Exposure to bisphenol A, but not phthalates, increases spontaneous diabetes type 1 development in NOD mice.
Exposure to bisphenol A, but not phthalates, increases spontaneous diabetes type 1 development in NOD mice.
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DOI：
10.1016/j.toxrep.2015.02.010
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发表时间：
2015
影响因子：
--
通讯作者：
Nygaard UC
中科院分区：
文献类型：
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作者：
Bodin J;Kocbach Bølling A;Wendt A;Eliasson L;Becher R;Kuper F;Løvik M;Nygaard UC
1型糖尿病（T1 DM）是一种由于遗传倾向导致的胰岛素产生胰腺β细胞的自身免疫性破坏，可由环境因素触发。我们以前已经表明，双酚A（BPA）加速非肥胖糖尿病（NOD）小鼠糖尿病的自发发展。在这里，我们假设，与BPA单独相比，口服暴露于与人体暴露相关的内分泌干扰物BPA和邻苯二甲酸盐的混合物会加速糖尿病的发展。NOD小鼠从受孕到整个生命周期通过饮用水暴露于BPA（1 mg/l）、邻苯二甲酸酯混合物（DEHP 1 mg/l、DBP 0.2 mg/l、BBP 10 mg/l和DiBP 20 mg/l）或BPA和邻苯二甲酸酯混合物的组合。之前的观察结果表明，BPA暴露增加了糖尿病和胰岛炎的患病率，并减少了胰腺中组织驻留巨噬细胞的数量，这一观察结果得到了证实，并通过证明BPA暴露也损害了腹腔巨噬细胞的吞噬活性而得到了扩展。仅暴露于邻苯二甲酸酯后，未观察到这些影响。邻苯二甲酸酯暴露与BPA结合似乎抑制了BPA对巨噬细胞数量和功能以及糖尿病发展的影响，但没有抑制胰岛炎的发展。单独暴露于BPA或与邻苯二甲酸酯联合暴露于BPA可降低体外刺激脾细胞和淋巴结细胞的细胞因子释放（TNFα、IL-6、IL-10、IFNγ、IL-4），表明免疫功能发生全身性变化。总之，暴露于BPA，而不是邻苯二甲酸酯或混合暴露于BPA和邻苯二甲酸酯，加速了NOD小鼠的糖尿病发展，显然部分是通过全身免疫改变，包括巨噬细胞功能下降。
Type 1 diabetes mellitus (T1DM) is an autoimmune destruction of insulin producing pancreatic beta-cells due to a genetic predisposition and can be triggered by environmental factors. We have previously shown that bisphenol A (BPA) accelerates the spontaneous development of diabetes in non-obese diabetic (NOD) mice. Here, we hypothesized that oral exposure to a mixture of the endocrine disruptors BPA and phthalates, relevant for human exposure, would accelerate diabetes development compared to BPA alone. NOD mice were exposed to BPA (1 mg/l), a mixture of phthalates (DEHP 1 mg/l, DBP 0.2 mg/l, BBP 10 mg/l and DiBP 20 mg/l) or a combination of BPA and the phthalate mixture through drinking water from conception and throughout life. Previous observations that BPA exposure increased the prevalence of diabetes and insulitis and decreased the number of tissue resident macrophages in pancreas were confirmed, and extended by demonstrating that BPA exposure also impaired the phagocytic activity of peritoneal macrophages. None of these effects were observed after phthalate exposure alone. The phthalate exposure in combination with BPA seemed to dampen the BPA effects on macrophage number and function as well as diabetes development, but not insulitis development. Exposure to BPA alone or in combination with phthalates decreased cytokine release (TNFα, IL-6, IL-10, IFNγ, IL-4) from in vitro stimulated splenocytes and lymph node cells, indicating systemic changes in immune function. In conclusion, exposure to BPA, but not to phthalates or mixed exposure to BPA and phthalates, accelerated diabetes development in NOD mice, apparently in part via systemic immune alterations including decreased macrophage function.