Influence of Endocrine Disruptors on Reproductive Neuroendocrine Function

描述（由申请人提供） 全世界每年生产60亿磅双酚A（BPA），并不断渗入我们的食品、饮料和环境。因此，93%的美国人携带这种化合物的生物学显著水平。 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，职业暴露于BPA的男性精子数量减少，女性暴露与反复流产有关。 我们目前还不了解BPA暴露与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BPA对生殖健康的明显急性影响，我们必须确定这些机制。本提案的总体目标是调查BPA暴露对成人生殖神经内分泌功能的急性生物学影响。具体来说，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，这是生殖生物学的中心介质。 专门的下丘脑神经元以接近节拍的脉冲释放GnRH，以控制垂体促黄体激素（LH）和促卵泡激素（FSH）的分泌。典型的释放模式控制配子成熟、排卵、类固醇激素分泌和黄体功能的维持。 因此，GnRH释放的中断对生殖生理有巨大的影响。 脉冲式GnRH释放受相互关联的信号传导机制影响，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kisspeptin）。BPA的已知生物活性，如类固醇受体结合和神经递质（谷氨酸）活性的调节，支持BPA通过改变GnRH脉动对生殖功能产生急性影响的假设。 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，使用体内微透析方法，他们提出了以下目标：1）确定BPA暴露期间GnRH释放的动力学，2）检查BPA暴露改变控制GnRH释放的信号传导机制的假设，3）检查基线生理差异（即类固醇激素特征）影响BPA对GnRH释放的影响的假设。 公共卫生相关性：通过环境暴露，93%的美国人携带可检测水平的双酚A（BPA）。 最近的证据表明，BPA会干扰成年人的生殖健康（例如，职业暴露于BPA的男性精子数量减少，女性暴露于BPA与反复流产有关，暴露于这种化合物的雌性实验动物受孕成功率较低）。 然而，我们并不确定BPA如何发挥这些作用。研究人员旨在了解BPA暴露于下丘脑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介质。 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，因此这项工作可能直接应用于BPA暴露的管理。

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.