流行病学研究始终将环境毒物暴露与2型糖尿病风险增加联系起来。我们的研究调查了广泛使用的阻燃剂,DechloranePlus(DP),使用啮齿动物和人体模型系统的胰腺β细胞。我们首先检查了雄性小鼠的胰腺组织,该小鼠每天口服给药赋形剂(玉米油)或DP(每天10、100或1000μg/kg),并在体内喂食食物或高脂肪饮食28天。在任一饮食组中,DP暴露均不影响胰岛大小或内分泌细胞组成。接下来,我们使用永生化大鼠β细胞(INS-1832/3)评估了在体外暴露于媒介物(DMSO)或DP(1、10或100nM)48小时的效果,初级小鼠和人类胰岛,和人干细胞衍生的胰岛样细胞(SC-胰岛)。在INS-1832/3细胞中,DP不会影响葡萄糖刺激的胰岛素分泌(GSIS),但会显着降低细胞内胰岛素含量。DP对小鼠胰岛或SC-胰岛中的GSIS没有影响,但对人胰岛中的GSIS有不同的影响,具体取决于供体。单独的DP不影响小鼠胰岛中的胰岛素含量,人类胰岛,或SC-胰岛,但是与对照条件相比,共同暴露于DP和糖脂毒性(GLT)应激条件(28.7mM葡萄糖0.5mM棕榈酸酯)的小鼠胰岛胰岛素含量降低。与单独的GLT相比,小鼠胰岛共同暴露于DP+GLT放大了Slc30a8的上调。我们的研究强调了使用不同的体外模型研究化学毒性的重要性和挑战。
Epidemiological studies consistently link environmental toxicant exposure with increased Type 2 diabetes risk. Our study investigated the diabetogenic effects of a widely used flame retardant, Dechlorane Plus (DP), on pancreatic β-cells using rodent and human model systems. We first examined pancreas tissues from male mice exposed daily to oral gavage of either vehicle (corn oil) or DP (10, 100, or 1000 μg/kg per day) and fed chow or high fat diet for 28-days in vivo. DP exposure did not affect islet size or endocrine cell composition in either diet group. Next, we assessed the effect of 48-hour exposure to vehicle (DMSO) or DP (1, 10, or 100 nM) in vitro using immortalized rat β-cells (INS-1 832/3), primary mouse and human
islets, and human stem-cell derived islet-like cells (SC-
islets). In INS-1 832/3 cells, DP did not impact glucose-stimulated insulin secretion (GSIS) but significantly decreased intracellular insulin content. DP had no effect on GSIS in mouse
islets or SC-
islets but had variable effects on GSIS in human
islets depending on the donor. DP alone did not affect insulin content in mouse
islets, human
islets, or SC-
islets, but mouse
islets co-exposed to DP and glucolipotoxic (GLT) stress conditions (28.7 mM glucose + 0.5 mM palmitate) had reduced insulin content compared to control conditions. Co-exposure of mouse
islets to DP + GLT amplified the upregulation of Slc30a8 compared to GLT alone. Our study highlights the importance and challenges of using different in vitro models for studying chemical toxicity.