Abstract：
Metabolism-disrupting chemicals (MDCs) are endocrine disruptors with obesogenic and/or diabetogenic action. There is mounting evidence linking exposure to MDCs to increased susceptibility to diabetes. Despite the important role of glucagon in glucose homeostasis, there is little information on the effects of MDCs on α-cells. Furthermore, there are no methods to identify and test MDCs with the potential to alter α-cell viability and function. Here, we used the mouse α-cell line αTC1-9 to evaluate the effects of MDCs on cell viability and glucagon secretion. We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 µM): bisphenol-A (BPA), tributyltin (TBT), perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS), and dichlorodiphenyldichloroethylene (DDE). Using two different approaches, MTT assay and DNA-binding dyes, we observed that BPA and TBT decreased α-cell viability via a mechanism that depends on the activation of estrogen receptors and PPARγ, respectively. These two chemicals induced ROS production, but barely altered the expression of endoplasmic reticulum (ER) stress markers. Although PFOA, TPP, TCS, and DDE did not alter cell viability nor induced ROS generation or ER stress, all four compounds negatively affected glucagon secretion. Our findings suggest that αTC1-9 cells seem to be an appropriate model to test chemicals with metabolism-disrupting activity and that the improvement of the test methods proposed herein could be incorporated into protocols for the screening of diabetogenic MDCs.
摘要：
代谢破坏化学物质（MDC）是具有致肥胖和/或致糖尿病作用的内分泌干扰物。越来越多的证据表明，暴露于MDCs与糖尿病易感性增加有关。尽管胰高血糖素在葡萄糖稳态中的重要作用，关于MDC对α细胞的影响的信息很少。此外，没有方法来鉴定和测试具有改变α细胞活力和功能的潜力的MDC。这里,我们使用小鼠α细胞系αTC1-9来评估MDC对细胞活力和胰高血糖素分泌的影响。我们测试了人体暴露浓度（0.1pM至1µM）的六种化学物质：双酚A（BPA），三丁基锡(TBT),全氟辛酸（PFOA），磷酸三苯酯(TPP),三氯生(TCS),和二氯二苯基二氯乙烯(DDE)。使用两种不同的方法，MTT测定和DNA结合染料，我们观察到BPA和TBT通过依赖于雌激素受体和PPARγ激活的机制降低α细胞活力，分别。这两种化学物质诱导ROS产生，但几乎没有改变内质网（ER）应激标志物的表达。虽然PFOA,TPP,TCS,DDE不会改变细胞活力，也不会诱导ROS产生或ER应激，所有四种化合物都对胰高血糖素分泌产生负面影响。我们的发现表明，αTC1-9细胞似乎是测试具有代谢破坏活性的化学物质的合适模型，并且本文提出的测试方法的改进可以纳入筛选糖尿病性MDC的方案中。
