ENVIRONMENTAL POLLUTANTS AND TOXICOLOGY OF THE LIVER

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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.