Abstract：
Humans are constantly exposed to many environmental pollutants, some of which have been largely acknowledged as key factors in the development of metabolic disorders such as diabetes and obesity. These chemicals have been classified as endocrine-disrupting chemicals (EDCs) and, more recently, since they can interfere with metabolic functions, they have been renamed as metabolism-disrupting chemicals (MDCs). MDCs are present in many consumer products, including food packaging, personal care products, plastic bottles and containers, and detergents. The scientific literature has ever-increasingly focused on insulin-releasing pancreatic β-cells as one of the main targets for MDCs. Evidence highlights that these substances may disrupt glucose homeostasis by altering pancreatic β-cell physiology. However, their potential impact on glucagon-secreting pancreatic α-cells remains poorly known despite the essential role that this cellular type plays in controlling glucose metabolism. In the present study, we have selected seven paradigmatic MDCs representing major toxic classes, including bisphenols, phthalates, perfluorinated compounds, metals, and pesticides. By using an in vitro cell-based model, the pancreatic α-cell line αTC1-9, we have explored the effects of these compounds on pancreatic α-cell viability, gene expression, and secretion. We found that cell viability was moderately affected after bisphenol-A (BPA), bisphenol-F (BPF), and perfluorooctanesulfonic acid (PFOS) exposure, although cytotoxicity was relatively low. In addition, all bisphenols, as well as di(2-ethylhexyl) phthalate (DEHP) and cadmium chloride (CdCl2), promoted a marked decreased on glucagon secretion, together with changes in the expression of glucagon and/or transcription factors involved in cell function and identity, such as Foxo1 and Arx. Overall, our results indicated that most of the selected chemicals studied caused functional alterations in pancreatic α-cells. Moreover, we revealed, for the first time, their direct effects on key molecular aspects of pancreatic α-cell biology.
摘要：
人类经常接触许多环境污染物，其中一些在很大程度上被认为是糖尿病和肥胖等代谢紊乱发展的关键因素。这些化学物质已被归类为内分泌干扰化学物质（EDCs）和，最近,因为它们会干扰代谢功能，它们已被更名为代谢干扰化学物质（MDCs）。MDC存在于许多消费品中，包括食品包装，个人护理产品,塑料瓶和容器，和洗涤剂。科学文献越来越关注释放胰岛素的胰腺β细胞作为MDC的主要靶标之一。证据表明，这些物质可能通过改变胰腺β细胞生理学来破坏葡萄糖稳态。然而,它们对分泌胰高血糖素的胰腺α细胞的潜在影响仍然知之甚少,尽管这种细胞类型在控制葡萄糖代谢中起着重要作用.在本研究中,我们选择了七个代表主要毒性类别的典型MDC，包括双酚,邻苯二甲酸酯,全氟化合物,金属，和杀虫剂。通过使用体外基于细胞的模型，胰腺α细胞系αTC1-9，我们已经探索了这些化合物对胰腺α细胞活力的影响，基因表达，和分泌。我们发现双酚A（BPA）后细胞活力受到中度影响，双酚F(BPF),全氟辛烷磺酸（PFOS）暴露，尽管细胞毒性相对较低。此外,所有的双酚,以及邻苯二甲酸二（2-乙基己基）酯（DEHP）和氯化镉（CdCl2），促进胰高血糖素分泌的显著下降，与胰高血糖素和/或参与细胞功能和身份的转录因子的表达变化，例如Foxo1和Arx。总的来说,我们的结果表明，研究的大多数选定的化学物质引起胰腺α细胞的功能改变。此外，我们透露，第一次,它们对胰腺α细胞生物学关键分子方面的直接影响。
