低剂量双酚A致肥胖效应的性别差异及其机制研究

There is increasing concern for the relationship between bisphenol A (BPA), a kind of environmental endocrine disruptors, and metabolism disorder diseases such as obesity. It was reported that exposure to low-dose BPA during the perinatal period of development resulted in an increase in body weight and accumulation of abdominal adipose tissue, however, few attention was paid to the gender specific effects. This study aims at evaluating the gender specific effects and mechanisms related to low-dose BPA exposure by integrating in vivo and in vitro studies. Ovariectomized/orchiectomized rats, as well as, PND21-35 female/male rats are exposed to low-dose BPA, and then geder specifi effects on body weight and their relationship with endogenous estrogen and estrogen receptors (ERα、ERβ、GPR30) are explored. 3T3-L1 cell line will be cultured for exploring underlying mechanisms in obesity development. After administrating of selective antagonist/agonist of estrogen receptors, the gender specific effects and mechanisms will be further studied. Bisphenol A at a dose equivalent to that can be found in the environment is designed as exposure level in this study. Factorial experiment design is applied so that interactions between factors can be analyzed. To illuminate the gender specif effects on body weight due to low-dose BPA exposure and related mechanisms will contribute to clarify the mechanisms of obesogens resulting in obesity, ultimately, benefit in preventing obesity and other metabolism disorders.

环境内分泌干扰物双酚A（BPA）与肥胖等代谢紊乱性疾病的关系日益受到研究者关注，围产期低剂量BPA暴露可导致子代体重的增加和腹部脂肪集聚，但是鲜有研究者关注BPA致肥胖效应的性别差异。本研究结合体内与体外研究综合评价低剂量BPA致肥胖效应的性别差异及其机制，将去势或新生雌雄大鼠暴露于低剂量BPA，探讨体重改变等效应的性别差异及其与内源性雌激素水平及雌激素受体（ERα、ERβ、GPR30）表达等之间的关系；并通过培养与肥胖发生相关的3T3-L1细胞株，在给予选择性雌激素受体拮抗剂或激动剂及性激素后，进一步探讨差异效应发生机制。研究采用接近环境暴露水平的BPA，并通过析因设计进行因素间交互作用分析。探明低剂量BPA致肥胖效应的性别差异及其发生原因有助于进一步阐明肥胖激素参与肥胖发生过程的机制以及预防肥胖等代谢性疾病。

双酚A（BPA）是目前全世界用量最大的合成化合物之一，具有拟雌激素效应。近年来低剂量BPA暴露与肥胖等代谢紊乱性疾病的关系受到越来越多的关注，但是鲜有研究者关注BPA致肥胖效应的性别差异。探讨低剂量BPA致肥胖效应的性别差异及其发生原因有助于进一步阐明BPA等肥胖激素参与肥胖发生过程的机制以及预防肥胖等代谢性疾病。本研究着重探讨围产期低剂量BPA暴露后雌雄子代性别差异性效应，并初步探讨其机制。我们发现围产期（从怀孕至哺乳期结束）给予50 μg/kg BPA的成年雄性子代体重和腹部脂肪显著增加以及糖耐量受损，脂肪组织中与脂肪酸合成相关的基因（(SREBP-1c, FAS)）表达水平增加、与脂肪酸氧化分解相关的基因（PPARα, CPT-1β）表达水平降低；在围产期暴露试验和去势动物研究中均发现BPA可以上调雄性脂肪组织中雌激素受体ERα表达水平，并且在体外BPA与雄性脂肪组织中雌激素受体的结合能力稍强于雌性。本研究提示低剂量BPA可能通过ERα参与脂质代谢而导致雄性子代体重和体脂的改变，但还需要进一步的研究来深入论证。