Influence of Endocrine Disruptors on Reproductive Neuroendocrine Function

摘要 全世界每年生产60亿磅的双酚A(BPA)，并持续不断地 渗入到我们的食物、饮料和环境中。因此，93%的美国人携带生物性携带者 这种化合物的含量很高。我们现在了解到，严重的接触可能会危及成年人 生殖健康和成功。作为证据，职业性接触双酚A的男性患病率降低。 精子数量和接触女性与反复流产有关。我们目前没有 了解双酚A暴露与生殖生物学之间的生物学联系。然而，鉴于 根据最新的暴露统计数据和双酚A对生殖健康的明显严重影响，当务之急是 我们确定了这些机制。这项建议的总体目标是调查急性生物学 双酚A暴露对成人生殖神经内分泌功能的影响具体地说，我们的目标是研究 BPA影响生殖中枢介质促性腺激素释放激素(GnRH)的释放 生物学。下丘脑神经元以近乎节律性的脉冲释放促性腺激素释放激素控制垂体 黄体生成素和卵泡刺激素的分泌。典型的发布模式 管理配子成熟、排卵、类固醇激素分泌和黄体功能的维持。 因此，GnRH释放的中断会对生殖生理产生巨大的影响。 促性腺激素释放激素受到相互关联的信号机制的影响，其中包括类固醇 激素(如雌二醇)、神经递质(如GABA和谷氨酸)和神经肽(如： Kispeptin)。双酚A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，支持双酚A对生殖有显著影响的假说 通过改变GnRH的搏动性来发挥作用。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，使用体内的 微透析方法，我们建议解决以下目标：1)测定促性腺激素释放激素的动力学 在双酚A暴露期间释放，2)检验双酚A暴露改变信号机制的假设 控制GnRH释放和3)检验基线生理差异(即类固醇)的假设 激素谱)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.