ENVIRONMENTAL POLLUTANTS & TOXICOLOGY OF THE LIVER

研究了2，3，7，8-四氯二苯并-对-二恶英对环境的影响 （TCDD）对男性生殖系统和胃肠道（GI）粘膜的影响。 TCDD会对男性生殖系统产生不利影响， 雄激素缺乏症（由于睾酮合成减少）， 降低血浆LH水平。 睾丸LH降低的程度 反应性导致雄激素缺乏将被确定， 机制负责阐明减少。 垂体应该 通过增加血浆LH水平来应对雄激素缺乏症 但没有成功。 垂体对下丘脑刺激的反应性 GnRH刺激，以及两个器官对类固醇反馈的敏感性 将确定抑制。 LH的质量和配置 还将评估经TCDD处理的大鼠分泌的TCDD。 此外该 男性对TCDC引起的生殖功能障碍的敏感性将 通过将它们作为幼崽而不是成年人暴露于TCDD来确定。 这些 实验应该产生重要的新信息， 四氯二苯并对二恶英对类固醇生成器官以及对垂体和下丘脑功能的影响， 并可能最终导致理解TCDD和相关的 化合物影响雌性和雄性的生殖性能。 TCDD类似物通过免疫抑制剂改变胃肠道粘膜的增殖和分化 未知机制 长期目标是确定 分子水平。 短期目标是观察这些胃肠道反应 转化为TCDD是由胃肠道营养激素胃泌素和/或多胺介导的。 具体目的是描述TCDD对大鼠和猴的营养效应 使用生物化学、药理学和组织学方法， 确定TCDD是否调节胃泌素介导的增殖反应， 胃肠道黏膜，看胃肠道黏膜是否有区域特异性增生 TCDD的作用与胃泌素相同，评估TCDD治疗是否引起 壁细胞损失，评估粘膜多胺生物合成是否 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TCDD是否改变胃底 粘膜胃泌素特异性结合。 这项研究可能表明， 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GI粘膜的过程 我们以前不知道的生长和分化。 最终 这些结果可以提供深入了解的致癌作用， 卤代芳烃对胃肠道粘膜的影响。

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.