In utero exposure to the ubiquitous plasticizer, bisphenol A (BPA) is associated with offspring obesity. As food intake/appetite is one of the critical elements contributing to obesity, we determined the effects of in vivo maternal BPA and in vitro BPA exposure on newborn hypothalamic stem cells which form the arcuate nucleus appetite center. For in vivo studies, female rats received BPA prior to and during pregnancy via drinking water, and newborn offspring primary hypothalamic neuroprogenitor (NPCs) were obtained and cultured. For in vitro BPA exposure, primary hypothalamic NPCs from healthy newborns were utilized. In both cases, we studied the effects of BPA on NPC proliferation and differentiation, including putative signal and appetite factors. Maternal BPA increased hypothalamic NPC proliferation and differentiation in newborns, in conjunction with increased neuroproliferative (Hes1) and proneurogenic (Ngn3) protein expression. With NPC differentiation, BPA exposure increased appetite peptide and reduced satiety peptide expression. In vitro BPA-treated control NPCs showed results that were consistent with in vivo data (increase appetite vs satiety peptide expression) and further showed a shift towards neuronal versus glial fate as well as an increase in the epigenetic regulator lysine-specific histone demethylase1 (LSD1). These findings emphasize the vulnerability of stem-cell populations that are involved in life-long regulation of metabolic homeostasis to epigenetically-mediated endocrine disruption by BPA during early life.

在子宫内接触普遍存在的增塑剂双酚 A (BPA) 与后代肥胖有关。由于食物摄入/食欲是导致肥胖的关键因素之一，我们确定了体内母体 BPA 和体外 BPA 暴露对形成弓状核食欲中心的新生儿下丘脑干细胞的影响。在体内研究中，雌性大鼠在怀孕前和怀孕期间通过饮用水接受BPA，并获得并培养新生后代初级下丘脑神经祖细胞（NPC）。对于体外 BPA 暴露，使用了来自健康新生儿的原发性下丘脑 NPC。在这两种情况下，我们研究了 BPA 对 NPC 增殖和分化的影响，包括假定的信号和食欲因素。母体 BPA 增加新生儿下丘脑 NPC 增殖和分化，同时增加神经增殖 (Hes1) 和原神经源 (Ngn3) 蛋白表达。随着 NPC 的分化，BPA 暴露增加了食欲肽的表达并减少了饱腹感肽的表达。体外BPA 处理的对照 NPC 显示的结果与体内数据一致（增加食欲与饱腹感肽表达），并进一步显示向神经元与神经胶质细胞命运的转变以及表观遗传调节剂赖氨酸特异性组蛋白去甲基化酶 1 (LSD1) 的增加）。这些发现强调了参与终生代谢稳态调节的干细胞群在生命早期容易受到 BPA 表观遗传介导的内分泌干扰的影响。