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: 8226251
• 负责人: Joseph Raymond Kurian
• 金额: $ 7.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8226251
• 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; Research Personnel; Selective Estrogen Receptor Modulators; Signal Transduction; Source; Sperm Count Procedure; Spontaneous abortion; Steroid Receptors; Testing; Woman; Work; bisphenol A; clinical application; drinking; early childhood; exposed human population; gamma-Aminobutyric Acid; in vivo; kisspeptin; men; polycarbonate; prenatal; public health relevance; receptor binding; reproductive; reproductive function; reproductive success; sperm quality; statistics; steroid hormone

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.

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、饮料和环境中。因此，93% 的美国人体内含有具有生物学意义的化合物。 我们现在了解到，急性暴露可能会损害成人的生殖健康和成功。 有证据表明，因职业接触 BPA 的男性精子数量减少，而女性接触 BPA 则与反复流产有关。 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以及 BPA 对生殖健康明显的严重影响，我们必须确定这些机制。该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，研究人员旨在研究 BPA 如何影响促性腺激素释放激素 (GnRH) 的释放，GnRH 是生殖生物学的核心介质。 专门的下丘脑神经元以近乎节拍的脉冲释放 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 释放的破坏对生殖生理学产生巨大影响。 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（例如雌二醇）、神经递质（例如 GABA 和谷氨酸）和神经肽（例如 Kisspeptin）。 BPA 的已知生物活性，例如类固醇受体结合和神经递质（谷氨酸）活性的调节，支持这样的假设：BPA 通过改变 GnRH 脉动对生殖功能产生急性影响。 事实上，研究人员的初步工作表明，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，使用体内微透析方法，他们建议解决以下目标：1）确定 BPA 暴露期间 GnRH 释放的动态，2）检查 BPA 暴露改变控制 GnRH 释放的信号机制的假设，3）检查基线生理差异（即类固醇激素谱）影响 BPA 对 GnRH 的影响的假设 GnRH 释放。 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)。 最近的证据表明，BPA 会干扰成人生殖健康（例如，因职业接触 BPA 的男性精子数量减少，女性接触 BPA 与反复流产有关，接触这种化合物的雌性实验动物受孕不太成功）。 然而，我们并不确定 BPA 是如何发挥这些作用的。研究人员旨在了解下丘脑接触 BPA 如何影响促性腺激素释放激素 (GnRH) 的释放，GnRH 是生殖生物学的核心介质。 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，这项工作可能对 BPA 暴露管理有直接的临床应用。