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） 每年全世界生产60亿磅的双酚A（BPA），并不断浸入我们的食物，饮料和环境中。因此，有93％的美国人具有这种​​化合物的生物学意义。 我们现在正在了解到，急性暴露可能损害成人生殖健康和成功。 作为证据，有职业接触BPA的男性患有精子数量减少并接触妇女的男性与反复流产有关。 我们目前不了解BPA暴露与生殖生物学之间的生物学联系。但是，鉴于BPA对生殖健康的最新暴露统计数据和明显的急性影响，我们必须确定这些机制。该提案的总体目的是研究BPA暴露对成人生殖神经内分泌功能的急性生物学影响。具体而言，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，这是生殖生物学的中央介体。 专门的下丘脑神经元几乎释放了GNRH，几乎是分析脉冲，以控制垂体黄体激素（LH）和卵泡刺激激素（FSH）分泌。典型的释放模式控制着配子的成熟，排卵，类固醇激素的分泌和黄体功能的维持。 因此，GNRH释放的破坏对生殖生理产生了巨大后果。 脉冲GNRH释放受相互关联的信号机制的影响，其中包括类固醇激素（例如雌二醇），神经递质（例如GABA和GABA和谷氨酸）和神经肽（例如Kisspeptin）。 BPA的已知生物学活性，例如类固醇受体结合和神经递质（谷氨酸）活性的调节，支持BPA通过改变GNRH脉冲性对生殖功能发挥急性影响的假设。 实际上，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的：1）确定BPA暴露期间GNRH释放的动态，2）检查BPA暴露的假说会改变信号传导的假设改变了控制GNRH释放的概况，并检查基础对基础的影响（即生理学差异）（即，均具有对基础的影响）（即，I.E. I.SE）（即）。 GnRH发布。 公共卫生相关性：通过环境暴露，有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干扰了成人生殖健康（例如，患有BPA的职业暴露于BPA的男性患者的精子数量减少，接触妇女的暴露与反复流产有关，而暴露于这种化合物的女性实验室动物在受想的构想方面不太成功）。 但是，我们不确定BPA如何施加这些影响。研究人员的目的是了解BPA对下丘脑释放的促性蛋白释放激素（GNRH）的暴露，这是生殖生物学的中心介体。 由于GnRH激动剂和拮抗剂已成为儿童早熟和延迟青春期的标准临床治疗，而成年人患者的不育症，这项工作可能直接临床应用BPA暴露。