Influence of Endocrine Disruptors on Reproductive Neuroendocrine Function

内分泌干​​扰物对生殖神经内分泌功能的影响

• 批准号: 8926439
• 负责人: Joseph Raymond Kurian
• 金额: $ 24.89万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-11 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926439
• 关键词: Acute; Address; Adult; Agonist; American; Biological; Blood; Catheters; Child; Clinical Treatment; Corpus Luteum Maintenance; Delayed Puberty; Dose; Endocrine Disruptors; Environment; Environmental Exposure; Estradiol; Exposure to; Female; Follicle Stimulating Hormone; Food; Functional disorder; Germ Cells; Glutamates; Gonadotropin Hormone Releasing Hormone; Hypothalamic structure; Infertility; Intravenous; Laboratory Animals; Learning; Luteinizing Hormone; Macaca mulatta; Measures; Mediator of activation protein; Metals; Microdialysis; Neurons; Neuropeptides; Neurosecretory Systems; Neurotransmitters; Occupational Exposure; Ovulation; Patients; Pattern; Physiologic pulse; Physiological; Pit and Fissure Sealants; Pituitary Gland; Precocious Puberty; Reproductive Biology; Reproductive Health; Reproductive Physiology; Selective Estrogen Receptor Modulators; Signal Transduction; Source; Sperm Count Procedure; Spontaneous abortion; Steroid Receptors; Testing; Woman; Work; abstracting; bisphenol A; clinical application; drinking; early childhood; exposed human population; gamma-Aminobutyric Acid; in vivo; kisspeptin; men; polycarbonate; prenatal; receptor binding; reproductive; reproductive function; reproductive success; sperm quality; statistics; steroid hormone

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.

抽象的 全世界每年生产 60 亿磅双酚 A (BPA)，并且还在不断增加 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 该化合物的显着水平。我们现在了解到，急性暴露可能会损害成人 生殖健康和成功。作为证据，职业接触 BPA 的男性的健康风险降低 精子数量和接触女性与反复流产有关。我们目前没有 了解 BPA 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以及 BPA 对生殖健康明显的严重影响，当务之急是 我们确定这些机制。该提案的总体目标是调查急性生物学 BPA 暴露对成人生殖神经内分泌功能的影响。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，GnRH 是生殖系统的中心介质 生物学。专门的下丘脑神经元以近乎节拍的脉冲释放 GnRH 来控制垂体 黄体生成素（LH）和卵泡刺激素（FSH）的分泌。典型的发布模式 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 释放的破坏会对生殖生理产生巨大影响。 脉冲式 GnRH 释放受到相互关联的信号传导机制的影响，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 吻肽）。 BPA 的已知生物活性，例如类固醇受体结合和调节 神经递质（谷氨酸）活性，支持 BPA 对生殖产生急性影响的假设 通过改变 GnRH 脉动来发挥作用。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 通过微透析方法，我们建议实现以下目标：1）确定 GnRH 的动态 BPA 暴露期间释放，2) 检查 BPA 暴露改变信号机制的假设 控制 GnRH 释放，3) 检查基线生理差异（即类固醇）的假设 激素谱）影响 BPA 对 GnRH 释放的影响。