Influence of Endocrine Disruptors on Reproductive Neuroendocrine Function

描述(由申请人提供) 全世界每年产生60亿磅的双酚A(BPA)，并不断地渗入到我们的食物、饮料和环境中。因此，93%的美国人携带有生物学意义的这种化合物。我们现在了解到，急性暴露可能会损害成年人的生殖健康和成功。作为证据，职业性接触双酚A的男性精子数量减少，与女性接触与反复流产有关。我们目前还不了解双酚A暴露和生殖生物学之间的生物学联系。然而，鉴于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，我们必须确定这些机制。这项建议的总体目标是调查双酚A暴露对成人生殖神经内分泌功能的急性生物学影响。具体地说，研究人员的目标是研究BPA如何影响促性腺激素释放激素(GnRH)的释放，GnRH是生殖生物学的中心媒介。专门的下丘脑神经元以几乎有节律的脉冲释放GnRH，以控制垂体黄体生成素(LH)和卵泡刺激素(FSH)的分泌。典型的释放模式支配配子成熟、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的脉动性释放受到相互关联的信号机制的影响，这些机制包括类固醇激素(如雌二醇)、神经递质(如GABA和谷氨酸)和神经肽(如Kispeptin)。已知的BPA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通过改变GnRH的搏动性而对生殖功能产生严重影响的假说。事实上，研究人员的初步工作表明，BPA直接影响GnRH的释放和神经元的活动。然而，为了更好地支持这一假设，他们建议使用体内微透析方法来解决以下目标：1)确定BPA暴露期间GnRH释放的动力学，2)检验BPA暴露改变控制GnRH释放的信号机制的假说，以及3)检验基线生理差异(即类固醇激素谱)影响BPA对GnRH释放的影响的假说。 公共卫生相关性：通过环境暴露，93%的美国人携带可检测到的双酚A(BPA)水平。最近的证据表明，双酚A干扰成人生殖健康(例如，职业接触双酚A的男性精子数量减少，接触女性与反复流产有关，接触这种化合物的雌性实验室动物受孕成功率较低)。然而，我们并不确定双酚A是如何发挥这些作用的。研究人员的目标是了解BPA暴露在下丘脑是如何影响促性腺激素释放激素(GnRH)的释放的，GnRH是生殖生物学的中心媒介。由于GnRH激动剂和拮抗剂已成为儿童性早熟和青春期延迟以及成人患者不孕症的标准临床治疗方法，这项工作可能对双酚A暴露的管理具有直接的临床应用价值。

DESCRIPTION (provided by applicant) 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, the investigators 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, the investigators' preliminary work indicates that BPA directly influences GnRH release and neuronal activity. However, to better support this hypothesis, using an in vivo microdialysis approach, they 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. Public Health Relevance: Through environmental exposures, 93% of Americans carry detectable levels of Bisphenol A (BPA). Recent evidence shows BPA interferes with adult reproductive health (e.g. men with occupational exposure to BPA suffer with reduced sperm counts, exposure to women is associated with repeated miscarriage, and female laboratory animals exposed to this compound are less successful in conceiving). However, we do not know with certainty how BPA exerts these effects. The investigators aim to understand how exposures of BPA to the hypothalamus influence release of gonadotropin releasing hormone (GnRH), a central mediator of reproductive biology. As GnRH agonists and antagonists have become standard clinical treatments for precocious and delayed puberty in children, and infertility in adult human patients, this work may have direct clinical application for management of BPA exposure.