LEAD TOXICITY--BIOCHEMICAL AND NEUROENDOCRINE MECHANISMS

在过去的几年里，铅对儿童的毒性作用已经成为 这是美国的一个主要环境问题。 主要关注铅中毒的行为和神经毒性效应， 很少有研究系统地研究慢性铅中毒的影响 生殖和生长的内分泌系统 发展 近2000年来人们都知道 暴露会破坏成年人的生殖功能， 不孕不育和流产可以追溯到古典时代。 在 对接触铅的男性工人的临床研究， 精子发生和对循环水平的可变影响 已经报道了垂体促性腺激素。 少数的动物研究， 文献表明，铅暴露会降低血浆中 雄性大鼠的睾酮进入去势范围， 对血清促黄体激素（LH）浓度的影响。 这 提示铅作用的多个部位; 1）在性腺水平 涉及铅对性腺类固醇生成的直接影响;以及2） 在下丘脑和/或垂体水平， 对类固醇反馈的反应 这后一个网站是假设 因为去势导致未处理大鼠血清LH升高 因为睾丸激素反馈减少 我们的初步数据支持 这样一个双位点的铅作用。 本申请提出， 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分泌）， 性腺类固醇生物合成和外周类固醇代谢。 具体而言，铅暴露的内分泌影响始于2005年， 对发育中的雄性和雌性大鼠进行子宫检查。 挑战 将在体内进行置换实验， 铅作用的下丘脑-垂体和性腺部位， 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

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.