LEAD TOXICITY--BIOCHEMICAL AND NEUROENDOCRINE MECHANISMS

铅毒性--生化和神经内分泌机制

• 批准号: 2155524
• 负责人: Martin J J Ronis
• 金额: $ 14.8万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2155524
• 关键词: animal puberty; gonads; growth /development; growth hormone releasing hormone; hypothalamic pituitary axis; insulinlike growth factor; laboratory rat; lead poisoning; luteinizing hormone; neuroendocrine system; northern blottings; radioimmunoassay; reproductive system disorder; scintillation counter; somatostatin; somatotropin; steroid biosynthesis; steroid hormone metabolism; thin layer chromatography; toxicant interaction; western blottings

In the last few years the toxic effects of lead in children has become a major environmental issue in the U.S. However, while much research has centered on behavioral and neurotoxic effects of lead poisoning, few studies have systematically examined the effects of chronic lead exposure on the endocrine systems of reproduction and growth during development. It has been known for nearly 2000 years that lead exposure disrupts adult reproductive function with reports of sterility and miscarriages dating back to classical times. In clinical studies of lead-exposed male workers, decreases in spermatogenesis and variable effects on circulating levels of pituitary gonadotropins have been reported. The few animal studies in the literature suggest that lead exposure decreases plasma levels of testosterone in male rats into the castrate range with little or no effect on serum luteinizing hormone (LH) concentrations. This suggests multiple sites of lead action; 1) at the level of the gonads involving a direct effect of lead on gonadal steroidogenesis; and 2) at the level of the hypothalamus and or pituitary involving changes in responsiveness to steroid feedback. This latter site is hypothesized because castration results in elevation of serum LH in untreated rats due to reduced feedback of testosterone. Our preliminary data support such a dual site of lead action. The current application proposes to examine in detail the molecular mechanisms underlying the lead-induced impairment of the endocrine systems of reproduction and growth in a developmental animal model. This proposal focuses on disruption of hypothalamic-pituitary function (especially secretion of LH and GH), gonadal steroid biosynthesis and peripheral steroid metabolism. Specifically, the endocrine effects of lead exposure initiated in utero will be examined on developing male and female rats. Challenge and replacement experiments will be conducted in vivo to define hypothalamic-pituitary and gonadal sites of lead action and the molecular mechanisms underlying lead-induced alterations in gonadal and peripheral sex steroid metabolism, reproductive physiology and the male pubertal growth spurt.

在过去的几年里，铅对儿童的毒性作用已经变得越来越严重。 美国的一个主要环境问题 然而，尽管大量研究 主要研究铅中毒的行为和神经毒性影响， 很少有研究系统地研究慢性铅的影响 生殖和生长期间内分泌系统的暴露 发展。 近 2000 年来，人们都知道 据报道，接触会破坏成人的生殖功能 不孕和流产可以追溯到古典时代。 在 对接触铅的男性工人进行的临床研究显示， 精子发生及其对循环水平的不同影响 垂体促性腺激素已有报道。 为数不多的动物研究 文献表明，铅暴露会降低血浆中 雄性大鼠的睾酮水平进入去势范围后几乎没有或没有 对血清黄体生成素（LH）浓度的影响。 这 建议多个先导作用位点； 1）在性腺水平 涉及铅对性腺类固醇生成的直接影响；和 2) 在下丘脑和/或垂体水平涉及变化 对类固醇反馈的反应。 后一个地点是假设的 因为去势会导致未经治疗的大鼠血清 LH 升高 由于睾丸激素的反馈减少。 我们的初步数据支持 这种先导作用的双位点。 目前的申请建议 详细研究铅诱导的分子机制 生殖和生长的内分泌系统受损 发育动物模型。 该提案的重点是破坏 下丘脑-垂体功能（尤其是 LH 和 GH 的分泌）， 性腺类固醇生物合成和外周类固醇代谢。 具体来说，铅暴露对内分泌的影响始于 将检查发育中的雄性和雌性大鼠的子宫。 挑战 并且将在体内进行替代实验来定义 下丘脑-垂体和性腺的铅作用部位和 铅诱导性腺改变的分子机制 和外周性类固醇代谢、生殖生理学和 男性青春期生长突增。