Abstract：
The neuroendocrine control of reproduction is strictly coordinated at the central level by the pulsatile release of gonadotropin-releasing hormone (GnRH) by the hypothalamic GnRH neurons. Alterations of the GnRH-network, especially during development, lead to long-term reproductive and systemic consequences, also causing infertility. Recent evidence shows that benzo[a]pyrene (BaP), a diffuse pollutant that can play a role as an endocrine disruptor, affects gonadal function and gamete maturation, whereas data demonstrating its impact at hypothalamic level are very scarce. This study investigated the effects of BaP (10 μM) in a primary cell culture isolated from the human fetal hypothalamus (hfHypo) and exhibiting a clear GnRH neuron phenotype. BaP significantly decreased gene and protein expression of both GnRH and kisspeptin receptor (KISS1R), the master regulator of GnRH neuron function. Moreover, BaP exposure increased phospho-ERK1/2 signaling, a well-known mechanism associated with KISS1R activation. Interestingly, BaP altered the electrophysiological membrane properties leading to a significant depolarizing effect and it also significantly increased GnRH release, with both effects being not affected by kisspeptin addition. In conclusion, our findings demonstrate that BaP may alter GnRH neuron phenotype and function, mainly interfering with KISS1R signaling and GnRH secretion and therefore with crucial mechanisms implicated in the central neuroendocrine control of reproduction.
摘要：
通过下丘脑GnRH神经元的促性腺激素释放激素（GnRH）的脉冲释放，在中枢水平上严格协调生殖的神经内分泌控制。GnRH网络的改变，特别是在开发过程中，导致长期的生殖和系统性后果，也会导致不孕。最近的证据表明，苯并[a]芘(BaP)，一种可以起到内分泌干扰物作用的扩散污染物，影响性腺功能和配子成熟，而证明其在下丘脑水平影响的数据非常缺乏。这项研究调查了BaP（10μM）在从人胎儿下丘脑（hfHypo）分离并表现出清晰的GnRH神经元表型的原代细胞培养物中的作用。BaP显著降低GnRH和kisspeptin受体（KISS1R）的基因和蛋白表达，GnRH神经元功能的主调节因子。此外，BaP暴露增加了磷酸化ERK1/2信号，与KISS1R激活相关的众所周知的机制。有趣的是,BaP改变了电生理膜特性，导致明显的去极化作用，并且还显着增加了GnRH释放，两种效果都不受kisspeptin添加的影响。总之,我们的研究结果表明，BaP可能会改变GnRH神经元的表型和功能，主要干扰KISS1R信号和GnRH分泌，因此与生殖的中枢神经内分泌控制有关的关键机制。
