which 321 proteins formed 6 clusters in protein dynamics analysis. The enriched pathways in cluster 3 showing distinct pattern of DEPs could explain the nonlinear response at 0.05 μg/L, indicating that OCP mixtures adversely affected proteins associated with mitochondrial function and energy metabolism. We proposed a feasible mechanism that decrease in expression of aldehyde dehydrogenase led to abnormal accumulation of aldehydes, reducing expression of glyceraldehyde 3-phosphate dehydrogenase, and resulting in disruption of glucose homeostasis. Our findings help to better understand the causality of T2DM by exposure to OCP mixtures and to identify biomarkers in the protein expression level.
有机氯农药（OCPs）混合物对 2 型糖尿病（T2DM）发展的影响及其潜在机制，尤其是在蛋白质水平上，很大程度上尚不清楚。我们将五种 OCPs 的混合物以 0、0.05、0.25、2.5 和 25μg/L 的浓度暴露于斑马鱼 12 周。在雌性斑马鱼肝脏中定量鉴定差异表达蛋白（DEPs），并进行其功能研究。仅在 0.05μg/L 时观察到显著的高血糖和低胰岛素水平，与其他浓度的 DEP 模式不同。共定量了 1082 种蛋白质，其中 321 种蛋白质在蛋白质动力学分析中形成 6 个簇。簇 3 中富集的通路显示出明显的 DEP 模式，可以解释 0.05μg/L 时的非线性反应，表明 OCP 混合物对与线粒体功能和能量代谢相关的蛋白质有不良影响。我们提出了一个可行的机制，即醛脱氢酶表达的减少导致醛的异常积累，降低了甘油醛 3-磷酸脱氢酶的表达，从而破坏了葡萄糖稳态。我们的研究结果有助于更好地理解 T2DM 由 OCP 混合物暴露引起的因果关系，并在蛋白质表达水平上识别生物标志物。
