摘要:
为利用和人类更为接近的动物模型来研究在高脂血症条件下,BPA暴露是否能促进脂类和糖类代谢异常,并探索潜在的毒性效应机制,选取渡边可遗传高脂血症家兔(WHHL)模型,通过灌胃的方式将其暴露于400 μg·kg-1体重的BPA溶液长达12周。在持续暴露第8周,检测了在空腹状态下,家兔血浆中葡萄糖、胰岛素和脂肪含量的变化,并根据所得结果进行了静脉注射胰岛素耐受试验(IVTT)。在暴露第12周,同样对空腹状态下,家兔血浆中的葡萄糖,胰岛素和脂肪含量进行了检测,并测量了血压和心率。然后,将所有的家兔进行解剖,通过苏木精-伊红(HE)及糖原(PAS)染色分别对心脏和肝脏部位的脂肪及糖原蓄积情况进行了病理学切片分析。同时,检测了肝脏中与脂类和糖类代谢相关基因在mRNA水平上的表达变化。结果显示,BPA暴露8周后促使WHHL家兔发生了胰岛素抵抗现象,导致第12周血糖及胰岛素含量升高,同时也促进了高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)及游离脂肪酸(NEFA)含量的上升。BPA暴露第12周,暴露组WHHL家兔的冠状动脉粥样硬化损伤程度未发生明显增加,但心肌细胞发生了肿胀,胞质中出现了脂肪的蓄积,同时伴随着心律失常。肝脏重量发生增加,肝细胞中同时出现了脂肪和糖原的蓄积现象,相关基因的表达发生了显著上调。研究结果表明,BPA持续暴露可促进WHHL家兔发生脂类和糖类代谢异常,其毒性效应机制可能和胰岛素抵抗及相关基因的异常表达有关。
Abstract:
In order to use an animal model that is more close to humans to study whether BPA exposure can accelerate the disorders of lipid and glucose metabolism in the setting of hyperlipidemia and explore the underlying toxic mechanisms. The Watanabe heritable hyperlipidemic (WHHL) rabbit was selected and exposed to 400 μg·kg-1 body weight BPA for 12 weeks by oral gavage. At 8 weeks, the fasting plasma glucose, insulin and lipid levels were detected. The intravenous insulin tolerance test (IVITT) was performed. At 12 weeks, the fasting plasma glucose, insulin and lipid levels were also detected, and the blood pressure and heart rate were analyzed as well. Then all the rabbits were anatomized. The pathological examination of lipid and glycogen accumulation in the heart and liver were observed through hematoxylin-eosin (HE) and periodic acid-schiff (PAS) staining. Meanwhile, the genes expression closely related to lipid and glucose metabolism was analyzed in the liver. Results showed that BPA accelerated insulin resistance in the WHHL rabbit after BPA exposure for 8 weeks, resulting in the increased of fasting plasma glucose and insulin levels at 12 weeks, and the change of some blood lipid levels (HDL-C, LDL-C and NEFA). At 12 weeks, the extent of coronary atherosclerosis lesions was not increased obviously. However, the hypertrophy of cardiac muscle cell was detected and lipid accumulation was observed in the cytoplasm, leading to arrhythmia. The liver weight was increased accompanied by lipid and glycogen accumulation in the hepatocyte. The related genes expression was up-regulated significantly. These results indicated that continuous exposure to BPA can accelerate the disorders of glucose and lipid metabolism in the WHHL rabbit, which may be associated with the insulin resistance and abnormal expression of related genes.
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