Bisphenol-A Treatment During Pregnancy in Mice: A New Window of Susceptibility for the Development of Diabetes in Mothers Later in Life
Bisphenol-A Treatment During Pregnancy in Mice: A New Window of Susceptibility for the Development of Diabetes in Mothers Later in Life
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DOI：
10.1210/en.2014-1952
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发表时间：
2015-05-01
期刊：
影响因子：
4.8
通讯作者：
Nadal, Angel
中科院分区：
文献类型：
--
作者：
Alonso-Magdalena, Paloma;Garcia-Arevalo, Marta;Nadal, Angel
现在有证据支持内分泌干扰物（EDCs）可以有害地影响葡萄糖代谢的假设。因此，内分泌干扰物开始被认为是糖尿病、肥胖症或两者发病率增加的重要因素。目前尚不清楚怀孕期间暴露于内分泌干扰物对母亲日后血糖稳态的可能影响。在这里，我们表明，分娩后几个月，母亲在怀孕期间接受广泛的EDC双酚A（BPA）治疗，在环境相关剂量下，表现出严重的葡萄糖耐受不良和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以及胰腺β细胞质量减少。细胞增殖能力下降与细胞周期激活因子：细胞周期蛋白D2和细胞周期蛋白依赖性激酶-4的表达减少。此外，β细胞凋亡率以及细胞周期抑制剂p16和p53的表达增加。相反，当用相同剂量的BPA处理雌性非妊娠小鼠时，没有观察到对葡萄糖代谢或胰岛素敏感性的影响。总之，这些研究结果表明，怀孕期间接触BPA对母亲的葡萄糖代谢具有有害的长期影响。这一发现强调了EDC暴露的易感性的新窗口，这可能对2型糖尿病的发展很重要。
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 beta-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. Inaddition, therateof beta-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.