ENVIRONMENTAL POLLUTANTS AND TOXICOLOGY OF THE LIVER

目的是研究2，3，7，8-四氯二苯并对二恶英的药效 (TCDD)对男性生殖系统和胃肠道(GI)粘膜的影响。 TCDD对男性生殖系统产生不利影响，并导致严重的 雄激素缺乏(由于睾酮合成减少) 降低血浆促黄体生成素水平。睾丸促黄体生成素下降的程度 将确定导致雄激素缺乏的反应性，并 造成这种下降的机制尚未阐明。脑下垂体应该 通过提高血浆促黄体生成素水平来应对雄激素缺乏 但未能如愿。脑垂体对下丘脑的反应性 GnRH刺激，以及两个器官对类固醇反馈的敏感性 抑制力将被确定。黄体生成素的质量和配置 TCDD处理的大鼠的分泌物也将被评估。此外， 男性对TCDD引起的生殖功能障碍的敏感性将是 通过将它们作为幼崽而不是成年动物暴露于TCDD来确定。这些 实验应该会产生重要的关于 TCDD对类固醇生成器官、垂体和下丘脑功能的影响， 并最终可能导致理解TCDD和相关的 化合物会影响雌性和雄性的生殖性能。 TCDD类似物改变胃肠道粘膜的增殖和分化 未知的机制。长期的目标是以一种 分子水平。短期目标是看看这些GI反应 TCDD是由胃肠营养激素胃泌素和/或多胺介导的。 具体目的是描述TCDD对大鼠和猴子的营养作用 使用生化、药理学和组织学方法的胃肠道粘膜， 确定TCDD是否调节胃泌素介导的增殖反应 胃肠道粘膜，看看局部胃肠道粘膜是否有增殖性 TCDD疗效与胃泌素相同，评估TCDD治疗是否引起 壁细胞丢失，评估粘膜多胺生物合成是否 被TCDD改变，确定TCDD治疗是否增加胃窦胃泌素 分泌，并评估TCDD是否改变了眼底 粘膜胃泌素特异性结合。这项研究可能表明，TCDD 调节胃窦胃泌素分泌，胃底粘膜胃泌素受体， 粘膜多胺生物合成，或调节胃肠道粘膜的过程 增长和分化，这是我们以前没有意识到的。最终 这些结果可能为深入了解黄曲霉毒素的致癌作用提供依据。 胃肠道粘膜上的卤代芳香烃。

The purpose is to study effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the male reproductive system and gastrointestinal (GI) mucosa. TCDD adversely affects the male reproductive system and causes a major androgenic deficiency (due to decreased testosterone synthesis) without decreasing plasma LH levels. The extent to which decreased testicular LH responsiveness causes the androgenic deficiency will be determined, and the mechanism responsible for the decrease elucidated. The pituitary should have responded to the androgenic deficiency by increasing plasma LH levels but failed to do so. The responsiveness of the pituitary to hypothalmaic GnRH stimulation, and the sensitivity of both organs to steroidal feedback inhibition will be determined. The quality and disposition of the LH secreted by TCDD-treated rats will also be assessed. In addition, the sensitivity of males to TCDD-induced reproductive dysfunction will be determined by exposing them as pups rather than as adults to TCDD. These experiments should yield significant new information concerning effects of TCDD on steroidogenic organs and on pituitary and hypothalamic function, and might ultimately lead to an understanding of how TCDD and related compounds affect the reproductive performance of females as well as males. TCDD analogs alter proliferation and differentiation of the GI mucosa by an unknown mechanism. The long-range goal is to determine the mechanism at a molecular level. The short-range objective is to see if these GI responses to TCDD are mediated by the GI trophic hormone gastrin and/or polyamines. Specific aims are to describe the trophic effect of TCDD on rat and monkey GI mucosa using biochemical, pharmacological, and histological approaches, determine if TCDD modulates a gastrin-mediated proliferative response in the GI mucosa, see if regional GI mucosa specificity of the proliferative effect of TCDD is the same as gastrin, assess whether TCDD treatment causes parietal cell loss, evaluate whether mucosal polyamine biosynthesis is altered by TCDD, determine if TCDD treatment increases antral gastrin secretion, and assess whether TCDD alters whether TCDD alters fundic mucosal gastrin specific binding. This research might show that TCDD modulates antral gastrin secretion, fundic mucosal gastrin receptors, mucosal polyamine biosynthesis, or a process that regulates GI mucosal growth and differentiation of which we were previously unaware. Ultimately these results could provide insight into the carcinogenic action of halogenated aromatic hydrocarbons on the GI mucosa.