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首页> 外文期刊>Archives of Toxicology >Tributyltin exposure at noncytotoxic doses dysregulates pancreatic beta-cell function in vitro and in vivo
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Tributyltin exposure at noncytotoxic doses dysregulates pancreatic beta-cell function in vitro and in vivo

机译：在非胞毒素剂量下的呋喃酯丁暴露在体外和体内胰蛋白酶诱导胰腺β细胞功能

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Tributyltin (TBT) is an endocrine disruptor. TBT can be found in food and in human tissues and blood. Several animal studies revealed that organotins induced diabetes with decreased insulin secretion. The detailed effect and mechanism of TBT on pancreatic beta-cell function still remain unclear. We investigated the effect and mechanism of TBT exposure at noncytotoxic doses relevant to human exposure on beta-cell function in vitro and in vivo. The beta-cell-derived RIN-m5F cells and pancreatic islets from mouse and human were treated with TBT (0.05-0.2 mu M) for 0.5-4 h. Adult male mice were orally exposed to TBT (25 mu g/kg/day) with or without antioxidant N-acetylcysteine (NAC) for 1-3 weeks. Assays for insulin secretion and glucose metabolism were carried out. Unlike previous studies, TBT at noncytotoxic concentrations significantly increased glucose-stimulated insulin secretion and intracellular Ca2+ ([Ca2+](i)) in beta-cells. The reactive oxygen species (ROS) production and phosphorylation of protein kinase C (PKC-pan) and extracellular signal-regulated kinase (ERK)1/2 were also increased. These TBT-triggered effects could be reversed by antiestrogen ICI182780 and inhibitors of ROS, [Ca2+](i), and PKC, but not ERK. Similarly, islets treated with TBT significantly increased glucose-stimulated insulin secretion, which could be reversed by ICI182780, NAC, and PKC inhibitor. Mice exposed to TBT for 3 weeks significantly increased blood glucose and plasma insulin and induced glucose intolerance and insulin resistance, which could be reversed by NAC. These findings suggest that low/noncytotoxic doses of TBT induce insulin dysregulation and disturb glucose homeostasis, which may be mediated through the estrogen receptor-regulated and/or oxidative stress-related signaling pathways.
机译：Tributyltin（TBT）是内分泌干扰。 TBT可以在食物和人体组织和血液中找到。几种动物研究表明，有机汀诱导胰岛素分泌减少的糖尿病。 TBT对胰腺β细胞功能的详细效果和机制仍然尚不清楚。我们调查了在体外和体内β细胞功能上有关的非胞间毒性剂量的TBT暴露的影响和机制。 β-细胞衍生的rin-m5f细胞和来自小鼠和人的胰岛胰岛用TBT（0.05-0.2μmm）处理0.5-4小时。成年雄性小鼠口服暴露于TBT（25μg/ kg /天），或没有抗氧化N-乙酰半胱氨酸（NaC）1-3周。进行胰岛素分泌和葡萄糖代谢的测定。与之前的研究不同，在β-细胞中，非胞素毒性浓度的TBT显着增加了葡萄糖刺激的胰岛素分泌和细胞内Ca 2 +（[Ca2 +]（I））。还增加了蛋白激酶C（PKC-PAN）和细胞外信号调节激酶（ERK）1/2的反应性氧物质（ROS）生产和磷酸化。这些TBT触发的效果可以通过Antiestrogen ICI182780和ROS的抑制剂逆转，[CA2 +]（I）和PKC，但不是ERK。类似地，用TBT处理的胰岛显着增加了葡萄糖刺激的胰岛素分泌，这可以通过ICI182780，NAC和PKC抑制剂逆转。暴露于TBT的小鼠3周明显增加血糖和血浆胰岛素，并诱导葡萄糖不耐受和胰岛素抵抗力，这可能通过NAC逆转。这些发现表明，低/非胞毒性剂量的TBT诱导胰岛素失衡和干扰葡萄糖稳态，其可以通过雌激素受体调节和/或氧化应激相关的信号传导途径介导。

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