Alonso-Magdalena Paloma, García-Arévalo Marta, Quesada Iván, Nadal Ángel
Departamento de Biología Aplicada (P.A.-M., I.Q.), Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) (P.A.-M., M.G.-A., I.Q., A.N.), Universidad Miguel Hernández de Elche, Elche 03202, Alicante, Spain.
Endocrinology. 2015 May;156(5):1659-70. doi: 10.1210/en.2014-1952. Epub 2015 Apr 1.
Evidence now exists supporting the hypothesis that endocrine-disrupting chemicals (EDCs) can harmfully impact glucose metabolism. Thus, EDCs are beginning to be considered important contributors to the increased incidence of diabetes, obesity, or both. The possible effect of exposure to EDCs during pregnancy on glucose homeostasis in mothers later in life is presently unknown. Here we show that several months after delivery, mothers treated with the widespread EDC bisphenol-A (BPA) during gestation, at environmentally relevant doses, exhibit profound glucose intolerance and altered insulin sensitivity as well as increased body weight. These mice presented a decreased insulin secretion both in vivo and in vitro together with reduced pancreatic β-cell mass. The proliferation capacity was decreased in association with a diminished expression of the cell cycle activators: cyclin D2 and cyclin-dependent kinase-4. In addition, the rate of β-cells apoptosis was increased as well as the expression of the cell cycle inhibitors p16 and p53. Conversely, no effects on glucose metabolism or insulin sensitivity were observed when female nonpregnant mice were treated with BPA at the same doses. Taken together, these findings reveal that BPA exposure during gestation has harmful long-term implications in glucose metabolism for the mother. This finding highlights a new window of susceptibility for EDC exposure that may be important for the development of type 2 diabetes.
现有证据支持这样的假说，即内分泌干扰化学物质（EDCs）会对葡萄糖代谢产生有害影响。因此，EDCs开始被认为是导致糖尿病、肥胖症发病率上升或两者兼有的重要因素。孕期接触EDCs对母亲日后生活中葡萄糖稳态的可能影响目前尚不清楚。在此我们表明，分娩数月后，孕期接受环境相关剂量广泛使用的EDC双酚A（BPA）处理的母亲表现出严重的葡萄糖不耐受、胰岛素敏感性改变以及体重增加。这些小鼠在体内和体外均表现出胰岛素分泌减少，同时胰腺β细胞数量减少。细胞增殖能力下降，同时细胞周期激活剂细胞周期蛋白D2和细胞周期蛋白依赖性激酶4的表达降低。此外，β细胞凋亡率增加，细胞周期抑制剂p16和p53的表达也增加。相反，当非妊娠雌性小鼠接受相同剂量的BPA处理时，未观察到对葡萄糖代谢或胰岛素敏感性的影响。综上所述，这些发现揭示了孕期接触BPA对母亲的葡萄糖代谢具有有害的长期影响。这一发现突出了EDC暴露的一个新的易感窗口，这可能对2型糖尿病的发展具有重要意义。
