Eckstrum Kirsten S, Edwards Whitney, Banerjee Annesha, Wang Wei, Flaws Jodi A, Katzenellenbogen John A, Kim Sung Hoon, Raetzman Lori T
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois.
Endocrinology. 2018 Jan 1;159(1):119-131. doi: 10.1210/en.2017-00565.
Critical windows of development are often more sensitive to endocrine disruption. The murine pituitary gland has two critical windows of development: embryonic gland establishment and neonatal hormone cell expansion. During embryonic development, one environmentally ubiquitous endocrine-disrupting chemical, bisphenol A (BPA), has been shown to alter pituitary development by increasing proliferation and gonadotrope number in females but not males. However, the effects of exposure during the neonatal period have not been examined. Therefore, we dosed pups from postnatal day (PND)0 to PND7 with 0.05, 0.5, and 50 μg/kg/d BPA, environmentally relevant doses, or 50 μg/kg/d estradiol (E2). Mice were collected after dosing at PND7 and at 5 weeks. Dosing mice neonatally with BPA caused sex-specific gene expression changes distinct from those observed with embryonic exposure. At PND7, pituitary Pit1 messenger RNA (mRNA) expression was decreased with BPA 0.05 and 0.5 μg/kg/d in males only. Expression of Pomc mRNA was decreased at 0.5 μg/kg/d BPA in males and at 0.5 and 50 μg/kg/d BPA in females. Similarly, E2 decreased Pomc mRNA in both males and females. However, no noticeable corresponding changes were found in protein expression. Both E2 and BPA suppressed Pomc mRNA in pituitary organ cultures; this repression appeared to be mediated by estrogen receptor-α and estrogen receptor-β in females and G protein-coupled estrogen receptor in males, as determined by estrogen receptor subtype-selective agonists. These data demonstrated that BPA exposure during neonatal pituitary development has unique sex-specific effects on gene expression and that Pomc repression in males and females can occur through different mechanisms.
发育的关键窗口期通常对内分泌干扰更为敏感。小鼠垂体有两个发育关键窗口期：胚胎期腺体形成和新生期激素细胞扩增。在胚胎发育过程中，一种环境中普遍存在的内分泌干扰化学物质双酚A（BPA）已被证明可通过增加雌性而非雄性的增殖和促性腺激素细胞数量来改变垂体发育。然而，新生期暴露的影响尚未得到研究。因此，我们从出生后第0天（PND0）至PND7给幼崽分别投喂0.05、0.5和50μg/kg/d的BPA（环境相关剂量）或50μg/kg/d的雌二醇（E2）。在PND7和5周龄时给药后收集小鼠。新生期给小鼠投喂BPA会导致性别特异性基因表达变化，这与胚胎期暴露所观察到的不同。在PND7时，仅雄性小鼠中，0.05和0.5μg/kg/d的BPA会使垂体Pit1信使核糖核酸（mRNA）表达降低。在0.5μg/kg/d的BPA处理下，雄性小鼠的Pomc mRNA表达降低，而在0.5和50μg/kg/d的BPA处理下，雌性小鼠的Pomc mRNA表达降低。同样，E2会降低雄性和雌性小鼠的Pomc mRNA表达。然而，在蛋白质表达方面未发现明显的相应变化。E2和BPA均抑制垂体器官培养物中的Pomc mRNA表达；雌激素受体亚型选择性激动剂的研究表明，这种抑制在雌性中似乎由雌激素受体-α和雌激素受体-β介导，而在雄性中由G蛋白偶联雌激素受体介导。这些数据表明，新生期垂体发育过程中暴露于BPA对基因表达具有独特的性别特异性影响，并且雄性和雌性中Pomc的抑制可能通过不同机制发生。
