Influence of Endocrine Disruptors on Reproductive Neuroendocrine Function

摘要 全世界每年生产60亿磅双酚A（BPA）， 渗入我们的食物、饮料和环境中。因此，93%的美国人在生物学上携带 这种化合物的含量很高我们现在了解到，急性暴露可能会危及成人 生殖健康和成功。有证据表明，职业性接触BPA的男性， 精子数量和接触女性与反复流产有关。我们目前不 了解BPA暴露与生殖生物学之间的生物学联系。但鉴于 根据最新的接触统计数据和BPA对生殖健康的明显急性影响， 我们决定这些机制。本提案的总体目标是研究急性生物学 BPA暴露对成年人生殖神经内分泌功能影响具体来说，我们的目标是研究如何 BPA影响促性腺激素释放激素（GnRH）的释放， 生物学专门的下丘脑神经元以接近节拍的脉冲释放GnRH以控制垂体 促黄体生成激素（LH）和促卵泡激素（FSH）分泌。典型的释放模式 控制配子成熟、排卵、类固醇激素分泌和维持黄体功能。 因此，GnRH释放的中断对生殖生理有巨大的影响。 GnRH的脉冲释放受相互关联的信号传导机制的影响，包括类固醇激素 激素（例如雌二醇）、神经递质（例如GABA和谷氨酸）和神经肽（例如谷氨酸）。 kisspeptin）。BPA的已知生物活性，如类固醇受体结合和调节 神经递质（谷氨酸）活性，支持BPA对生殖系统产生急性影响的假设。 通过改变GnRH脉动性来发挥作用。事实上，我们的初步工作表明，BPA直接影响 GnRH释放和神经元活动。然而，为了更好地支持这一假设，使用体内 微透析的方法，我们建议解决以下目标：1）确定GnRH的动态 2）检验BPA暴露改变信号机制的假设 3）检查基线生理差异（即类固醇） 激素分布）影响BPA对GnRH释放的影响。

Abstract Six billion pounds of bisphenol A (BPA) is produced throughout the world each year and is continually leaching into our food, drinks and environment. Consequently, 93% of Americans carry biologically significant levels of this compound. We are now learning that acute exposures likely compromise adult reproductive health and success. As evidence, men with occupational exposure to BPA suffer with reduced sperm counts and exposure to women is associated with repeated miscarriage. We do not currently understand the biological connections between BPA exposure and reproductive biology. However, given the latest exposure statistics and apparent acute impact of BPA on reproductive health, it is imperative that we determine these mechanisms. The overall objective of this proposal is to investigate the acute biological impact of BPA exposure on adult reproductive neuroendocrine function. Specifically, we aim to study how BPA influences the release of gonadotropin releasing hormone (GnRH), a central mediator of reproductive biology. Specialized hypothalamic neurons release GnRH in nearly metronomic pulses to control pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretions. Typical release patterns govern gamete maturation, ovulation, steroid hormone secretion and maintenance of luteal function. Consequently, disruption of GnRH release has tremendous consequences on reproductive physiology. Pulsatile GnRH release is influenced by inter-related signaling mechanisms, which include steroid hormones (e.g. estradiol), neurotransmitters (e.g. GABA and glutamate) and neuropeptides (e.g. kisspeptin). The known biological activities of BPA, such as steroid receptor binding and modulation of neurotransmitter (glutamate) activity, support the hypothesis that BPA exerts acute effects on reproductive function by altering GnRH pulsatility. In fact, our preliminary work indicates that BPA directly influences GnRH release and neuronal activity. However, to better support this hypothesis, using an in vivo microdialysis approach, we propose to address the following aims: 1) determine the dynamics of GnRH release during BPA exposure, 2) examine the hypothesis that BPA exposure alters signaling mechanisms that control GnRH release and 3) examine the hypothesis that baseline physiologic differences (i.e. steroid hormone profile) influence the effects of BPA on GnRH release.