Maternal Exposure to Bisphenol-A During Pregnancy Increases Pancreatic β-Cell Growth During Early Life in Male Mice Offspring
Maternal Exposure to Bisphenol-A During Pregnancy Increases Pancreatic β-Cell Growth During Early Life in Male Mice Offspring
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DOI：
10.1210/en.2016-1390
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发表时间：
2016-11-01
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：
Garcia-Arevalo, Marta;Alonso-Magdalena, Paloma;Nadal, Angel
代谢关键器官(如内分泌胰腺)发育过程中的变化会影响生命后期的表型。有证据表明，在子宫或围产期暴露于双酚A(BPA)会导致成年后葡萄糖代谢受损。然而，怀孕期间接触双酚A如何影响后代早期生命中的胰岛β细胞生长和功能还没有被探索。我们将妊娠小鼠暴露于溶剂(对照组)或双酚A(10和100微克/千克·天，BPA10和BPA100)中，并在出生后(P)P0，P21，P30和P120天检查后代。BPA10和BPA100小鼠的出生体重低于对照组，随后体重增加，直到第30天。在这个年龄段，在非禁食状态下，暴露于双酚A的动物的血浆胰岛素、C肽和瘦素浓度升高。与对照组相比，BPA10组胰岛素分泌和含量减少，BPA100组胰岛素分泌和含量保持不变。全球基因表达分析表明，双酚A处理的动物胰岛中与细胞分裂相关的基因增加。这与P0、P21和P30时胰腺β细胞质量的增加以及β细胞增殖增加和细胞凋亡减少有关。相反，在P120，双酚A处理的动物表现出与对照组相同或减少的β细胞质量，并改变了空腹血糖水平。这些数据表明，在子宫内暴露于环境相关剂量的BPA会改变与β细胞生长调节有关的基因的表达，增加β细胞的质量/面积，并在生命早期改变β细胞的增殖。早期生命中胰岛素信号过多可能导致成年后糖耐量受损。
Alterations during development of metabolic key organs such as the endocrine pancreas affect the phenotype later in life. There is evidence that in utero or perinatal exposure to bisphenol-A (BPA) leads to impaired glucose metabolism during adulthood. However, how BPA exposure during pregnancy affects pancreatic beta-cell growth and function in offspring during early life has not been explored. We exposed pregnant mice to either vehicle (control) or BPA (10 and 100 mu g/kg.d, BPA10 and BPA100) and examined offspring on postnatal days (P) P0, P21, P30, and P120. BPA10 and BPA100 mice presented lower birth weight than control and subsequently gained weight until day 30. At that age, concentration of plasma insulin, C-peptide, and leptin were increased in BPA-exposed animals in the nonfasting state. Insulin secretion and content were diminished in BPA10 and maintained in BPA100 compared with control. A global gene expression analysis indicated that genes related with cell division were increased in islets from BPA-treated animals. This was associated with an increase in pancreatic beta-cell mass at P0, P21, and P30 together with increased beta-cell proliferation and decreased apoptosis. On the contrary, at P120, BPA-treated animals presented either equal or decreased beta-cell mass compared with control and altered fasting glucose levels. These data suggest that in utero exposure to environmentally relevant doses of BPA alters the expression of genes involved in beta-cell growth regulation, incrementing beta-cell mass/area, and beta-cell proliferation during early life. An excess of insulin signaling during early life may contribute to impaired glucose tolerance during adulthood.